Pharmacology with Dr. Geoffrey A

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#The Autonomic Nervous System

• Parasympathetic nervous system • Sympathetic nervous system #Visceral reflex arcs

#The Adrenal Medulla

#Splanchnic Nerves




#The Nigro-Striatal Pathway #Neuroleptic Malignant Syndrome

The Autonomic Nervous System


The Autonomic Nervous System

The Autonomic Nervous System

Visceral sensory


Visceral motor

1 26 Sep 2019


Autonomic nervous system

• The autonomic nervous system is the subdivision of the peripheral nervous system that regulates body activities that are generally not under conscious control

• Visceral motor innervates non-skeletal (non- somatic) muscles

• Visceral sensory will be covered later


To repeat…

• ANSisthesubdivisionoftheperipheralnervous system that regulates body activities that are generally not under conscious control

• Visceralmotorinnervatesnon-skeletal(non-somatic) muscles

• Composedofaspecialgroupofneuronsserving: – Cardiac muscle (the heart)

– Smooth muscle (walls of viscera and blood vessels)

– Internal organs

– Skin


Basic anatomical difference between the motor pathways of the voluntary somatic nervous system (to skeletal muscles) and those of the autonomic nervous system

• Somaticdivision:

– Cell bodies of motor neurons reside in CNS (brain or spinal


– Their axons (sheathed in spinal nerves) extend all the way

to their skeletal muscles

• Autonomicsystem:chainsoftwomotorneurons

– 1st = preganglionic neuron (in brain or cord)

– 2nd = gangionic neuron (cell body in ganglion outside CNS) – Slower because lightly or unmyelinated

(see next diagram)


• Axon of 1st (preganglionic) neuron leaves CNS to synapse with the 2nd (ganglionic) neuron

• Axon of 2nd (ganglionic) neuron extends to the organ it serves

Diagram contrasts somatic (lower) and autonomic:

this dorsal root ganglion is sensory

Note: the autonomic ganglion is motor




Divisions of the autonomic nervous system (visceral

motor part of it)

• Parasympathetic division • Sympathetic division


Divisions of the autonomic nervous system • Parasympathetic division

• Sympathetic division

Serve most of the same organs but cause

opposing or antagonistic effects

Parasysmpathetic: routine maintenance “rest &digest”

Sympathetic: mobilization & increased metabolism

“fight, flight or fright” or “fight, flight or freeze”


2 26 Sep 2019


Parasympathetic: craniosacral

Sympathetic: thoracolumbar


Where they come from

Parasympathetic nervous system

“rest & digest”

• Also called the craniosacral system because all its preganglionic neurons are in the brain stem or sacral levels of the spinal cord

– Cranial nerves III,VII, IX and X

– In lateral horn of gray matter from S2-S4

• Only innervate internal organs (not skin)

• Acetylcholine is neurotransmitter at end organ as well as at preganglionic synapse: “cholinergic”


Parasympathetic continued

• Cranialoutflow

– III – pupils constrict

– VII – tears, nasal mucus, saliva

– IX – parotid salivary gland

– X (Vagus n) – visceral organs of thorax & abdomen:

• Stimulates digestive glands

• Increases motility of smooth muscle of digestive tract • Decreases heart rate

• Causes bronchial constriction

• Sacraloutflow(S2-4):formpelvicsplanchnicnerves – Supply 2nd half of large intestine

– Supply all the pelvic (genitourinary) organs



(only look at this if it helps you)


Sympathetic nervous system

“fight, flight or fright”

• Alsocalledthoracolumbarsystem:allitsneuronsarein lateral horn of gray matter from T1-L2

• Lead to every part of the body (unlike parasymp.)

– Easy to remember that when nervous, you sweat; when afraid,

hair stands on end; when excited blood pressure rises

(vasoconstriction): these sympathetic only

– Also causes: dry mouth, pupils to dilate, increased heart &

respiratory rates to increase O2 to skeletal muscles, and liver to release glucose

• Norepinephrine(akanoradrenaline)isneurotransmitter released by most postganglionic fibers (acetylcholine in preganglionic): “adrenergic”


Sympathetic nervous system continued

• Regardlessoftarget,allbegin same

• Preganglionicaxonsexit spinal cord through ventral root and enter spinal nerve

• Exitspinalnervevia communicating ramus

• Entersympathetic trunk/chain where postganglionic neurons are

• Hasthreeoptions…


3 26 Sep 2019


Options of preganglionic axons in sympathetic trunk

(see next slides for drawing examples)

1. Synapse on postganglionic neuron in chain ganglion then return to spinal nerve and follow its branch to the skin

2. Ascend or descend within sympathetic trunk, synapse with a posganglionic neuron within a chain ganglion, and return to spinal nerve at that level and follow branches to skin

3. Enter sympathetic chain, pass through without synapsing, form a splanchnic nerve that passes toward thoracic or abdominal organs

– These synapse in prevertebral ganglion in front of aorta

– Postganglionic axons follow arteries to organs


Synapse in chain ganglia

at same level or different level


Pass through ganglia and synapse in prevertebral ganglion




Adrenal gland is exception

On top of kidneys

Adrenal medulla (inside part) is a major organ of the sympathetic nervous system


Adrenal gland is exception

• Synapse in gland

• Can cause body-wide release of epinephrine aka adrenaline and norepinephrine in an extreme emergency

(adrenaline “rush” or surge)


4 26 Sep 2019




Visceral sensory system

Gives sensory input to autonomic nervous system


Visceral sensory neurons

• Monitor temperature, pain, irritation, chemical changes and stretch in the visceral organs

– Brain interprets as hunger, fullness, pain, nausea, well-being

• Receptors widely scattered – localization poor (e.g. which part

is giving you the gas pain?)

• Visceral sensory fibers run within autonomic nerves,

especially vagus and sympathetic nerves

– Sympathetic nerves carry most pain fibers from visceral organs of body


• Simplified pathway: sensory neurons to spinothalamic tract to

thalamus to cerebral cortex

• Visceral pain is induced by stretching, infection and cramping

of internal organs but seldom by cutting (e.g. cutting off a colon polyp) or scraping them


Referred pain: important to know

Plus left shoulder,

Pain in visceral organs is often perceived to be somatic in origin: referred to somatic regions of body that receive innervation from the same spinal cord segments

from spleen

Anterior skin areas to which pain is referred from certain visceral organs 28

Visceral sensory and autonomic neurons participate in visceral reflex arcs

• Many are spinal reflexes such as defecation and micturition


• Someonly involve peripheral neurons: spinal cord not involved (not shown)*

*e.g. “enteric” nervous system: 3 neuron reflex arcs entirely within the wall of the gut


Central control of the Autonomic NS

Amygdala: main limbic region for emotions

-Stimulates sympathetic activity, especially previously learned fear- related behavior

-Can be voluntary when decide to recall frightful experience – cerebral cortex acts through amygdala

-Some people can regulate some autonomic activities by gaining extraordinary control over their emotions

Hypothalamus: main integration center

Reticular formation: most direct influence over autonomic function


5 26 Sep 2019


Autonomic Nervous System

• A. Comparison of somatic and autonomic nervous systems

• B. Anatomy of autonomic motor pathways 1. Overview

a. Preganglionicneurons b. Autonomic ganglia

c. Postganglionicneurons

• C. Physiological effects of the ANS

1. ANS neurotransmitters

2. Parasympatheticandsympathetic


The ANS regulates the activities of cardiac muscle, smooth muscle, and glands.

• Structurally,theANSconsistsoftwomain components:

1. visceral afferent neurons 2. visceral efferent neurons

• Functionally,theANSoperates:

1. without conscious control

2. reflex arc dependent

3. medulla and hypothalamus override

Comparison of Somatic and Autonomic Nervous Systems


cutaneous receptors proprioceptors special senses

may become conscious

excitatory for skeletal muscles

single motor neuron



baroreceptors mechanoreceptors


excitatory or inhibitory for cardiac muscle, smooth

muscles, and glands two motor neurons

Comparison of Somatic and Autonomic Efferent Pathways

Sympathetic Versus Parasympathetic Divisions

Overview of Autonomic Pathways

• Preganglionic neuron

• 1. first of the two autonomic motor neurons

• 2. cell body located in gray matter of spinal cord or brain

• 3. preganglionic axon passes from the CNS in a spinal or cranial nerve

• 4. axon terminates in a ganglion

6 26 Sep 2019


Overview of Autonomic Pathways

• Ganglion

• 1. collection of nerve cell bodies located in a

specific site outside the CNS

• 2. cell bodies give rise to postganglionic neurons

Overview of Autonomic Pathways

• Postganglionic neuron

• 1. second of the two autonomic motor neurons

• 2. cell body located in ganglion

• 3. postganglionic axon passes from the ganglion to the effector

• 4. peripheral effector is either stimulated or inhibited

Sympathetic Nervous System

• 1. lateral gray horns (T1-L2)

• 2. thoracolumbar outflow

• 3. ganglia

a. sympathetic trunk (paravertebral)

b. Prevertebral (collateral)

• 4. preganglionic axons short

• 5. postganglionic axons long

Parasympathetic Nervous System

• 1. lateral gray horns (S2-4)

• 2. cranial gray matter


• 3. craniosacral outflow

• 4. terminal ganglia

• 5. preganglionic axons long

• 6. postganglionic axons short

Physiological Effects of ANS

• 1. dual (duel?) innervation

• 2. different neurotransmitters • 3. parasympathetic tone

7 26 Sep 2019


ANS Neurotransmitters



all preganglionic neurons

all postganglionic parasympathetic neurons sympathetic neurons few postganglionic sympathetic neurons

acetylcholinesterase catechol-O-methyl transferase monoamine oxidase



most postganglionic

Neurotransmitters and Receptors of the Autonomic Nervous System

Sympathetic System

• 1. energy expenditure system

• 2. fight-or-flight response

• 3. dominates parasympathetic NS • 4. effects

Parasympathetic System

• 1. energy conservation-restoration system • 2. rest-and-recovery

• 3. dominates sympathetic NS

• 4. SLUD

The ANS and Visceral Sensory Neurons


8 26 Sep 2019


Sympathetic Nervous System


Anatomy of Autonomic Motor Pathways

• Preganglionic neuron • Postganglionic neuron

• Two divisions:

• Sympathetic

• Parasympathetic


Structure of the Sympathetic Division


Sympathetic Trunk Ganglia

• Located on both sides of the vertebral column

• Linked by short nerves into sympathetic trunks

• Joined to ventral rami by white and gray rami communicantes

• Fusion of gangliafewer ganglia than spinal nerves

Copyright © 2005 Pearson Education, Inc., publishing as Benjamin Cummings

Copyright © 2005 Pearson Education, Inc., publishing as Benjamin Cummings

Sympathetic Trunk Ganglia

Prevertebral Ganglia

• Unpaired, not segmentally arranged • Occur only in abdomen and pelvis

• Lie anterior to the vertebral column • Main ganglia

– Celiac, superior mesenteric, inferior mesenteric, inferior hypogastric ganglia

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9 26 Sep 2019


Sympathetic Division

• A single sympathetic preganglionic fiber has many axon collaterals and may synapse with 20 or more postganglionic neurons.

• The postganglionic axons typically terminate in several visceral effectors and therefore the effects of sympathetic stimulation are more widespread than the effects of parasympathetic stimulation.


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Sympathetic Division of the ANS

Sympathetic Pathways to Periphery

Copyright © 2005 Pearson

Education, Inc., publishing Figure 15.9 as Benjamin Cummings

Copyright © 2005 Pearson Education, Inc., publishing as Benjamin Cummings

Sympathetic Pathways to the Head

Sympathetic Division

• Thoracolumbar division- Preganglionic neurons originate from the thoracic and lumbar levels of the spinal cord (T1-L2).

• Sympathetic ganglia:

Sympathetic trunk (vertebral chain) ganglia.

Prevertebral (collateral) ganglia: celiac, superior mesenteric, inferior mesenteric, aorticorenal and renal.


Sympathetic Pathways to Thoracic Organs

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10 26 Sep 2019


Sympathetic Pathways to the Abdominal Organs

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Sympathetic Pathways to the Pelvic Organs

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The Role of the Adrenal Medulla in the Sympathetic Division

• Major organ of the sympathetic nervous system

• Secretes great quantities epinephrine (a little norepinephrine)

• Stimulated to secrete by preganglionic sympathetic fibers

Copyright © 2005 Pearson Education, Inc., publishing as Benjamin Cummings

Copyright © 2005 Pearson Education, Inc., publishing as Benjamin Cummings

The Adrenal Medulla

Postganglionic Neurons in the

Sympathetic Division

• An axon may synapse with postganglionic neurons in the ganglion it first reaches or

• Sympathetic chains or

• An axon may continue, without synapsing, through

the sympathetic trunk ganglion to end at a prevertebral ganglion and synapse with postganglionic neurons there or

• An axon may pass through the sympathetic trunk ganglion and a prevertebral ganglion and then to the adrenal medulla.


Postganglionic neurons in the Sympathetic Division


11 26 Sep 2019


Parasympathetic Nervous System


Structure of the Parasympathetic Division


The Parasympathetic Division

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Cranial Outflow

• Preganglionic fibers run via: – Oculomotor nerve (III)

– Facial nerve (VII)

– Glossopharyngeal nerve (IX) – Vagus nerve (X)

• Cell bodies located in cranial nerve nuclei in the brain stem

Copyright © 2005 Pearson Education, Inc., publishing as Benjamin Cummings

Outflow via the Vagus Nerve (X)

• Fibersinnervatevisceral organs of the thorax and most of the abdomen

• Stimulates-digestion, reduction in heart rate and blood pressure

• Preganglioniccellbodies – Located in dorsal motor

nucleus in the medulla

• Ganglionicneurons

– Confined within the walls of organs being innervated

Copyright © 2005 Pearson Education, Inc., publishing as Benjamin Cummings

Parasympathetic Nervous System: Sacral Outflow

• Emerges from S2-S4

• Innervates organs of the pelvis and lower


• Preganglionic cell bodies

– Located in visceral motor region of spinal gray matter

• Form splanchnic nerves

Copyright © 2005 Pearson Education, Inc., publishing as Benjamin Cummings

12 26 Sep 2019


Parasympathetic Division

• Craniosacral division: Preganglionic neurons originate from the cranial nerves III, VII, IX and X and sacral spinal nerves S2-S4.

• Parasympathetic ganglia: terminal ganglia.

• Presynaptic neuron usually synapses with 4-5 postsynaptic neurons all of which supply a single visceral effector.


Putting the Two Together

To Compare and Functional Cooperation – Reciprocity


Comparison of Somatic and Autonomic Nervous Systems

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Anatomical Differences in Sympathetic and Parasympathetic Divisions (Recall)

• Issuefromdifferent regions of the CNS

– Sympathetic – also called the thoracolumbar division

– Parasympathetic – also called the craniosacral division

Copyright © 2005 Pearson Education, Inc., publishing as Benjamin Cummings

Anatomical Differences in Sympathetic and Parasympathetic Divisions

• Length of postganglionic fibers

– Sympathetic – long postganglionic fibers

– Parasympathetic – short postganglionic fibers

• Branching of axons

– Sympathetic axons – highly branched

• Influences many organs

– Parasympathetic axons – few branches

• Localized effect

Copyright © 2005 Pearson Education, Inc., publishing as Benjamin Cummings

Anatomical Differences in Sympathetic and Parasympathetic Divisions

Copyright © 2005 Pearson Education, Inc., publishing as Benjamin Cummings

13 26 Sep 2019


Anatomical Differences in Sympathetic and Parasympathetic Divisions

Copyright © 2005 Pearson Education, Inc., publishing as Benjamin Cummings

Neurotransmitters of Autonomic Nervous System

• Neurotransmitter released by preganglionic axons

– Acetylcholine for both branches (cholinergic)

• Neurotransmitter released by postganglionic


– Sympathetic – most release norepinephrine (adrenergic)

– Parasympathetic – release acetylcholine

Copyright © 2005 Pearson Education, Inc., publishing as Benjamin Cummings

Cholinergic and Adrenergic Neurons in the Autonomic Nervous System


Cholinergic Neurons

Cholinergic neurons → acetylcholine (ACh).

Cholinergic neurons include-

1. All sympathetic and parasympathetic preganglionic neurons.

2. Sympathetic postganglionic neurons that innervate most sweat glands.

3. All parasympathetic postganglionic neurons.


Cholinergic Receptors Cholinergic receptors release acetylcholine.

• Two types: Nicotinic receptors Muscarinic receptors


Adrenergic Neurons and Receptors • Release norepinephrine (noradrenaline).

• Most sympathetic postganglionic neurons are adrenergic.

• Two types of receptors: Alpha receptors-

Beta receptors-


14 26 Sep 2019


Comparison of Somatic and Autonomic Nervous Systems


Comparison of Somatic and Autonomic Nervous Systems


Autonomic Plexuses in the Thorax, Abdomen and Pelvis


Autonomic Plexuses

• A network of sympathetic and parasympathetic axons.

• Cardiac plexus- heart.

• Pulmonary plexus- the bronchial tree.

• Celiac plexus- largest. Supplies the stomach, spleen, pancreas, liver, gallbladder, and adrenal medullae.


Autonomic Plexuses (Cont’d)..

• Superior mesenteric plexus- small intestine and proximal colon.

• Inferior mesenteric plexus- distal colon and rectum.

• Hypogastric plexus- urinary bladder and genital organs.

• Renal plexus- kidneys and ureters.


Pathway from Spinal Cord to Sympathetic Trunk Ganglia:

• Preganglionic axons → anterior root of a spinal nerve → white ramus → sympathetic trunk ganglion.

• White rami communicantes: structures containing sympathetic preganglionic axons that connect the anterior ramus of the spinal nerve with the ganglia of the sympathetic trunk.


15 26 Sep 2019


Organization of Sympathetic Trunk


• Sympathetic trunk ganglia: 3 cervical, 11 or 12 thoracic, 4 or 5 lumbar, 4 or 5 sacral and 1 coccygeal.

• Postganglionic neurons from the

superior cervical region-head and heart.

middle cervical ganglion and the inferior cervical ganglion-heart.

• Thoracic sympathetic trunk- heart, lungs, and bronchi.


Pathways from Sympathetic Trunk Ganglia to Visceral Effectors

• Axons leave the sympathetic trunk in 4 possible ways:

– spinal nerves

– cephalic periarterial nerves – sympathetic nerves

– splanchnic nerves


Spinal nerves

• Gray ramus: Axons of some postganglionic neurons leave the sympathetic trunk by entering a short pathway called a gray ramus and merge with the anterior ramus of a spinal nerve.

• Gray rami communicantes: structures containing sympathetic postganglionic axons that connect the ganglia of the sympathetic trunk to spinal nerves.


Cephalic Periarterial Nerves

• Some sympathetic preganglionic neurons that enter the sympathetic trunk ascend to the superior cervical ganglion where they synapse with postganglionic neurons. Some of these leave the sympathetic trunk by forming cephalic periarterial nerves.

• Serve visceral effectors in the skin of the face and head.


Sympathetic Nerves

• Some axons of the postganglionic neurons leave the trunk by forming sympathetic nerves.

• Innervate the heart and lungs.


Splanchnic Nerves continued..

• Some sympathetic preganglionic axons pass through the sympathetic trunk without terminating in it. Beyond the trunk they form nerves called splanchnic nerves which extend to prevertebral ganglia.

• T5-T9 or T10- Greater splanchnic nerve.

• T10-T11- Lesser splanchnic nerve.

• L1-L4- Lumbar splanchnic nerve.


16 26 Sep 2019


Splanchnic Nerves to the Adrenal Medulla

• Some sympathetic preganglionic axons pass, without synapsing, through the sympathetic trunk, greater splanchnic nerves and celiac ganglion into the adrenal medulla (modified sympathetic ganglia).

• Release hormones into blood- 80% epinephrine, 20% norepinephrine.


Cranial Parasympathetic Outflow

The cranial outflow has four pairs of ganglia and are associated with the vagus nerve.

1. Ciliary ganglia-

2. Pterygopalatine ganglia-

3. Submandibular ganglia-

4. Otic ganglia-

 Vagus nerve carries nearly 80% of the total craniosacral flow.


Sacral Parasympathetic Outflow

• ConsistsofS2-S4.

• Pelvicsplanchnicnerves


Physiology of the ANS

• Autonomic tone- a balance between the sympathetic and parasympathetic activity.

• Regulated by the hypothalamus.


Sympathetic Responses

• Stress ↑ sympathetic system ↑ fight-or-flight response.

• ↑ production of ATP.

• Dilation of the pupils.

• ↑ heart rate and blood pressure.

• Dilation of the airways.

• Constriction of blood vessels that supply the kidneys and gastrointestinal tract.


Sympathetic Responses continued..

• ↑ blood supply to the skeletal muscles, cardiac muscle, liver and adipose tissue

• ↑ glycogenolysis ↑ blood glucose. • ↑ lipolysis.


17 26 Sep 2019


Parasympathetic Responses

• Rest-and-digest response.

• Conserve and restore body energy.

• ↑ digestive and urinary function.

• ↓ body functions that support physical activity.


Integration and Control of Autonomic Functions

• Direct innervation- brain stem and spinal cord. • Hypothalamus is the major control and

integration center of the ANS.

• It receives input from the limbic system.


All this is possible because of our partners please support them for;

Health benefits: Motivation books:

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Affects 5–10% of the general population.

It is due to sudden, excessive depolarization of

some or all cerebral neurons. Common neurologic disorder with sudden and

recurring seizures Caused by abnormal electrical impulses in the brain This may be:

• • •

localized (focal or partial seizure);

spread to cause a secondary generalized seizure; may affect all cortical neurons simultaneously

(primary generalized seizure).

Abnormal electrical discharges in the cerebral cortex caused by sudden, excessive firing of neurons

Result in a change in behavior of which the patient is not aware While conscious, the patient may or may not lose movement control Loss of body control may affect one area or the entire body

Causes of Seizures

1. Cardiovascular disease 2. High fever

3. Hypocalcemia

4. High or low blood sugar 5. Hypoxia

6. Infection (meningitis)

7. Metabolic abnormalities

8. Brain tumor

9. Toxic substances

10. Trauma or injury to the head 11. ETOH withdrawal


Classification of seizures


F – frontal

O – occipital T – temporal

Rang et al. Pharmacology – 5th Ed. (2003)

18 26 Sep 2019


1. Carboxamides (enzyme inductors – CYP450): Carbamazepine (+ neuropathic pain – n. trigeminus, postherpetic pain, etc.), Oxcarbazepine

2. Hydantoins: Phenytoin (enzyme inductor), used in digitalis intoxication too

3. Barbiturates (Phenobarbital – enzyme inductors) and their analogues (Primidone – prodrug)

4. Succinimides: Ethosuximide (casp. 250 mg – petit mal)

5. Valproates (enzyme inhibitors): Sodium valproate (Depakin®) 6. Benzodiazepines: Clonazepam, Clorazepate, Diazepam

t1/2 43 h, amp. 10 mg/2 ml i.m./i.v., Lorazepam, Nitrazepam

7. GABA analogues: Gabapentin, Tiagabine

8. Hetereogenic anticonvulsants: Lamotrigine, Levetiracetam,

Pregabalin (partial seizures, peripheral neuropathic pain), Topiramate, Vigabatrin


Antiepileptics inhibit the neuronal discharge or its spread in one or

more of the following ways:

(1) Enhancing GABA synaptic transmission: barbiturates, benzo- diazepines, gabapentin, levetiracetam, tiagabine, vigabatrin, topira- mate, valproate; the result is increased permeability to chloride ion, which reduces neuronal excitability. Valproate and topiramate block GABA transaminase and tiagabine blocks reuptake of GABA.

(2) Reducing cell membrane permeability to voltage-dependent sodium channels: carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate, valproate.

(3) Reducing cell membrane permeability to calcium T-channels: valproate, ethosuximide; the result is diminishing of the generation

of action potential.

(4) Inhibiting excitory neurotransmitter glutamate: lamotrigine.


Barbiturates Benzodiazepines Gabapentin Levetiracetam Tiagabine Topiramate Valproate Vigabatrin


Carbamazepine Lamotrigine Oxcarbazepine Phenytoin Topiramate Valproate






Antiseizure drugs enhanced GABA Synaptic transmission

Goodman & Gilman’s

The Pharmacologic Basis of Therapeutics – 11th Ed. (2006)

Antiseizure drugs, enhanced Na+ channel inactivation Goodman & Gilman’s The Pharmacologic Basis of Therapeutics – 11th Ed. (2006)

Antiseizure drugs, induced reduction of current through T-type Ca2+ channels.

Goodman & Gilman’s The Pharmacologic Basis of Therapeutics – 11th Ed. (2006)




Goodman & Gilman’s The Pharmacologic Basis of Therapeutics – 11th Ed. (2006)

Effects of three antiseizure drugs on sustained high-frequency firing of action potentials by cultured neurons. Intracellular recordings were made from neurons while depolarizing current pulses, approximately 0.75 s in duration, were applied (on-off step changes indicated by arrows). In the absence of a drug, a series of high-frequency repetitive action potentials filled the entire duration of the current pulse. Phenytoin, carbamazepine, and sodium valproate all markedly reduced the number of action potentials elicited by the current pulses.

ion channels,

reducing membrane excitability. The t1/2 of the drug falls from 35 to

20 h over the first few weeks of therapy due to the induction of hepatic

enzymes that metabolize it as well as other drugs (including adrenal

corticosteroids, hormonal contraceptives, theophylline and warfarin.

Standard tablets are taken twice a day.

Carbamazepine is a drug of first choice for focal and secondary generalized epilepsy but aggravates myoclonic and absence seizure. It is useful for the treatment of trigeminal neuralgia, postherpetic pains, etc.

Adverse reactions (ARs): reversible blurring of vision,


▼VALPROIC ACID (Sodium valproate) acts by inhibiting GABA transaminase and increases the concentration of inhibitory neuro- transmitter GABA at its receptors. Valproic acid has t1/2 13 h and 90% bound to plasma albumin. It is a nonspecific inhibitor of meta- bolism, and inhibits its own metabolism, and that of lamotrigine, phenobarbital, phenytoin and carbamazepine. Valproic acid is effective for treatment of generalized and partial epilepsy, febrile convulsion and post-traumatic epilepsy.

ARs can be troublesome: weight gain, teratogenicity, polycystic ovary syndrome, and loss of hair which grows back curly. Nausea can be a problem, rarely, liver failure (risk maximal at 2–12 weeks). Ketone metabolites may cause confusion in urine testing in diabetes mellitus.

▼PHENYTOIN (t1/2 6–24 h) has saturation kinetics. It is extensively hydroxylated in the liver and this process becomes saturated at the doses needed for therapeutic effect (therapeutic plasma concentration range is 10–20 mg/L). Phenytoin is a potent inducer of hepatic metabo- lizing enzymes affecting itself and other drugs (carbamazepine, war- farin, adrenal and gonadal steroids, thyroxine, tricyclic antidepressant, doxycycline, vitamin D, folate).

Drugs that inhibit phenytoin metabolism

include: valproic acid, cimetidine, co-trimoxazole, isoniazid, chloram- phenicol, some NSAIDs, disulfiram. Phenytoin is 90% bound to plasma albumin and small changes in binding will result in a higher concentra- tion of free active drug. It is used to prevent all types of partial seizure, generalized seizure, and st. epilepticus. It is not used for absence attacks.

ARs: impairment of cognitive function (which has led many physicians to prefer carbamazepine and valproate), sedation, hirsutism, skin rashes, gum hyperplasia (due to the inhibition of collagen metabolism), hyperglycemia, anaemia, osteomalacia.

Saturation kinetics. Phenytoin is extensively hyd- roxylated in the liver and this process becomes saturated at about the doses needed for therapeutic effect. Thus phenytoin at low doses exhibits first- order kinetics but saturation or zero-order kinetics develop as the therapeutic plasma concentration range (10–20 mg/L) is approached, i.e. the dose increments of equal size produce disproportional rise in steady-state plasma concentration.

Basic & Clinical Pharmacology – 10th Ed. (2007)

Nonlinear relationship of phenytoin dosage and plasma concentrations.

Five different patients (identified by different symbols) received increasing dosages of phenytoin by mouth, and the steady-state serum concentration was measured at each dosage. The curves are not linear, since, as the dosage increases, the metabolism is storable. Note also the marked variation among patients in the serum levels achieved at any dosage.

20 26 Sep 2019



•Diazepam given intravenously or rectally is highly effective for stopping continuous seizure activity, especially generalized tonic- clonic status epilepticus. The drug is occasionally given orally on a long-term basis, although it is not considered very effective in this application, probably because of the rapid development of tolerance. A rectal gel is available for refractory patients who need acute control of bouts of seizure activity.

•Lorazepam appears in some studies to be more effective and longer-acting than diazepam in the treatment of status epilepticus and is preferred by some experts.

•Clonazepam (t1/2 25 h) is a benzodiazepine used as a second line drug for treatment of primary generalized epilepsy and status epilepticus.

Clonazepam, Clorazepate, Diazepam, Lorazepam, Nitrazepam

GABAA- site



GABAA- benzo- diazepine receptor complex


By Bennett and Brown (2003)

+ Barbitu- rate sate


▼BARBITURATES (enzyme inducers)

Antiepilepsy members include phenobarbital (phenobarbitone – ( t1/2 100 h), methylphenobarbital and primidone (which is largely metabolized to phenobarbital, i.e. it is a prodrug). They are still used for generalized seizures; sedation is usual.

Primidone and its active metabolites

Basic & Clinical Pharmacology – 10th Ed. (2007)

▼LAMOTRIGINE (t1/2 6–24 h) inhibits excitory neurotransmitter glutamate. Lamotrigine is effective for the treatment of partial and secondarily generalized tonic-clonic seizure. It is generally well tolerated but may cause serious ARs of the skin, including Stevens–Johnson syndrome and toxic epidermal necrolysis.

▼TOPIRAMATE (t1/2 21 h) is used as adjunctive treatment for partial seizure, with or without secondary generalization. ARs: sedation, weight loss, acute myopia, raised intraocular pressure.

▼ETHOSUXIMIDE (t1/2 55 h) blocks T-type calcium ion channels. It is active in absence seizures (petit mal). ARs: gastric upset, CNS effects and allergic reactions.


• Any causative factor must be treated (cerebral neoplasm etc). • Educate the patient about the disease, duration of treatment

and need for compliance.

• Avoid precipitating factor (alcohol, sleep deprivation, emotional

stress, and caffeine).

• Anticipate natural variation: fits may occur around menstrual

periods in women – catamenial (monthly) epilepsy.

• Give antiepileptics only if seizure type and frequency require it

(e.g. more than one fit every 6–12 months).

Grand mal: I choice – valproate or Lamotrigine

Alternative – Carbamazepine, Topiramate or Phenytoin

Petit mal: I choice – Ehosuximide or valproate

Alternative – Clonazepam or Lamotrigine

Partial seizures: I choice – Carbamazepine or valproate

Alternative – Phenytoin, Lamotrigine, Vigabatrin, Topiramaatus epilepticus: I choice – Diazepam or Lorazepam (i.v.)

Alternative – Phenobarbital (i.m./i/v.)


21 26 Sep 2019


Treatment of status epilepticus in adults

Patient in opisthotonus (grand mal)


(1) The decision whether or not to initiate drug therapy after a single seizure remains controversial since approximately 25% of patients may not have another seizure.

(2) Therapy should start with a single drug (70% of patients can be controlled on one drug (monotherapy).

(3) Anticonvulsant drug therapy should be appropriate to the type of seizure.

(4) The choice of drugs is also determined by the patient’s age and sex.

(5) If the attempt to control epilepsy by use of a single drug is unsuccessful, it should be withdrawn and replaced by a second line drug, though these are effective in only 10% of patients.

There is little evidence that 2 or 3 drugs are better than one, but more drugs often mean more ARs.

(6) Effective therapy must never be stopped suddenly, only gradually.

(7) After a period of at least 2–3 years free from seizures, with- drawal of anticonvulsants can be considered. In general, dis- continuing the antiepileptic drug therapy is associated with about 20% relapse during withdrawal and a further 20% relapse over the following 5 years. It is recommended that the antiepi- leptic drug be withdrawn over a period of 6 months. If a fit occurs during this time, full therapy must begin again until the patient has been free from seizure for a further 2–3 years.


Psychosis is a thought disorder characterized by disturbances of reality and perception, impaired cognitive functioning, and inappropriate or diminished affect (mood).

Psychosis denotes many mental disorders.

Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a

marked thinking disturbance.

Psychosis-Producing Drugs

1) Levodopa

2) CNS stimulants

a) Cocaine

b) Amphetamines

c) Khat, cathinone, methcathinone

3) Apomorphine 4) Phencyclidine


• Pathogenesis is unknown.

• Onset of schizophrenia is in the late teens –

early ‘20s.

• Genetic predisposition — Familial incidence.

• Multiple genes are involved.

• Afflicts 1% of the population worldwide.

• May or may not be present with anatomical changes.

22 26 Sep 2019



• A thought disorder.

• The disorder is characterized by a divorcement from reality in the mind of the person (psychosis).

• It may involve visual and auditory hallucinations, delusions, intense suspicion, feelings of persecution or control by external forces (paranoia), depersonalization, and there is attachment of excessive personal significance to daily events, called “ideas of reference”.


Positive Symptoms.

Hallucinations, delusions, paranoia, ideas of reference.

Negative Symptoms.

Apathy, social withdrawal, anhedonia, emotional blunting, cognitive deficits, extreme inattentiveness or lack of motivation to interact with the environment.

These symptoms are progressive and non-responsive to medication.

Etiology of Schizophrenia


Biological Correlates

1) Genetic Factors,2)Neurodevelopmental abnormalities,3)Environmental stressors.

Characterized by several structural and functional abnormalities in the brains of schizophrenic patients:

1) Enlarge cerebral ventricles.

2) Atrophy of cortical layers.

3) Reduced volume of the basal ganglia.

Dopamine Theory of Schizophrenia

Many lines of evidence point to the aberrant increased activity of the dopaminergic system as being critical in the symptomatology of schizophrenia.

There is a greater occupancy of D2 receptors by dopamine => greater dopaminergic stimulation

Dopamine Theory of Schizophrenia

Dopamine Correlates:

• Antipsychotics reduce dopamine synaptic activity.

• These drugs produce Parkinson-like symptoms.

• Drugs that increase DA in the limbic system cause


• Drugs that reduce DA in the limbic system (postsynaptic

D2 antagonists) reduce psychosis.

• Increased DA receptor density (Post-mortem, PET).

• Changes in amount of homovanillic acid (HVA), a DA

metabolite, in plasma, urine, and CSF.


Anatomic Correlates of Schizophrenia…

Areas Associated with Mood and Thought Processes:

Frontal cortex Amygdala Hippocampus Nucleus accumbens Limbic Cortex

23 26 Sep 2019


Dopamine Theory of Schizophrenia

Evidence against the Theory?

• Antipsychotics are only partially effective in most (70%) and ineffective for some patients.

• Phencyclidine,anNMDAreceptorantagonist, produces more schizophrenia-like symptoms in non- schizophrenic subjects than DA agonists.

• AtypicalantipsychoticshavelowaffinityforD2 receptors.

• Focusisbroadernowandresearchisgearedto produce drugs with less extrapyramidal effects.

Dopamine System

There are four major pathways for the dopaminergic system in the brain:

I. The Nigro-Stiatal Pathway.

II. The Mesolimbic Pathway.

III. The Mesocortical Pathway.

IV. The Tuberoinfundibular Pathway.




 Tyrosine hydroxylase L-Dopa

 Dopa decarboxylase Dopamine (DA)

 Dopamine  hydroxylase Norepinephrine (NE) (Noradrenaline) Phenylethanolamine-

 -N-methyltransferase Epinephrine (EPI) (Adrenaline)


– There are at least 5 subtypes of receptors:

– –

D1 and D5: mostly involved in postsynaptic inhibition.

D2, D3, and D4: involved in both pre-and postsynaptic inhibition.

D2: the predominant subtype in the brain: regulates mood, emotional stability in the limbic system and movement control in the basal ganglia.

24 26 Sep 2019


Antipsychotic treatments SCHIZOPHRENIA IS FOR LIFE There is no remission

 In 1940’s Phenothiazenes were isolated and were used as pre-anesthetic medication, but quickly were adopted by psychiatrists to calm down their mental patients.

 In 1955, chlorpromazine was developed as an antihistaminic agent by Rhône-Pauline Laboratories in France. In-patients at Mental Hospitals dropped by 1/3.

Antipsychotics treatment Antipsychotics/Neuroleptics

• Antipsychotics are the drugs currently used in the prevention of psychosis.

• They have also been termed neuroleptics, because they suppress motor activity and emotionality.

** These drugs are not a cure **

• Schizophrenics must be treated with medications indefinitely, in as much as the disease in lifelong and it is preferable to prevent the psychotic episodes than to treat them.


Although the antipsychotic/neuroleptics are drugs used mainly in the treatment of schizophrenia, they are also used in the treatment of other psychoses associated with depression and manic-depressive illness, and psychosis associated with Alzheimer’s disease. These conditions are life-long and disabling.

NON-compliance is the major reason for relapse.


Old antiphsychotics /neuroleptics are D2 dopamine receptor

antagonists. Although they are also effective antagonists at ACh, 5-HT, NE receptors.

Three old major groups:Phenothiazines;Thioxanthines;Butyrophenones

Tyrosine Tyrosine

Dopamine Synapse

dopamine receptor antagonist




It appears that the specific interaction of antipsychotic drugs with D2 receptors is important to their therapeutic action.

The affinities of most older “classical” agents for the D2 receptors correlate with their clinical potencies as antipsychotics.

Both D1 and D2 receptors are found in high concentrations in the striatum and the nucleus accumbens.

Clozapine has a higher affinity for the D4 receptors than for D2.

Recently it has been found that most antipsychotic drugs may also bind D3 receptors (therefore, they are non-selective).

• Antipsychotics produce catalepsy (reduce motor activity).


Antipsychotics reverse hyperkinetic behaviors (increased locomotion and stereotyped behavior).

– BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS. Antipsychotics prevent the dopamine inhibition of prolactin release from pituitary.


25 26 Sep 2019



Absorption and Distribution

• Most antipsychotics are readily but incompletely absorbed.

• Significant first-pass metabolism.

• Bioavailability is 25-65%.

• Most are highly lipid soluble.

• Most are highly protein bound (92-98%).

• High volumes of distribution (>7 L/Kg).

• Slow elimination.

**Duration of action longer than expected, metabolites are present and relapse occurs, weeks after discontinuation of drug.**



• Mostantipsychoticsarealmostcompletelymetabolized.

• Mosthaveactivemetabolites,althoughnotimportantin therapeutic effect, with one exception. The metabolite of thioridazine, mesoridazine, is more potent than the parent compound and accounts for most of the therapeutic effect.

Excretion:Antipsychotics are almost completely metabolized and thus, very little is eliminated unchanged.Elimination half- lives are 10-24 hrs.

Antipsychotic/Neuroleptics 1) Phenothiazines

• Aliphatic Piperidine

Chlorpromazine Thioridazine Trifluopromazine Piperacetazine


Fluphenazine Perfenazine

Mesoridazine Acetophenazine Carphenazine

Prochlorperazine Trifluoperazine

* Most likely to cause extrapyramidal effects.


2)Thioxanthines:Thiothixene,Chlorprothixene(Closely related to phenothiazines)

3) Butyrophenones:Haloperidol,Droperidol

The acute effects of antipsychotics do not explain why their therapeutic effects are not evident until 4-8 weeks of treatment.

Blockade of D2 receptors

Short term/Compensatory effects:

 Firing rate and activity of nigrostriatal and mesolimbic DA neurons.

 DA synthesis, DA metabolism, DA release


[Drug dose]

Butyrophenone Phenothiazine Thioxanthene

Newer drugs have higher affinities for D1, 5-

HT or -AR


NE, GABA, Glycine and

Glutamate have also been implicated in schizophrenia.


Presynaptic Effects

Blockade of D2 receptors

Compensatory Effects

 Firing rate and activity of nigrostriatal and mesolimbic DA neurons.

 DA synthesis, DA metabolism, DA release.

Postsynaptic Effects

Depolarization Blockade

Inactivation of nigrostriatal and mesolimbic DA neurons. 

Receptor Supersensitivity

26 26 Sep 2019



Clinical Extra Pyramidal effects.

Drug Potency toxicity Sedation Hypote.

Chlorpromaz. Low Medium Medium High

Haloperidol Thiothixene Clozapine Ziprasidone Risperidone Olanzapine Sertindole

High Very High High Medium Medium Very low Medium Very Low High Low

High Very Low High Very Low

Very High Low Medium Medium Low Medium

Low Low Medium Very low

Very low Low Very low Very Low


Chlorpromazine: 1 = 5-HT2 = D2 > D1 > M > 2 Haloperidol: D2 > D1 = D4 > 1 > 5-HT2 >H1>M = 2 Clozapine: D4 = 1 > 5-HT2 = M > D2 = D1 = 2 ; H1 Quetiapine: 5-HT2 = D2 = 1 = 2 ; H1 Risperidone: 5-HT2 >> 1 > H1 > D2 > 2 >> D1 Sertindole: 5-HT2 > D2 = 1


Clinical Problems with antipsychotic drugs include:

1) 2)


a) b) c) d) e)

Failure to control negative effect Significant toxicity

Parkinson-like symptoms Tardive Dyskinesia (10-30%) Autonomic effects Endocrine effects

Cardiac effects Poor Concentration

DA neuron


GABA neuron

ACh neuron


GABA – neuron

Substantia Nigra

Inhibition of Motor Activity

The Nigro-Striatal Pathway

 Some antipsychotics have effects at muscarinic acetylcholine receptors:

• dry mouth

• blurred vision

• urinary retention

• Constipation Clozapine,Chlorpromazine

Thioridazine  Some antipsychotics have effects at -adrenergic

receptors:orthostatic hypotension Chlorpromazine,Thioridazine

 Some antipsychotics have effects at H1- histaminergic receptors:sedation



 Blockade of D2 receptors in lactotrophs in breast increase prolactin concentration and may produce breast engorgement and galactorrhea.

Neuroleptic Malignant Syndrome

Is a rare but serious side effect of neuroleptic (antipsychotic) therapy that can be lethal. It can arise at any time in the course of treatment and shows no predilection for age, duration of treatment, antipsychotic medication, or dose.

27 26 Sep 2019


Neuroleptic Malignant Syndrome

• Occurs in pts. hypersensitive to the Ex.Py. effects of antipsychotics.

• Due to excessively rapid blockade of postsynaptic dopamine receptors.

• The syndrome begins with marked muscle rigidity.

• If sweating is impaired, a fever may ensue. The stress

leukocytosis and high fever associated with this

syndrome may be mistaken for an infection.

• Autonomic instability with altered blood pressure and

heart rate is another midbrain manifestation.

• Creatine kinase isozymes are usually elevated, reflecting muscle damage.

Neuroleptic Malignant Syndrome


Vigorous treatment with antiparkinsonian drugs is recommended as soon as possible.

Muscle relaxants such as diazepam, dantrolene or bromocriptine may be helpful.

Drug Interactions:Additive effects with sedatives, anticholinergics, antihistaminergics -AR blocking drugs, quinidine-like action (thioridazine).

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Pharmacology with Dr. Geoffrey A

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28 26 Sep 2019



• The Pituitary Gland

• Somatostatin

• Adrenocorticosteroids • Oxytocin

• Thyroid

• Calcium

• Parathyroid Hormone

• Irritable Bowel Syndrome

• Malabsorbtion Syndrom

• Inflammation Bowel Disease • Motility agents

Major endocrine glands


• Are recognized six main groups of drugs acting on endocrine system. Some of them are employed in clinical practice like replacement therapy because these types of drugs can act as natural hormone secretion.

• Others may act stimulating the natural hormonal production, secretion or potentiating their physiological action.

• But, also are employed in clinical practice a lot of drugs which can act on contrary, by inhibition of natural hormone action in biochemical or physiological level.

Both types of drugs are recognized as:

1. Pituitary hormones and their Hypothalamic releasing factors.

2. Adrenocorticotropic hormone (ACTH); Adrenocorticosteroids and their antagonists.

3. ThyroidandAntithyroiddrugs.

4. Gonodal hormones (Estrogens, progestins

and Androgens) and their inhibitors.

5. Pancreatic hormones and antidiabetic


6. Agents that affect calcification and bone mineral homeostasis.

The Hypothalamus

Small structure at the base of the brain.

Regulates many body functions, including appetite and body temperature.

Regulates the pituitary gland.

The Pituitary Gland

• A sort of master gland.

• It is a cherry-sized endocrine gland.

• The hormones it secretes affect the growth and secretion of other endocrine glands.

• The real boss is the hypothalamus.

29 26 Sep 2019


Interaction between hypothalamus and pituitary (hypothalamic-pituitary axis)

H ipotálam o Hypothalamus


H IPAÓntFerIiSorIS AN TpiEtuRitaIrOy R




This interaction is a feedback control system.

Anterior Pituitary

• Derived during embryological development from the roof of the mouth.

• Most of the hormones are released from the anterior pituitary.

• Hormones released from the anterior pituitary are dormant unless directed to be released by the hypothalamus via Releasing Factors.

• They are: Growth hormone (GH), Luteinizing hormone (LH), Follicle stimulating hormone (FSH), Prolactin (PRL), Adrenocorticotropic hormone (ACTH), Thyroid stimulating hormone (TSH).

Hypothalamic Hormones:

Pituitary Hormones:

Target Gland or Structure:

Anterior Pituitary & Hypothalamic Hormone Receptors

These hormones can be classified according to hormone structure and the types of receptors that they activate.

• GH & prolactin are single-chain protein hormones with significant homology. Both hormones activate receptors of the JAK/STAT superfamily (Janus kinase family of intracellular tyrosine kinases and the Signal Transducer and Activator of Transcription family of nuclear transcription factors).

• TSH, FSH & LH are dimeric proteins that activate G protein- coupled receptors. They share a common chain. Their chains, though somewhat similar to each other, differ enough to confer receptor specificity.

• ACTH is a single peptide that is cleaved from a larger precursor that also contains the peptide endorphin. It acts through a G protein-coupled receptor.

Gondotropin RF Corticotropin RF Thyrotropin RF Growth Hor


Follicle SH & Adrenocorticoptropic

Thyrotropin SH

Thyroid Gland (thyroxine)


Growth Hormone

Cells of body


Bones, breasts & cells of body

Lutenizing Hor.

Ovaries & Testes

(androgens, estrogen)

Hormone (ACTH)

Adrenal Gland (cortisol)


• It is a peptide hormone with 191-amino acids.

• Structurally similar to prolactin and chorionic somatomammotropin.

• GH stimulates somatic growth and regulates metabolism.

• Growth hormone–releasing hormone (GHRH) is the major stimulator.

• Somatostatin is the major inhibitor of the synthesis and release of GH.


• GH controls synthesis of insulin-like growth factor 1 (IGF-1, also called somatomedin-C), which largely controls growth.

• Although IGF-1 is produced by many tissues, the liver is the major source.

• A variant of IGF-1 occurs in muscle, where it plays a role in enhancing muscle strength. It is less under control of GH than is the liver variant.

30 26 Sep 2019


GH- Pharmacological effects

• The metabolic effects of GH are biphasic.

• Initially exerts insulin-like effects, increasing glucose uptake in muscle and fat, stimulating amino acid uptake and protein synthesis in liver and muscle, and inhibiting lipolysis in adipose tissue.

• Several hours later, more profound anti–insulin- like metabolic effects occur:

Inhibition of glucose uptake and use, causing blood glucose and lipolysis to increase, which increases plasma free fatty acids.

GH- Pharmacological effects cont.

• Promotes longitudinal growth indirectly through:

 Somatomedins (IGFs).

GH stimulates growth plate cartilage & liver

synthesis of: IGF-I & IGF-II

 Somatomedins are mediator of processes

promoting bone growth:

–cellular proliferation,

–increased proline to hydroxyproline conversion

(cartilage synthesis).

GH deficiency Reduced somatomedin Short stature

GH- Summary of Pharmacological effects

Direct effects

•  lipolysis   fat utilization •  blood sugar (anti-insulin


Indirect effects

• skeletal growth

• cell proliferation

• protein anabolism

GH as Juvenile


GH = Pituitary dwarfism

GH as an Adult



31 26 Sep 2019


GH- Pharmacokinetics

• Circulating endogenous GH has a half-life of 20- 25 min and is predominantly cleared by the liver.

• Recombinant human GH (rhGH) is administered

SC 3-6 times per week.

• Peak levels occur in 2-4 hrs and active blood

levels persist for approximately 36 hrs.

• Somatropin injectable suspension is a long- acting preparation of rhGH enclosed within microspheres. These microspheres degrade slowly after SC injection such that the rhGH is

released over about 1 month.

GH- Uses

 Growth failure in pediatric patients associated with:

• GH deficiency.

• Turner’s syndrome (chromosomal anomaly in girls).

• Chronic renal failure.

• Small for gestational age babies unable to catch up by 2.

• Prader-Willi syndrome (autosomal dominant genetic

disease that is associated with growth failure, obesity,

and carbohydrate intolerance).

 Growth hormone deficiency in adults.

 Wasting in patients with HIV infection (Increased lean body mass, weight, and physical endurance).

 (?) adult athletes – to increase muscle mass.

 (?) anti-aging.

 (?) Idiopathic short stature (Non-GH deficient short stature (NGHDSS) children).

GH- Adverse effects

• Creutzfeldt-Jakob disease (is a brain damage). • Children generally tolerate the treatment well: rarely- hypothyroidism, scoliosis, intracranial

hypertension. Following rapid growth:

– Slipped capital femoral epiphyses: limp; lower extremity pain (rare).

• In adults: peripheral edema, myalgia, arthralgia, pancreatitis, gynecomastia. Leukemia incidence (slight increase may not be causal). Screening suggested for hypothyroidism & diabetes during GH treatment.

GH- Preparations

Recombinant forms are used.

• somatropin (191-amino acid form).

• somatrem (192 amino acid form (additional methionine).

GH- Antagonists

• They are needed from the tendency of GH-producing cells in the anterior pituitary to form secreting tumors.

• Pituitaryadenomasoccurmostcommonlyinadults.

• Acromegaly adversely affects the skeletal, muscular,

CVS, respiratory and metabolic systems.

• Small GH-secreting adenomas can be treated with GH


• Larger pituitary adenomas are treated with

transsphenoidal surgery or radiation.

– Somatostatin&somatostatinanalogs.

– Bromocriptine- a dopamine receptor agonist reduce

the production of GH.

– Pegvisomant-preventsGHfromactivatingitsreceptor.


• Major inhibitor of GH synthesis and release.

• Also inhibits the release of TSH, insulin and glucagon; it decreases the release of most GI hormones and reduces gastric acid and

pancreatic secretion.

• Octreotide and Lanreotide are long-acting

analogues of somatostatin, used for the treatment of tumours secreting vasoactive intestinal peptide, carcinoid tumours, glucagonomas and various pituitary adenomas. They has a place in the therapy of acromegaly and of bleeding oesophageal varices.

32 26 Sep 2019



• It is generally given SC. The peak action is at 2 hours, and the suppressant effect lasts for up to 8 hours.

ADR: Pain at the injection site and GI disturbances. Gallstones, postprandial hyperglycaemia and acute hepatitis has occurred in a few cases.


• FSH– stimulates gametogenesis.

• LH– regulates gonadal steroid hormone production.

• Human chorionic gonadotrophin (hCG): extracted from urine of pregnant women. Contains the biologic activity of LH. It is secreted by the chorion and placenta. Stimulates ovarian corpus luteum to produce progesterone and maintain placenta.

• Human menopausal gonadotrophin (hMG): extracted from urine of postmenopausal women. Contains a mixture of LH and FSH.


• LH & FSH control the production of the sex hormones.

• Their synthesis and release are stimulated by gonadotropin-releasing hormone (GnRH) and suppresed by estrogen and testosterone by negative feedback mechanism.

• Pulsatile GnRH is required to stimulate the gonadotroph cells to produce and release LH & FSH.

• Sustained, nonpulsatile administration of GnRH or GnRH analogs inhibits the release of FSH & LH by the pituitary in both women and men, resulting in hypogonadism.


• In women, they stimulate ovarian follicular development and ovulation.

• In men, FSH acts in Sertoli cells and is essential for spermatogenesis; LH acts on Leydig cells of the testes to stimulate testosterone biosynthesis.

LH and FSH

• Secreted in pituitary gonadotropes.

• Composed of an identical 89-amino acid a-chain

and, a 115-amino acid b-chain unique to each

hormone that confers receptor specificity.

• Bind to high-affinity membrane receptors in testes

and ovaries.

• Activate G protein-coupled receptors which exhibit

distinctive Ca2+ signaling properties and activate

adenylyl cyclase (responsible for cAMP formation).

• cAMP acts as second messenger and triggers activation of its protein kinase and phosphorylation

of proteins necessary for steroid-genesis.

LH and FSH- Pharmacokinetics

• They are administered IM or SC, usually on a daily basis.

• LH (half-life: 30-60 min, clearance: 30ml/min in women, 50ml/min in men).

• FSH (half-life: 4-5 hours, clearance: 15ml/min in women, not determined in men).

33 26 Sep 2019



– Female infertility

• controlled ovarian hyperstimulation in assisted reproductive technology (ART) such as in vitro fertilization.

• anovulation

– Male infertility: oligospermia – hCG + hMG

• Adverse Effects:

– Multiple pregnancies (15-20%)

– Ovarian hyperstimulation (OHSS) (0.5-4%) – Headache, Depression, Precocious puberty – Edema, Gynecomastia in men


• Preparations

– hCG (Pregnyl, Profasi, APL®)

– Menotropin (hMG)

– Urofollitropin (uFSH)

– rFSH – shorter t1/2 , more expensive

• Follitropin  (Gonal-f®)

• Follitropin  ( Puregon®) – rLH (Lutropin, Luveris®)

r- recombinant u- urinary

Prolactin (PRL)

• It is produced in lactotrophs (constitute about 30% of the cells of the anterior pituitary).

• The pituitary doubles in size during pregnancy, largely because of hyperplasia and hypertrophy of lactotrophs.

• In humans, its major function is stimulating milk

production when appropriate circulating levels of estrogens, progestins, corticosteroids, and insulin are present. Its release also occurs during sexual activity and stress.

• Itmaybeasensitiveindicatorofpituitarydysfunction;it is the hormone most frequently produced in excess by pituitary tumors, and it may be one of the hormones to become deficient from infiltrative disease or tumor compression of the pituitary.

Prolactin (PRL)

• Estrogens increase both prolactin secretion and proliferation of lactotrophs through release, from a subset of lactotrophs, of the neuropeptide galanin.

• Prolactin production is inhibited by the catecholamine dopamine acting through the D2 subtype of dopamine receptors.

• Agonists of Dopamine (bromocriptine, pergolide, cabergoline, quinagolide) suppress prolactin release. Bromocriptine and pergolide are antiparkinson drugs.

• Dopamine antagonists (used mainly as antipsychotic drugs) are potent stimulants of prolactin release (chlorpromazine, thioridazine, fluphenazine, haloperidol, etc.).


Adrenocorticotropic hormone (ACTH)

• Also known as corticotropin.

• Corticotropin-releasing hormone (CRH) is the

primary stimulator of its release.

• ACTH induces the adrenal cortex to release cortisol

and several weak androgens, such as

dehydroepiandrosterone (DHEA).

• Circulating cortisol and other corticosteroids

(including exogenous corticosteroids) inhibit the

release of CRH and ACTH.

• The CRH-ACTH-cortisol axis is a central

component of the response to stress. Without ACTH, the adrenal cortex atrophies and cortisol release virtually ceases.

34 26 Sep 2019


ACTH- Preparations

• ACTH is available as a synthetic derivative in the forms of cosyntropin (trade name cortrosyn), and synacthen.

• Both are very rarely used in place of glucocorticoids to treat secondary adrenal insufficiency, but are used primarily to conduct the ACTH stimulation test.


• For clinical use we have natural and synthetic corticosteroids and they completely replace the natural hormone functions.

Mineralocorticoids (regulate water and electrolyte balance): Aldosterone (its realesed from the adrenal cortex stimulated by Angiotensin II), fludrocortisone (synthetic).

Glucocorticoids (widespread actions on intermediate metabolism and regulatory effects): Hydrocortisone.

Androgens: Dehydroepiandrosterone.


Mechanism of action

Actions of Glucocorticoids (Induction)

• The synthesis of many proteins is induced by glucocorticoids:

• Example: annexin-1 (lipocortin-1), which has several functions, including inhibition of phospholipase A2



PLA2 Arachidonic acid

Actions of Glucocorticoids (Repression)

• Some transcription factors (NF-kB, AP-1, etc) normally switch on the synthesis of a family of proteins involved in inflammation:

– Cyclooxygenase (see next slide),

– Numerous cytokines and interleukines, – Numerous cell adhesion molecules, and – Inducible form of nitric oxide synthase.

Metabolism of Arachidonic Acid: Biosynthesis of Prostanoids

Arachidonic acid

Thromboxane A2

Glucocorticoids inhibitthe transcription

of cyclo-oxygenase (their main anti- inflammatory effect)



PGD2 Prostaglandin D2


Cyclo-oxygenase Endoperoxides


(Specific PG synthases)

PGF2α Prostacyclin prostaglandin F2α

Prostaglandin E2

35 26 Sep 2019


Glucocorticoids- Pharmacological Actions

• Suppression of the anterior pituitary gland:

– Inhibition of the release of ACTH (prolonged use leads to suppression of the pituitary adrenal


• Metabolic effects – lipids:

–Re-distribution of body fat (inter-scapular fat pad, trunkal obesity, moon face).

• Metabolic effects – carbohydrates: – Insulin insensitivity.

– Hyperglycaemia.

– Loss of control in diabetics.

• Skin: Abdominal striae, thinning of the skin, acne, conjunctival oedema, hirsuitism.

Glucocorticoids- Pharmacological Actions cont.

• Inhibition of inflammatory and immune responses:

– Early and late responses both affected.

– Tendency to acute infections (Staphylococcus,

Streptococcus, etc.).

– Tendency to chronic infections (TB).

– Use in acute rejection episodes.

– Suppression of lymphocyte proliferation

(leukaemia, lymphomas).

• Increased susceptibility to infection: Oral candidiasis,

pneumonia and other infections.

• Impaired scar formation (fibroblast activity):

– Delayed would healing.

• Muscle: Proximal myopathy.

Glucocorticoids- Pharmacological Actions cont.

• CNS: Elevation of mood, depression (rarely), acute psychosis.

• Bones:

– Inhibition of Vit D-dependent activation of osteoblasts.

– Decrease the intestinal absorption of calcium and

increase renal excretion of calcium.

– Inhibition of matrix deposition (collagen).

– Increased collagenase activity.

– Osteoporosis and Ischaemic necrosis (especially

femoral head).

• CVS:Retentionofsaltandwater,elevationofBP,lossof

therapeuticcontrolin hypertension.

• Other effects: Increased appetite, negative nitrogen

balance, cataracts.

Patients lack cortisol from zona fasciculata

Moon face in a patient suffering Cushing’s syndrome

Signs & symptoms associated with prolonged exposure to inappropriately high levels of hormone cortisol. This can be caused by taking glucocorticoid drugs, or diseases that result in excess cortisol, ACTH or CRH levels.

Glucocorticoids-Therapeutic uses

• Replacement for primary adrenocortical insufficiency (Addison’s disease).

• Replacement for secondary or tertiary adrenocortical insufficiency (Lacking ACTH or CRH).

• DiagnosisofCushing’ssyndrome.

• Replacement therapy for

congenital adrenal hyperplasia (Group of diseases resulting from an enzyme defect in the synthesis of one or more of the

adrenal steroid hormones).

• Relief of inflammatory symptoms (Arthritis, asthma,

skin conditions, allergies, etc.)

• P. carinii pneumonia– increases oxygenation and

decreases the incidence of respiratory failure and mortality.

36 26 Sep 2019


Glucocorticoids-Therapeutic uses cont.

• Acceleration of lung maturation in premature infants (to decrease the incidence of respiratory distress syndrome, intraventricular hemorrhage, and death in babies delivered prematurely).

• H. influenzae type B meningitis – decrease the long-term neurological impairment.

• Ocularinflammatorydiseases.

• Skindiseases(Inflammatorydermatoses)

• GITdiseases(Inflammatoryboweldisease)

• Hepaticdiseases–prednisolone–

• Malignancies(Lymphomas)

• Cerebraledema.

• Miscellaneous (Sarcoidosis, thrombocytopenia (to

decrease bleeding tendency), organ transplantation, spinal cord injury.

Glucocorticoids- Adverse effects

Glucocorticoids- Preparations

• IV and IM steroids: Hydrocortisone (acute asthma, adrenal insufficiency), dexamethasone (cerebral edema), methylprednisolone, prednisolone.

• IM:Cortisone,desoxycorticosterone,triancinolone.

• Inhaled steroids: Budesonide, beclometasone,


fluticasone, triancinolone (Asthma


• Topical steroids: Beclometasone, dexamethasone,

hydrocortisone, triancinolone (skin, eye drops etc).

• Intra-articular injection: Prednisolone,


• Oral: Prednisolone, prednisone, dexamethasone (inflammatory diseases).

Corticosteroid withdrawal should be


• Sudden cessation leads to acute adrenal insufficiency, due to the prolonged suppression of the HPA axis.

• Need weeks/months/year to have full recovery of the HPA axis.

• Normal withdrawal symptoms- fever, muscle and joint pain and malaise.

Contraindications: Peptic ulcer, osteoporosis, hypertension, infection, psychosis.

Antagonists of Adrenocortical Agents

• They are synthetic inhibitors:

1. Metyrapone (Interferes with cortisol and corticosterone synthesis); used in tests of adrenal function and to treat hypercorticotism- Cushing ́s syndrome in pregnancy).

2. Aminoglutethimide (Blocks the conversion of cholesterol to pregnanelolone causing a reduction in the synthesis of all hormonally active steroids; used in treatment of breast cancer and Cushing’s syndrome due to adrenocortical cancer (malignances of adrenal cortex).

Antagonists of Adrenocortical Agents

3. Ketoconazole (antifungal imidazole derivative; potent, non-selective inhibitor of adrenal and gonadal steroid synthesis, used in Cushing’s syndrome).

4. Mifepristone (has strong anti-progestin activity; blocks glucocorticoid receptors).

5. Trilostane (Interferes with the synthesis of adrenal and gonadal hormones, comparable to aminoglutethimide).

37 26 Sep 2019


Posterior Pituitary

• Derived from nervous tissue.

• Hormones released from the posterior pituitary are synthesized in the hypothalamus.

• Posterior pituitary releases Oxytocin and Antidiuretic hormone (also called vasopressin or arginine vasopressin) in response to neural impulses.

• Both hormones have ring structure and travel in blood unbound and have a T1/2 ~2-3 min.

Vasopressin (ADH)

• ADH acts primarily to promote water conservation by the kidney by increasing the permeability of the distal tubular epithelium to water.

• At high concentrations also causes vasoconstriction.

• Like aldosterone, ADH plays an important role in maintaining fluid homeostasis and vascular and cellular hydration.

• The main stimulus for ADH release is increased osmotic pressure of water in the body, which is sensed by osmoreceptors in the hypothalamus.

Vasopressin (ADH)

• The other two major stimulus is volume depletion and hypotension, which is sensed by baroreceptors in the left atrium, pulmonary veins, carotid sinus and aortic arch, and then transmitted to the CNS through the vagus and glossopharyngeal nerves.

• Other stimulants for ADH release: pain, stress, emesis, hypoxia, exercise, cholinergic agonists, β-blockers, angiotensin, prostaglandins, etc.

• Inhibitors of ADH release: alcohol, phenytoin, low dosis of morphine, haloperidol, fluphenazine, glucocorticoids, etc.

Vasopressin (ADH)

• High plasma tonicity & low BP  ADH  antidiuretic and pressor effects.

Interacts with 2 types of receptors:

–V1- in vascular smooth muscle cells  Vasoconstriction

–V2- in renal tubule cells  water reabsorption in collecting tubules (it binds V2 receptors in the basolateral membranes, increasing expression of aquaporin (water channels) in the apical membranes of the nephron).

Vasopressin (ADH)

• A lack of ADH causes central diabetes insipidus.

• An inability of the kidneys to respond normally to ADH causes nephrogenic diabetes insipidus.

• Removal of the pituitary gland usually does not result in permanent diabetes insipidus because some of the remaining hypothalamic neurons produce small amounts of ADH.

Vasopressin (ADH)

• Uses:

– Diabetes insipidus – 0.1-0.2 mg TID – Nocturnal enuresis – 0.2 mg at HS

• Adverse Effects:

– Headache, nausea, abdominal cramps, agitation, and allergic reactions occur rarely. Overdosage can result in hyponatremia and seizures.

• Caution in patients with Coronary artery disease (CAD).

38 26 Sep 2019


Vasopressin (ADH)

• Preparations: – Vasopressin

• Parenteral (IM, SC)

– Desmopressin (Minirin®)

• long-acting

• ↓ V1, ↑ V2

• Oral, nasal and parenteral (IV, SC)


• Synthesized in both sexes but well recognized physiological effects only in women.

• It has 2 major targets: the myoepithelial cells of the breast, which surround the alveoli of the mammary gland, and the smooth muscle cells of the uterus.

• Suckling stimulates the production of oxytocin, which causes the myoepithelial cells to contract. This contraction causes milk to move from the alveoli to large sinuses for ejection.


• It stimulates contraction of uterine smooth muscle cells, and uterine sensitivity to oxytocin increases throughout pregnancy (The uterus is more responsive to oxytocin in late pregnancy than in early pregnancy).

• However, plasma levels do not increase sharply during parturition, and the role of oxytocin in the initiation of labor is unclear.

• There is no recognized stimulus for oxytocin release in men, although men have extremely low levels.


• Effects (in summary)

– Milk ejection in lactating women.

– Uterine contraction at therapeutic levels.

– Vasodilatation (To compensated the local constriction of the uterine muscle).

–Weak anti-diuretic & pressor effects at high concentrations by activation of vasopressin receptors.


• Preparation

– Oxytocin 5 iu/ml

• Pharmacokinetic – Parenteral only:

• i.v. for induction or augmentation

• i.m. for postpartum hemorrhage – Short half-life (~ 3 min)

39 26 Sep 2019


Oxytocin- Uses

• Diagnostic: Oxytocin Challenge Test/Contraction Stress Test.

Oxytocin- Uses • Therapeutic:

–Induction and reinforcement of labor (slow IV infusion):

– Uterine inertia.

– Incomplete abortion.

– Post maturity.

– Maternal diabetes, preecampsia,

eclampsia (uteroplacental insufficiency). – Postpartum hemorrhage.

– Impaired milk ejection.


• Adverse Effects:

– From uterine overstimulation:

• uterine rupture

• fetal death

• placental abruption

– Activation of vasopressin receptors can cause excessive fluid retention, or water intoxication, leading to hyponatremia, heart failure, seizures, and death.

–Bolus injections can cause hypotension and reflex tachycardia. (To avoid it, is administered IV as dilute solutions at a controlled rate).

Oxytocin • Contraindications:

– Any predispositions for uterine rupture: fetal distress,


abnormal fetal presentation, cephalopelvic disproportion (CPD).


and Antithyroid drugs

Thyroid hormones

• Thyrotrophin-releasing hormone (TRH), released from the hypothalamus in response to various stimuli, releases TSH (thyrotrophin) from the anterior pituitary.

• Thyroid gland releases two different types of hormones:

1. Tetraiodothyronine or Thyroxine (T4) and Triiodothyronine (T3).

2. Calcitonin (involved in the control of plasma Ca2+).

 The first ones have function in growth, metabolism and the regulation of thyroid function.

40 26 Sep 2019



Main steps in the synthesis, storage & secretion of thyroid hormones

 Uptake of plasma iodide by the follicle cells.

 Oxidation of iodide by thyroidal peroxidase to iodine.

 Iodide organification: iodination of tyrosine residues

of thyroglobulin molecule to form monoiodotyrosine

(MIT) and diiodotyrosine (DIT).

 Secretion of thyroid hormone.

• Iodide (I-) is essential for thyroid hormone synthesis, but excess of endogenous or exogenous iodide inhibits the increased thyroid hormone production.

• The peptide somatostatin also reduces basal TSH release.

Disorders of the thyroid gland

• They are common and consist in two general presentations:

Changes in the size or shape of the gland (nodules and goiter). See next slide

– Simple non-toxic goitre (caused by dietary iodine deficiency, usually with normal thyroid function).

Changes in secretion of hormones from the gland (The presentation of overt hyper or hypothyroidism often presents the clinician with dramatic clinical manifestation).


• In infants causes cretinism and in severe cases (in adults) myxedema.

• Manifestations: Low metabolic rate, slow speech, deep hoarse voice, lethargy, bradycardia, sensitivity to cold and mental impairment. Patients also develop a characteristic thickening of the skin, which gives myxoedema its name.

• Hashimoto’s thyroiditis, a chronic autoimmune disease (immune reaction against thyroglobulin or some other component of thyroid tissue) can lead to hypothyroidism and myxoedema.

• Therapy of thyroid tumours with radioiodine is another cause of hypothyroidism.

Hyposecretion of T3 and T4

The most prevalent endocrine disorder in the newborn.

Thyroid deficiency during development, caused by congenital absence or incomplete development of the thyroid causes cretinism, characterized by gross retardation of growth and mental deficiency.

Severe cases of hypothyroidism

Myxedem a



41 26 Sep 2019


Thyroids Hormones

• They are used in hypothyroidism (myxedema and also in diffuse non-toxic goitre), Hashimoto’s thyroiditis (lymphadenoid goitre) and thyroid carcinoma. Neonatal hypothyroidism requires prompt treatment for normal development.

• Levothyroxine sodium (T4)

• Liothyronine sodium (T3)

• Liotrix (T4+T3) (4:1)

• Thyroid desiccated – Natural


Levothyroxine sodium

• Treatment of choice for maintenance therapy because of its stability, content uniformity, low cost, lack of allergenic foreign protein, easy laboratory measurement of serum levels, and long half-life (7 days), which permits once- daily administration.

• In addition, T4 is converted to T3 intracellularly; thus, administration of T4 produces both hormones.

• Contraindication: Thyrotoxicosis.


• Is 3 to 4 times more potent,

• Is more rapidly metabolised, and

• Has a more rapid effect than levothyroxine.

• But it is not recommended for routine

replacement therapy because:

–Its shorter half-life (24 h), which requires multiple daily doses,

– Its higher cost, and

– The greater difficulty of monitoring its

adequacy of replacement by conventional laboratory tests.

Liothyronine cont.

• Because of its greater hormone activity and consequent greater risk of cardiotoxicity, should be avoided in patients with cardiac disease.

• It is best used for short-term suppression of TSH, in severe hypothyroid states when a rapid response is desired.

• Contraindication: Thyrotoxicosis.

Hyperthyroidism (Thyrotoxicosis)

• In thyrotoxicosis, there is excessive activity of the thyroid hormones, resulting in a high metabolic rate, an increase in skin temperature and sweating, and a marked sensitivity to heat. Nervousness, tremor, tachycardia and increased appetite associated with loss of weight occur.

• There are several types of hyperthyroidism, but only two are common: diffuse toxic goitre (also called Graves’ disease or exophthalmic goitre) and toxic nodular goitre.

Hypersecretion of TSH or T3 or T4

42 26 Sep 2019



• First-line treatment (particularly in USA).

• The isotope used is 131I (usually as sodium salt).

• Given orally; taken up & processed by the thyroid

in the same way as the stable form of iodide, eventually becoming incorporated into thyroglobulin.

• The isotope emits both, β radiation (short range) and γ rays.

• γ rays do not cause damage, but the β particles are absorbed by the tissue and exert a powerful cytotoxic action affecting only thyroid follicle cells, resulting in significant destruction of the tissue.

Radioiodine cont.

• T1/2 of 8 days and by 2 months its radioactivity has effectively disappeared.

• Given as one single dose, but its cytotoxic effect on the gland is delayed for 1-2 months and does not reach its maximum for a further 2 months.

• Hypothyroidism will eventually occur.

• Contraindication: Pregnant women or nursing mothers, since it crosses the placenta to destroy the fetal thyroid gland, and is

excreted in breast milk.

Thioamides or thioureylenes

• Carbimazole, methimazole, propylthiouracil.

• They prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions and blocking iodine organification, thus reducing iodination of


• In addition, they block coupling of the iodotyrosines.

• Given orally.

• Used for hyperthyroidism either to prepare patients

for thyroidectomy or for long-term management.

• Carbimazole is a prodrug, is converted to

methimazole in vivo (is widely used in UK).

• Methimazole is about 10 times more potent than


Thioamides or thioureylenes cont.

• Propylthiouracil may be used in patients who suffer sensitivity reactions to carbimazole.

• They cross the placenta and also appear in the milk,

but this effect is less pronounced with propylthiouracil, because it is more strongly bound to plasma protein. They should be used with caution during pregnancy.

• After degradation, the metabolites are excreted in the urine.

• ADR: Nausea, mild GI disturbances, headache, rashes and pruritus, arthralgia; rarely myopathy, alopecia, bone marrow suppression including pancytopenia and agranulocytosis, jaundice.

Ionic inhibitors

• Iodine/iodide.

• Iodine is converted in vivo to iodide (I-).

• Iodine is given orally in high doses in a solution

with potassium iodide (‘Lugol’s iodine’).

• Transiently reduces thyroid hormone secretion and

decreases vascularity of the gland.

• Indications: Thyrotoxicosis (pre-operative) and as

part of the treatment of severe thyrotoxic crisis

(thyroid storm).

• Allergic reactions can occur (these include angio-

oedema, rashes, drug fever, lacrimation, conjunctivitis, pain in the salivary glands and a cold-like syndrome).

Other drugs used

• β-blockers (e.g. propranolol) are useful for decreasing many of the signs and symptoms of hyperthyroidism (tachycardia, dysrhythmias, tremor and agitation). They are used:

–During the preparation of thyrotoxic patients for surgery.

–In most hyperthyroid patients during the initial treatment period while the thioamides or radioiodine take effect.

– As part of the treatment of acute hyperthyroid crisis.

• Guanethidine (noradrenergic-blocking agent) used in eye drops to ameliorate the exophthalmos of


• Glucocorticoids (e.g. prednisolone) may be needed to

mitigate severe exophthalmia in Graves’ disease.

43 26 Sep 2019


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parathyroid hormone

The Parathyroid Glands • Most people have four

• On posterior surface of thyroid gland

(sometimes embedded)

Hormone –

↑ number & activity of


Most important hormone in regulation of Ca2+ balance.


Parathyroids (two types of cells)

• Rarechiefcells

• Abundantoxyphilcells

(unknown function)

• ChiefcellsproducePTH

– Parathyroid hormone, or parathormone

– A small protein hormone


• •

• •

Function of PTH (parathyroid hormone or “parathormone”)

Increases blood Ca++ (calcium) concentration when it gets too low

Mechanism of raising blood calcium

1. Stimulates osteoclasts to release more Ca++ from bone

2. Decreases secretion of Ca++ by kidney

3. Activates Vitamin D, which stimulates the uptake of Ca++ from the intestine

Unwitting removal during thyroidectomy was lethal

Has opposite effect on calcium as calcitonin (which

lowers Ca++ levels)

Human, bovine, and porcine PTH molecules are all single polypeptide chains of 84 amino acids with molecular masses of approximately 9500 daltons. Biological activity is associated with the N-terminal portion of the peptide;

residues 1 to 27 are required for optimal binding to the

PTH receptor and hormone activity.



↑ bone resorption, which ↑blood Ca2+ & HPO42-

Kidney changes: ↑ rate of removal of Ca2+ & Mg2+ from urine & return to blood

Net effect – ↑circulating Ca2+ & ↓ HPO42- Calcitonin is PTH antagonist

Also promotes formation of calcitriol from vitamin D, which increases rate of Ca2+, Mg2+, & HPO42- from GI

Control – Negative feedback via blood Ca2+ levels

Physiological Functions. The primary function of PTH is to maintain a constant concentration of Ca2+ in the extracellular fluid. The principal processes regulated are renal Ca2+ absorption and mobilization of bone Ca2+

44 26 Sep 2019


Alterations of parathyroid function

 Hyperparathyroidism is characterized by greater than normal secretion of parathormone (PTH)

Three types do exist:

primary – PTH secretion is autonomous and not under

the usual feedback control mechanism

secondary – compensatory response of parathyroid glands to chronic hypocalcemia

tertiary – loss of sensitivity of hyperplastic parathyroid gland  level of autonomous secretion of PTH

The main manifestations of hyperparathyroidism and mechanisms of their onset

a) renal colic, nephrolithiasis, recurrent urinary tract infections, renal failure:

– they result from hypercalcemia, calciuria, hyperphosphaturia, proximal tubular bicarbonate leak, urine pH  6

Mechanisms: – calcium phosphate salts precipitate in alkaline urine in renal pelvis, and in collecting ducts

b) abdominal pain, peptic ulcer disease

– result from hypercalcemia  stimulated hypergastrinemia   elevated HCl secretion

g) polyuria, polydipsia

– they result from direct effect of hypercalcemia on renal tubule   responsiveness to ADH

h) constipation – is due to decreased peristalsis induced by hypercalcemia (smooth muscle weakness)

i) anorexia, nausea, vomiting – due to stimulation of vomiting center by hypercalcemia

j) hypertension – due to secondary renal disease

c) pancreatitis – due to hypercalcemia

d) bone disease – osteitis fibrosa and cystica; osteoporosis results from PTH hypersecretion stimulated bone resorption

and metabolic acidosis

e) muscle weakness, myalgia

– probably due to PTH excess and its direct effect on striated muscle and on nerves  myopathic changes, suppressed nerve conduction

f) neurologic and psychiatric alterations

– result from hypercalcemia  neuropathy develops


is characteristic by abnormally low PTH levels

b) lowering of the threshold for nerve and muscle excitation

– muscle spasms, hyperreflexia, clonic – tonic convulsions, laryngeal spasms – tetany

c) dry skin, loss of body and scalp hair, hypoplasia of developing teeth, horizontal ridges on the nails, cataracts, basal ganglia calcifications (Parkinsonian sy.)

Mechanisms involved: unknown up to now

d) hyperphosphatemia  inhibition of renal enzyme necessary for

the conversion of vitamin D to its most active form further depression of serum calcium level by reducing GIT absorption of calcium.

Causes: – damage to the parathyroid gland due to thyroid surgery


a) depressed serum calcium level and increased serum phosphate level

Mechanisms involved:

–  resorption of Ca from GIT, from bone and from renal tubules

- reabsorption of phosphates by the renal tubules

45 26 Sep 2019



are drugs that mimic the stimulatory effect of calcium to inhibit PTH secretion by the parathyroid glands; adverse event with cinacalcet is hypocalcemia .

PTH acts chiefly on the kidney increasing

renal tubular reabsorption and bone resorption of

calcium; it increases calcium absorption from the gut, indirectly, by stimulating the renal synthesis of 25-hydroxycholecalciferol (calcifediol).

It increases the rate of bone remodelling (mineral and collagen) and osteocyte activity with, at high doses,

an overall balance in favour of resorption (osteoclast activity) with a rise in plasma calcium concentration (and fall in phosphate); but, at low doses, the

balance favours bone formation (osteoblast activity).

Parathyroid hormone (PTH)

• Calcitonin is a hypocalcemic hormone whose actions generally oppose those of PTH.

• ChemistryandImmunoreactivity.Calcitoninisasingle- chain peptide of 32 amino acids with a disulfide bridge linking the cysteine residues in positions 1 and 7.

• RegulationofSecretion.Thebiosynthesisandsecretionof calcitonin are regulated by the plasma Ca2+ concentration. Calcitonin secretion increases when plasma Ca2+ is high and decreases when plasma Ca2+ is low.

• Calcitonin secretion is stimulated by a number of agents, including catecholamines, glucagon, gastrin, and cholecystokinin, but there is little evidence for a physiological role for secretion in response to these stimuli.

Mechanism of Action. Calcitonin actions are mediated by the calcitonin receptor (CTR), which is a member of the PTH/secretin subfamily of GPCRs.The hypocalcemic and hypophosphatemic effects of calcitonin are caused predominantly by direct inhibition of osteoclastic bone resorption.

Although calcitonin inhibits the effects of PTH on osteolysis, it inhibits neither PTH activation of bone cell adenylyl cyclase nor PTH-induced uptake of Ca2+ into bone. Calcitonin interacts directly with receptors on osteoclasts to produce a rapid and profound decrease in ruffled border surface area, thereby diminishing resorptive activity.

Depressed bone resorption reduces urinary excretion of Ca2+, Mg2+, and hydroxyproline. Plasma phosphate concentrations are lowered owing also to increased urinary phosphate excretion. Direct renal effects of calcitonin vary with species.

Agents affecting calcification and bone turnover

Hypercalcemia. Hypercalcemia can be life-threatening. Such patients frequently are severely dehydrated because hypercalcemia compromises renal concentrating mechanisms. Thus, fluid resuscitation with large volumes of isotonic saline must be early and aggressive (6 to 8 L/day). Agents that augment Ca2+ excretion, such as loop diuretics.

Corticosteroids administered at high doses (e.g., 40 to 80 mg/day of prednisone) may be useful when hypercalcemia results from sarcoidosis, lymphoma, or hypervitaminosis D.

Calcitonin (CALCIMAR, MIACALCIN) may be useful in managing hypercalcemia. Reduction in Ca2+ can be rapid, although “escape” from the hormone commonly occurs within several days.

• The recommended starting dose is 4 units/kg of body weight administered subcutaneously every 12 hours; if there is no response within 1 or 2 days, the dose may be increased to a maximum of 8 units/kg every 12 hours.

• Plicamycin (mithramycin, MITHRACIN) is a cytotoxic antibiotic that also decreases plasma Ca2+ concentrations by inhibiting bone resorption. Reduction in plasma Ca2+ concentrations occurs within 24 to 48 hours when a relatively low dose of this agent is given (15 to 25 mg/kg of body weight) to minimize the high systemic toxicity of the drug.

• Intravenous bisphosphonates (pamidronate, zoledronate) have proven very effective in the management of hypercalcemia . These agents potently inhibit osteoclastic bone resorption.

46 26 Sep 2019


• OralsodiumphosphatelowersplasmaCa2+concentrations and may offer short-term calcemic control of some patients with primary hyperparathyroidism who are awaiting surgery. However, the risk of precipitating calcium phosphate salts in soft tissues throughout the body is of concern.

• HypocalcemiaandOtherTherapeuticUsesofCalcium. Hypoparathyroidism is treated primarily with vitamin D . Dietary supplementation with Ca2+ also may be necessary.

Calcium is used in the treatment of calcium deficiency states and as a dietary supplement. Ca2+ salts are specific in the immediate treatment of hypocalcemic tetany regardless of etiology.


– calcium

• Calcium:Ca2+,theionizedformofelementalcalcium,is

essential for the Ca2+ component of current flow across excitable membranes, fusion and release of storage vesicles, and muscle contraction. Intracellular Ca2+ also acts in the submicromolar range as a critical second messenger.

• Achangeinplasmaalbuminconcentrationof1.0g/dlfrom the normal value of 4.0 g/dl can be expected to alter total calcium concentration by approximately 0.8 mg/dl.

The extracellular Ca2+ concentration is tightly controlled by hormones that affect its entry at the intestine and its exit at the kidney; when needed, these same hormones regulate withdrawal from the large skeletal reservoir.

• Calcium Stores. The skeleton contains 99% of total body calcium in a crystalline form resembling the mineral hydroxyapatite [Ca10(PO4)6(OH)2]; other ions, including Na+, K+, Mg2+, and F-, also are present in the crystal lattice.

• CalciumAbsorptionandExcretion.IntheUnitedStates, about 75% of dietary calcium is obtained from milk and dairy products. The adequate intake value for calcium is 1300 mg/day in adolescents and 1000 mg/day in adults. After age 50, the adequate intake is 1200 mg/day.

• The efficiency of intestinal Ca2+ absorption is inversely related to calcium intake. Thus, a diet low in calcium leads to a compensatory increase in fractional absorption owing partly to activation of vitamin D.

Phosphate :In addition to its roles as a dynamic constituent of intermediary and energy metabolism and as a key regulator of enzyme activity when transferred by protein kinases from ATP to phosphorylatable serine, threonine, and tyrosine residues, phosphate is an essential component of all body tissues, being present in plasma, extracellular fluid, cell membrane phospholipids, intracellular fluid, collagen, and bone tissue. More than 80% of total body phosphorus is found in bone, and about 15% is in soft tissue.

Biologically, phosphorus (P) exists in both organic and inorganic forms. Organic forms include phospholipids and various organic esters.

In extracellular fluid, the bulk of phosphorus exists as inorganic phosphate in the form of NaH2PO4 and Na2HPO4; the ratio of disodium to monosodium phosphate at pH 7.40 is 4:1,

Absorption, Distribution, and Excretion. Phosphate is absorbed from and to a limited extent secreted into the gastrointestinal tract. Phosphate is a ubiquitous component of ordinary foods; thus, an inadequate diet rarely causes phosphate depletion.

47 26 Sep 2019


• RoleofPhosphateinUrineAcidification.Despitethefactthat the concentration and buffering capacity of phosphate in extracellular fluid are low, phosphate is concentrated progressively in the renal tubule and becomes the most abundant buffer system in the distal tubule and terminal nephron.

• The exchange of H+ and Na+ in the tubular urine converts disodium hydrogen phosphate (Na2HPO4) to sodium dihydrogen phosphate (NaH2PO4), permitting the excretion of large amounts of acid without lowering the urine pH to a degree that would block H+ transport.

• ActionsofPhosphateIon.Iflargeamountsofphosphateare introduced into the gastrointestinal tract by oral administration or enema, a cathartic action will result. Thus phosphate salts are employed as mild laxatives.

vitamin D,

Skin • Skin – Cholecalciferol

Inactive vitamin D formed by UV radiation  liver  kidney for full activation [calcitriol].

Essential for calcium absorption from intestines.

• VitaminD

Vitamin D traditionally was viewed as a permissive factor in calcium metabolism because it was thought to permit efficient absorption of dietary calcium and to allow full expression of the actions of PTH. We now know that vitamin D exerts a more active role in calcium homeostasis.

• Receptors for the activated form of vitamin D are expressed in many cells that are not involved in calcium homeostasis, including hematopoietic cells, lymphocytes, epidermal cells, pancreatic islets, muscle, and neurons.

• ChemistryandOccurrence.Ultravioletirradiationofseveral animal and plant sterols results in their conversion to compounds possessing vitamin D activity. The principal provitamin found in animal tissues is 7 dehydrocholesterol, which is synthesized in the skin. Exposure of the skin to sunlight converts 7 dehydrocholesterol to cholecalciferol (vitamin D3)

• There is no consensus regarding optimal vitamin D intake, and determination of vitamin D requirements is remarkably unsupported by clinical measurements. The recommended dietary allowance of vitamin D for infants and children is 400 IU, or 10 mg.

• Absorption,Fate,andExcretion.BothvitaminsD2andD3are absorbed from the small intestine, although vitamin D3 may be absorbed more efficiently. Most of the vitamin appears first within chylomicrons in lymph. Bile is essential for adequate absorption of vitamin D; deoxycholic acid is the major constituent of bile in this regard

• MetabolicActivation.Whetherderivedfromdietor endogenously synthesized, vitamin D requires modification to become biologically active. The primary active metabolite of the vitamin is calcitriol [1a,25-dihydroxyvitamin D, 1,25(OH)2D], the product of two successive hydroxylations of vitamin D

• 25-Hydroxylation of Vitamin D. The initial step in vitamin D activation occurs in the liver, where cholecalciferol and ergocalciferol are hydroxylated in the 25-position to generate 25-OH-cholecalciferol (25-OHD, or calcifediol) and 25-OH- ergocalciferol, respectively.

• 1a-Hydroxylation of 25-OHD. After production in the liver, 25- OHD enters the circulation and is carried by vitamin D-binding globulin. Final activation to calcitriol occurs primarily in the kidney but also takes place in other sites, including keratinocytes and macrophages

48 26 Sep 2019


• 24-Hydroxylase. Calcitriol and 25-OHD are hydroxylated to 1,24,25(OH)2D and 24,25(OH)2D, respectively, by another renal enzyme, 24-hydroxylase, whose expression is induced by calcitriol and suppressed by factors that stimulate the 25-OHD- 1a-hydroxylase.

• PhysiologicalFunctionsandMechanismofAction.Calcitriol augments absorption and retention of Ca2+ and phosphate. Although regulation of Ca2+ homeostasis is considered to be its primary function, accumulating evidence underscores the importance of calcitriol in a number of other processes.

• The mechanism of action of calcitriol is mediated by the interaction of calcitriol with the vitamin D receptor (VDR). Calcitriol binds to cytosolic VDRs within target cells, and the receptor-hormone complex translocates to the nucleus and interacts with DNA to modify gene transcription.

• IntestinalAbsorptionofCalcium.Calciumisabsorbed predominantly in the duodenum, with progressively smaller amounts in the jejunum and ileum. The colon also contributes to calcium absorption because ileostomy reduces absorption.

• RenalRetentionofCalciumandPhosphate.Theeffectsof calcitriol on the renal handling of Ca2+ and phosphate are of uncertain importance. Calcitriol increases retention of Ca2+ independently of phosphate.

Calcitriol affects maturation and differentiation of mononuclear cells and influences cytokine production and immune function

Clinical anatomy and physiology of small and large intestine



absorption Calcium


Large intestine


Pancreatic enzymes

Oil-soluble vitamins

Amino acids

Fatty acids

Bile acids


excretion motility

Magnesium Iron


Water-soluble vitamins

Vitamin B12


Serotonin is the main neuromediator that regulates the gut activity


– Serotonin

– Acetylcholine

– Nitric oxide

– Substance C

– Vasoactive intestinal peptide – Cholecystokinin

Visceral sensytivity

– Serotonin

– Calcitonin

– Neurokinin A – Enkephalin


– Serotonin

– Acetylcholine




Diarrhea Constipation Anorexia Weight loss Abdominal pain Bloating Meteorism

Syndrome of intestinal dyspepsia Maldigestion syndrome Malabsorbtion syndrome

Bleeding from lower part of GI tract Acute abdomen

Irritable bowl syndrome


Whipple’s disease Lactase insufficiency Inflammatory bowl diseases:

Crone’s disease Ulcerative colitis

Cardinal symptoms of lower part of gastrointestinal tract disorders


Small intestine 26 Sep 2019


1. 2. 3.


Transit of soft stools with a lot of fluid > 3 times per day

Imperative demand of defecation

«small intestine»

•Without blood or mucus •Without tenesmus

•Polyfecalia but not very frequent


•A touch of blood or mucus •Tenesmus

•Stool is frequent but with small portions

«large intestine»

Diarrhea: types, etiology, pathogenesis

Acute (up to 1-2 weeks)

Food poisoning (due for microbs or not)

Bacterial infections: E.coli, Shigella, Salmonella, Campylobacter, Yersinia Viral infections: Rotavirus Protozoan infections: Entamoeba, Giardia lamblia


antibiotics (Сl.deficile)


antacids (Mg)

anticholinesterase drugs


preparations withAu


cardiac glycosides

Chronic (> 4 weeks)

Osmotic diarrhea (osmotic laxatives and lactose)

Secretory diarrhea (bacterial toxins, hormones, fatty and bile acids, laxatives)

Inflammatory diarrhea (infections, inflammatory bowl diseases, celiacia, lymphoma, iscemia)

Hypermotoric diarrhea (irritated bowl syndrome)

• •

Diagnosis of diarrhea

If chronic – full investigation in every case

Acute – investigation is indicated if there are “signs of anxiety” or special anamnesis’ data

Plan of investigation depend on anamnesis data

Signs of anxiety

• Symptoms >48 hours

• Severe pain

• Body temperature >38,9°С

• Blood or helminthes in stool

• Signs of dehydration (dry mouth, thirst, reduction of skin turgor, oligo- or anuria, vertigo)

Principles of treatment of diarrhea

• Elimination of the cause

• Correction of water and electrolytes disorders • In some cases – antidiarrheal agents

50 26 Sep 2019


Diagnostic criteria of constipation 1) 2 or more of criteria listed below:

1. Straining efforts in course of defecation at least in 25% of defecations

2. Solid stool at least in 25% of defecations

3. Feeling of incomplete evacuation at least in 25% of defecations

4. Feeling of anorectal obstruction at least in 25% of defecations

5. Need in hand manipulation to facilitate the defecation at least

in 25% of defecations

6. Less than 3 defecations per week

2) Liquid [watery] stool without laxatives – a very rare event

Malabsorbtion syndrome

Maldigestion syndrome – insufficiency of digestion

• Maldigestion – impaired digestion of food

• Cause – enzymes deficiency (congenital or acquired)

• It may be due to impairment of:

luminal digestion, membrane digestion, intracellular digestion, mixed forms

• Clinical manifestation: diarrhea, meteorism, other dyspeptic disorders

• It is a component of malabsorption syndrome

51 26 Sep 2019


Malabsorption syndrome: key points

• Malabsorption – disorder of absorption of one or more nutritive materials in small intestine with impairment of metabolic processes

• There are congenital and acquired forms

• Intestinal manifestations: diarrhea, polyfecalia, steatorrhea,

creatorrhea, amylorrhea

• Malabsorption syndrome affects the metabolism of proteins, carbohydrates, fat, vitamins, minerals, water and electrolytes

Malabsorption syndrome: causes

• Enterogenic – enteritis, Crone’s disease, infections, parasites, ischemia • Gastrogenic – peptic ulcer, gastritis, cancer

• Pancreatogenic – pancreatitis, mucoviscidosis, tumors

• Hepatogenic – acute and chronic liver diseases

• Postresection state

•Endocrinogenic – DM, disthyreosis

• Drugs

• Radiation

Pathogenic factors

• enzimopathy

• damage of specific transport mechanisms • immunologic disorders

• small intestine bacterial overgrowth

• motility abnormalities

• morphologic changes of mucose


•Gross malnutrition is usually easy to recognize

•Lesser degrees may be difficult to detect, particularly if oedema is present

•Malnutrition may be due to starvation, to maldigestion of food or to malabsorption


•The clinical history

•The physical examination

•More subtle indices of malnutrition include muscle function tests and evaluation of creatinine excretion and levels of albumin, hemoglobin, ferritin and iron-binding capacity, prothrombin time

• •

• •

Diagnosis of malabsorption

Blood tests – detection of nutrients deficiency

↓albumin, cholesterol, iron, calcium, magnesium, vitamin A, folic acid

Stool tests

steatorrhea, creatorrhea, amylorrhea, рН <6,0 big fecal mass (>500 g/day),

amount of fat in stool >6 g/day

Assessment of absorption function with specific tests

absorption test with D-xilose Schilling test

Instrumental methods

X-ray investigation of small intestine abdominal ultrasound

endoscopy of small intestine with biopsy

52 26 Sep 2019


Treatment of malabsorption syndrome

1. Treatment of basic disease

2. Correction of absorption disorders:

• Diet with high protein and low fat intake or special


• Replacement therapy with vitamins A, D, Е, К, В12, folic acid

and iron preparations

• enzymes

• In case of increased peristalsis – loperamid, in sever cases – octreotid

• binding and enveloping (smekta and other)

Celiac disease (gluten enteropathy): key points

• Genetic disease- deficiency of peptidase that hydrolise the protein gluten

of cereals (wheat, rye, and barley)

• Accumulation of gluten and gliadin → autoimmune inflamation → death

of villi and damage of intestine mucosa

• Clinical picture: malabsorption. Commonly – minimal signs: osteoporosis,

anemia without gastrointestinal manifestations

• Diagnosis:

biopsy of small intestine

serological tests: antibodies to gliadin, endomiosin, reticulin

• Treatment: aglutenic diet, in sever cases – glucocorticoides

Celiac disease biopsy of small intestine

normal pathology

First described in 1907

Whipple’s disease

Etiology: Tropheryma Whipplei [trophi (nutrition) и eryma (barier)], first successful culture was received in 2000.

Prevalence: a rare disease, male:female8:1, mean age 50

Clinical manifestations: malabsorption syndrome, diarrhea, weight loss, fever, arthritis

and arthralgias, cardiac involvment

Diagnosis: biopsy of small intestine. Specific sign – infiltration of mucosa with big macrophages with SHIK-positive granules. In the cells – T. Whipplei.

Treatment: antibiotics

Whipple’s disease

Functional bowl disorders

Functional meteorism

Functional constipation

Functional diarrhea

 Irritable bowl syndrome

 Undifferentiated functional bowl disorders

53 26 Sep 2019


Irritable Bowel Syndrome

Irritable bowel syndrome

• IBS has probably existed for a long time and under many names.

• There is increasing awareness of its importance in the community, family practice, and gastroenterology.

• IBS is not a disorder defined by an unequivocal pathophysiology or a uniform clinical presentation.

• The definition of IBS is based on the clinician recognizing a frequently occurring symptom cluster.

• The general acceptance of that cluster has been formalized in consensus conferences, creating the regulary updated ‘Rome criteria’.

Irritable Bowl syndrome


15% of adult population

Etiology not clear

Visceral hypersensitivity Motility disorder Neurotransmitter inbalance  Infection

Psychosocial factors

Visceral Sensitivity in IBS


Dorsal root ganglion Brain stem Ascending pain pathway

Spinal cord


Diagnostic criteria of IBS Rome criteria III (2006 г.)

•Recurrent abdominal pains or discomfort: 3 days per month 3 previous months


Any 2 or more of down listed criteria: • Relief after defecation; and/or

• Start is associated with changed frequency of stool; and/or • Start is associated with changed consistency of stool

* Presence of named criteria during last 3 months, if first manifestation appeared 6 months before diagnosis

Clinical variants of IBS

pain syndrome + diarrhea

pain syndrome + constipation

pain syndrome + diarrhea / constipation

Diarrhea & Diarrhea, constipation pain &


Constipation & pain

54 26 Sep 2019


IBS: clinical manifestations

Abdominal pain and discomfort – usually not localized, variable

Change of frequency and/or character of stool

 bloating

 urgency

feeling of incomplete evacuation mucous in the stool

chest pain, headache heartburn

nausea or dyspepsia

difficult swallowing

sensation of a lump in the throat

“Red Flags”

Additional diagnostic screening needed for atypical presentations

such as:

• Anemia

• Fever

• Persistent diarrhea

• Rectal bleeding

• Severe constipation

• Weight loss

• Nocturnal symptoms of pain and abnormal bowel function

• Family history of GI cancer, inflammatory bowel disease, or celiac disease

• New onset of symptoms in patients 50+ years of age

Differential Diagnosis

• Inflammatory bowel disease

• Infection (Giardia lamblia )

• Peptic ulcer disease

• Motility disorders

• Chronic pancreatitis

• Malabsorption/Bacterial


• Gynecological disorders

Management of IBS

Positive diagnosis of the syndrome, exclusion of organic disorders

Life style modification

↑ fibers consumption, change of nutrition character, assessment of patient’s psychological status

Symptomatic therapy

Antagonists/agonists of serotoninergic receptors

Alternative therapy


Alosetron (Lotronecs) (in case of diarrhea)



Tegaserod (Zelnorm) (in case of constipation)

Holistic therapy


Correction cognitive changes



Inflammatory bowel disease (IBD)

A general term for a group of chronic inflammatory disorders of unknown cause involving the gastrointestinal tract.

• may be divided into two major groups – chronic nonspecific ulcerative colitis (UC) – Crohn’sdisease(CD)

• While the occurrence of both diseases peaks between the ages of 15 and 35, they have been reported from every decade of life.

• While the causes of UC and CD remain unknown, certain features of these diseases have suggested several areas of possible importance. These include familial or genetic, infectious, immunologic, and psychological factors

55 26 Sep 2019


Inflammatory bowel disease

• Nonspecificulcerative colitis (UC)

• Crohn’sdisease(CD)

Crohn’s disease

Nonspecific ulcerative colitis

Colitis of unknown etiology

Crohn’s disease

• Etiologyisunknown


Nonspecific ulcerative colitis

• Geneticandimmunologicalfactorsleadtoabnormalitiesin recognizing auto antigens in GIT

Ulcerative colitis

Crohn’s disease

Localization of damage

Volume of damage Depth of damage

Ulcerative colitis

• Chronic diffuse inflammation of large intestine with edema and superficial ulceration of mucosa

• Starts always from damage of rectum, and than the process involves other parts of large intestine

• Symptoms: rectal bleeding, fever, diarrhea, abdominal pain, moderate anemia.


– Toxic megacolon (dilation of the gut with

thinning of gut wall, high risk of perforation)

– Large intestine carcinoma (constant regeneration of epithelium—> displasia).

Crohn’s disease

• Chronic granulematose (in some cases transmural) inflammation of the gut wall of unknown origin

• Damage may be localized in any part of GIT from oral cavity up to anus, damaged areas, crypt abscesses

• 45%: terminal ilea involvement and larg intestine

• 33%: small intestine

• 25%: large intestine

• Symptoms: abdominal pain, diarrhea, fever


• Strictures, fistulas


• Gall bladder stones (abnormalities of bile acids absorption)

• Hydronephrosis (adhesion of ureter to stricture)

• Adenocarcinoma of large intestine, anal zone)

Extraintestinal manifestations of inflammatory diseases of intestine

56 26 Sep 2019











Abdominal pain Trasmural damage

Granulomas Cobblestoning mucosa Asymmetria Involvement of ilea

Rectal damage

Rectal bleeding Strictures, fistulas Crypt abscesses

Differential diagnosis of IBD


± – + ± ±


++ ±

+++ –

Treatment of IBD

Experimental treatment (IL 10, azathioprin iv)

Inhibitor of tumor necrosis factor α (TNF α)




Sulfonamides, salysilates

Motility Agents

Adverse Effects

Laxatives that contain sodium, phosphate,

or magnesium will be absorbed and excreted through the kidneys. The absorbed ion load may produce

• CNSdepression

• Cardiacarrhythmias

• Edemainrenalimpairedpatients

• Depressedmusclefunction

Osmotic laxatives can cause a large loss of water leading to dehydration, especially in elderly patients

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BIPOLAR DISORDER & Vulnerable Populations

• Antidepressants

• Mania

• Anxiety

• Drugs in Pregnancy

• Geriatric Pharmacology

• Herbals and Supplements regulations • Newer drugs


• Major depression may well represent a spectrum of disorders, varying in severity from mild and self-limited conditions that approach everyday human distress to extraordinarily severe, psychotic, incapacitating, and deadly diseases.

• Rates of diagnosis and appropriate treatment of major mood disorders have improved somewhat in recent years with the advent of better-accepted and safer mood-altering medicines.

• Nevertheless, the majority of patients with depression or bipolar disorder are diagnosed after years of delay, if at all, and many remain inadequately treated or studied, especially children, the elderly, those with bipolar depression, and those with severe, chronic, or psychotic forms of depression.

• all currently available antidepressants, except bupropion, are classified as having their primary actions on the metabolism, reuptake, or selective receptor antagonism of serotonin, norepinephrine, or both

• •

• •


There is no definitive link between discrete biological lesions and the

pathogenesis of the most severe mental illnesses (other than delirium and the dementias).

Even without such a link, we can provide effective medical treatment for psychiatric patients. It would be clinical folly to underestimate the importance of psychological and social factors in the manifestations of mental illnesses or to overlook psychological aspects of the conduct of biological therapies

Moreover, results of genetic studies have demonstrated that inheritance accounts for only a portion of the causation of mental illnesses, leaving room for environmental and psychological hypotheses.

Current brain imaging and biochemical studies in patients do not support a single biologic abnormality instead prevailing hypotheses emphasize an underlying role for several brain circuits that have a propensity to become dysfunctional, especially following certain stressors, in individuals with a range of genetic predispositions.

• The monoamine theory of depression

• A leading hypothesis that arose from such considerations was that antidepressants enhance the biological activity of monoamine neurotransmitters in the CNS and that anti-adrenergic compounds may induce depression.

• These observations led to speculation that a deficiency of aminergic transmission in the CNS might cause depression, whereas an excess may result in mania.

Evidence implicates alterations in the firing patterns of a subset of biogenic amines in the CNS, Norepinephrine (NE) and Serotonin (5-HT).

Activity of NE and 5 -HT systems?.

Turnover of Biogenic Amines:Dopamine–Synthesis: tyrosine AH L- DOPA AADC dopamine

–Origin: substantia nigra, ventral tegmental area–Targets: basal ganglia, cerebral cortex

• Norepinephrine–Synthesis: dopamine DβHβ Norepinephrine –Origin: locus ceruleus–Targets: cerebral cortex

Serotonin–Synthesis: tryptophan TPH 5-HTP AADC serotonin –Origin:raphenuclei–Targets: cortex, basal ganglia, hippocampus,

58 26 Sep 2019


• Molecular mechanisms of anti depressants

• Most antidepressants exert important actions on the metabolism of monoamine neurotransmitters and their receptors, particularly norepinephrine and serotonin

• The development of reversible, selective MAO inhibitors with potentially broad applications (e.g., selegiline[eldepryl] for Parkinson’s disease) was stimulated by the understanding that the early MAO inhibitors result in irreversible and nonselective blockade of both MAO-A and MAO-B, which were responsible for the metabolic breakdown of dopamine, norepinephrine, and serotonin in neuronal tissues.

• Three other MAO inhibitors that are used for purposes unrelated to MAO inhibition are furazolidone (FUROXONE, an anti-infective); procarbazine (MATULANE; N-methylhydrazine, indicated for the treatment of Hodgkin’s disease); and linezolid (ZYVOX, an antibiotic used for serious infections).

Available Antidepressants

• 1) Tricyclics and Tetracyclics (TCA):Imipramine , Doxepin Desipramine ,

Amoxepine, Trimipramine,Maprotiline Clomipramine , Amitriptyline, Nortriptyline,Protriptyline

• 2) Monoamine Oxidase Inhibitors (MAOIs) Tranylcypramine Phenelzine Moclobemide

• 3) Serotonin Selective Reuptake Inhibitors (SSRIs):Fluoxetine,Fluvoxamine Sertraline, Paroxetine, Citalopram

• 4) Dual Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) Venlafaxine Duloxetine

• 5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs) Nefazodone Trazodone

• 6) Norepinephrine and Dopamine Reuptake Inhibitor (NDRI):Bupropion

• 7) Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs)


• 8) Noradrenalin Specific Reuptake Inhibitor (NRI):Reboxetine

• 9) Serotonin Reuptake Enhancer:Tianeptine

Dopamine pathways do many things:Control flow of blood through the brain

Motor control (nigrostriatal) system :

Behavioural control

• Dopamine is the brain’s motivational chemical. It works on

glutamate synapses to modulate their excitability.

A shortage of brain dopamine causes an indecisive personality, unable to initiate even the body’s own movement. Parkinson’s disease. Time stops.L-DOPA therapy.

Excess dopamine, more arousal. Attention defecit .disorder. May cause schizophrenia.Dopamine’s action is essential for drug addiction.


Polymorphisms of genes involved in aminergic (dopamine/serotonin) neurotransmission

Effects on personality?

Dopamine D4 receptor – novelty seeking Promoter of serotonin transporter gene – harm avoidance/anxiety

Other neuromodulators (NE, serotonin) probably

work in a similar way to dopamine

They assist with the selection/maintenance of different neural ensembles

Biogenic Theory of Depression

• The precise cause of affective disorders remains elusive.

• Evidence implicates alterations in the firing patterns of a subset of biogenic amines in the CNS, Norepinephrine (NE) and Serotonin (5-HT).

Activity of NE and 5 -HT systems?

The monoamines:Dopamine;Epinephrine (adrenergic);Norepinephrine(noradrenergic);Serotonin


Cl- Na+

Cl- Na+


GABAA receptor


Glutamate/AMPA receptor


59 26 Sep 2019


The purpose of antidepressants is to increase the [neurotransmitters] in the synapse


1. Processing signals relate to plain & pleasure. Regulating body homeostasis

2. Emotion and feeling

3. Attention

4. Wakefulness & sleep

5. learning

The construction of consciousness.

Fast: GABA, glutamate, acetylcholine

Slow: biogenic amines:Dopamine;Serotonin/5-HT


Ion pumps

Ion channels

Neurotransmitter receptors

Neurotransmitter receptors

Second messengers

Protein kinases

Transcription Factors Cell nucleus

Neuromodulatory inputs




Neuromodulatory inputs





Excitatory input




1 D1



Ca2+-dependent Kinases/phosphatases

Down-stream substrates

Gene expression




IP3 + DG

Short-term synaptic modification

Long-term synaptic modification

NE System

Almost all NE pathways in the brain originate from the cell bodies of neuronal cells in the locus coereleus in the midbrain, which send their axons diffusely to the cortex, cerebellum and limbic areas (hippocampus, amygdala, hypothalamus, thalamus).

• Mood: — higher functions performed by the cortex.

• Cognitive function: — function of cortex.

• Drive and motivation: — function of brainstem

• Memory and emotion: — function of the

hippocampus and amygdala.

• Endocrine response: — function of hypothalamus.

 and  receptors.

NE potentiation of responses to GABA

Purkinje cells

A synapse that uses norepinephrine (NE)

60 26 Sep 2019


MAO Inhibitors

Monoamine oxidase, located on outer membrane of mitochondria; deaminates catecholamines free in nerve terminal that are not protected by vesicles


Selective inhibitor, reboxetine

Cocaine blocks the NET


GABA response




Noradrenergic potentiation of cerebellar Purkinje cell responses

to GABA: cAMP as intracellular intermediary.


Reuptake of NE

Unless -adrenergic activation of postsynaptic cell takes place…




Stabilization of LTP


Inhibition of

protein phosphatase I

Active during memory formation

Serotonin System

As with the NE system, serotonin neurons located in the pons and midbrain (in groups known as raphe nuclei) send their projections diffusely to the cortex, hippocampus, amygdala, hypothalamus, thalamus, etc. –same areas implicated in depression. This system is also involve in:

• Anxiety.

• Sleep.

• Sexual behavior.

• Rhythms (Suprachiasmatic nucleus). • Temperature regulation.

• CSF production.


61 26 Sep 2019


Noradrenergic Control of Serotonergic Release





2-AR 1-AR

5-HT1 5-HT2




A synapse that uses serotonin/5-HT

Fluoxetine/Prozac blocks the SERT

Re-uptake of 5-HT/serotonin

Treatment of depression. anxiety disorders, obsessive-compulsive disorders

• Thus, fluoxetine and fluvoxamine were the first widely used selective serotonin reuptake inhibitors (often abbreviated as SSRIs or SRIs).

• Development of these agents was paralleled by the identification of compounds with selectivity for norepinephrine reuptake, along with others effective against both serotonin and norepinephrine reuptake-again with potential for applications beyond depression and/or anxiety (e.g., atomoxetine [STRATTERA]).

• Since these agents all have a three-ring molecular core and most share pharmacological (norepinephrine-reuptake inhibition) and clinical (antidepressant and anxiolytic) properties, the name “tricyclic antidepressants” is used for this group.

• Selective Serotonin Reuptake Inhibitors. Citalopram and fluoxetine are racemates; sertraline and paroxetine are separate enantiomers. Escitalopram is the (S)-enantiomer of citalopram. Fluoxetine and its major metabolite norfluoxetine are highly active against serotonin transport and also may have antimigraine effects not found with the (R)-enantiomer of fluoxetine.

• Monoamine Oxidase Inhibitors. The nonselective MAO inhibitors in clinical use are reactive hydrazines (phenelzine and isocarboxazid) or amphetamine derivatives . Selegiline , a propargylamine, contains a reactive acetylenic bond and is relatively specific for MAO-B

• Knowledge of the pharmacological properties of antidepressant drugs remains incomplete, and coherent interpretation is limited by a lack of a compelling psychobiological theory of mood disorders. The actions of imipramine-like tricyclic antidepressants include a range of complex, secondary adaptations to their initial and sustained actions as inhibitors of norepinephrine neuronal transport (reuptake) and variable blockade of serotonin transport

Selective Serotonin Reuptake Inhibitors (SSRI’s)

• Act by inhibition of presynaptic reuptake of serotonin in central synapses. Not as sedating as many of the tricylic compounds.Also do not have the anticholinergic side effects of the tricyclics.Some are potent inhibitors of P450 enzyme systems, and may lead to drug interactions:• Fluoxetine (Prozac®),• Sertaline (Zoloft®)• Citalopam (Celexa®)• Paroxetine (Paxil®)

• Adverse effects: anxiety, tremor, Overdose of SSRI alone is rarely

lethal.Should not be administered with nonselective MAO inhibitors,

Suicide as an adverse effect?

Bupropion• Structurally related to the tricyclics, but seems to have a

different therapeutic mechanism, related to altered release of NE.Not sedating or anticholinergic, but does sometime induce hallucinations or seizures. Also effective in treating tobacco addiction

MAO Inhibitors• Non-selective, irreversible enzyme inhibitors – long duration of action.Therapeutic effect is due to is enhancement of CNS amine levels.

62 26 Sep 2019


• Therapeutic indications

• various antidepressant agents have found broad utility in other disorders that may or may not be related psychobiologically to the mood disorders.

• Encouragement to find new indications has increased with the advent of newer agents that are less toxic, simpler to use, and often better accepted by both physicians and patients

• Temporary suppression of enuresis with low (e.g., 25 mg) pre-bedtime doses of tricyclic antidepressants, including imipramine and nortriptyline, by uncertain mechanisms in children and in geriatric patients, as well as a beneficial effect of duloxetine on urinary stress incontinence

Attention-deficit/hyperactivity disorder in children and adults, for which imipramine, desipramine, and nortriptyline appear to be effective, even in patients responding poorly to or who are intolerant of the stimulants (e.g., methylphenidate) that have been the standard agents for this disorder.

Newer norepinephrine selective reuptake inhibitors also may be useful in this disorder; atomoxetine is approved for this application. Utility of SSRIs in this syndrome is not established, and bupropion, despite its similarity to stimulants, appears to have limited efficacy

Panic disorder, tricyclic antidepressants and MAO inhibitors, as well as high- potency benzodiazepines (notably alprazolam, clonazepam, and lorazepam)are effective in blocking the autonomic expression of panic itself, thus facilitating a comprehensive rehabilitation program .

Imipramine and phenelzine are well-studied antidepressants for panic disorder. SSRIs also may be effective , but b adrenergic receptor antagonists, buspirone, and low-potency benzodiazepines usually are not, and bupropion can worsen anxiety.

• SSRIs are agents of choice in obsessive-compulsive disorder, as well as in possibly related syndromes of impulse dyscontrol or obsessive preoccupations, including compulsive gambling, trichotillomania, bulimia (not anorexia) nervosa, and body dysmorphic disorder

• Tricyclic and Selective Serotonin Reuptake Inhibitors. The imipramine- like tricyclics have been largely replaced by the newer, less-toxic SSRIs and other atypical modern agents, which now are accepted broadly as drugs of first choice, particularly for medically ill or potentially suicidal patients and in the elderly and young

• The MAO inhibitors generally are considered drugs of late choice for the treatment of severe depression, even though the evidence for the efficacy of adequate doses of tranylcypromine or phenelzine is convincing.

methylphenidate or amphetamines demonstrate well-established effectiveness for the treatment of pediatric and adult attention disorder

• Buspirone has beneficial actions in anxious patients, particularly those with generalized anxiety of mild or moderate severity. Unlike potent benzodiazepines and antidepressants, buspirone lacks beneficial actions in severe anxiety with panic attacks. It is not efficacious as a monotherapy in obsessive-compulsive disorder, although it may have useful anti-obsessional activity when added to SSRIs

• Current medications (SSRIs and tricyclic antidepressants) focus on blockade of norepinephrine and serotonin uptake, thereby prolonging their synaptic effects.

• serotonin agonists (e.g., sunepitron, PRX-0002), largely for anxiety; serotonin antagonists (e.g., AR-A2, deramciclane, SB-243213), mainly for depression; agents with partial-agonist effects at dopamine and serotonin receptors, much like some atypical antipsychotics (e.g., SLV- 308, SLV-318); inhibitors of MAO-A (moclobemide, selegiline)

• Treatment of depression

• Many patients will not report symptoms of depression unless asked specifically.

Patients who are depressed may be suicidal – it is essential to inquiry about their intentions

• The response of an individual patient to a particular antidepressant cannot be predicted, and treatment often requires sequential trials of several drugs

• Major adverse effects are due to excessive accumulation of amines in the circulation .Tyramine: the “cheese effect. Drug interactions: SSRI’s, sympathomimetics

• Safe in carefully controlled circumstances, but “real world” use may lead to serious adverse effects.


CNS effect:Elevating the mood that is depressed. It blocks the reuptake of NE or 5-HT. onset is slow and requires 2~3w.The latency period can be as long as 4w.

Autonomic nervous system: Anticholinergic activity

Cardiovascular system: Tachycardia, arrhythmias, orthostatic hypotension quinidine-like action

The choice of an antidepressant for the treatment of depression rests primarily on practical considerations such as cost, availability,adverse effects, potential drug interactions, the patient’s history of response or lack thereof, and patient preference.

Other factors such as the patient’s age, gender, and medical status may also guide antidepressant selection. For example, older patients are particularly sensitive to the anticholinergic effects of the TCAs.

At present, SSRIs are the most commonly prescribed first-line agents in the treatment of both MDD and anxiety disorders. Their popularity comes from their ease of use, tolerability, and safety in overdose.

Bupropion, mirtazapine, and nefazodone are the antidepressants with the least association with sexual side effects and are often prescribed for this reason. Bupropion is not thought to be effective in the treatment of the anxiety disorders and may be poorly tolerated in anxious patients.

63 26 Sep 2019


Tricyclic antidepressants are oxidized by hepatic microsomal enzymes, followed by conjugation with glucuronic acid. The major metabolite of imipramine is desipramine; biotransformation of imiprimine or desipramine occurs largely by oxidation to 2-hydroxy metabolites, which retain some ability to block the transport of amines and have particularly prominent cardiac depressant actions. In contrast, amitriptyline and its major demethylated by-product, nortriptyline, undergo preferential oxidation at the 10 position.

• Antidepressants are metabolized more rapidly by children and more slowly by over 60 years of age as compared with young adults

• Most tricyclic antidepressants are extensively oxidized by CYP1A2. Citalopram, imipramine, and the meta-chlorophenylpiperidine metabolite of trazodone and nefazodone are substrates for CYP2C19, while atomoxetine, duloxetine, mirtazapine, paroxetine, trazodone, and some tricyclics are substrates for CYP2D6. Nefazodone and some tricyclic and SSRI antidepressants are oxidized by CYP3A3/4

Antidepressants -MAO Inhibitors Trade name

• Drug Isocarboxazid



Patient taking Parnate, a MAOI should avoid foods containing tyramine

ie cheese, red wine, avocado MAOI -> hypotension For elderly, Nardil is the most commonly prescribed one for the elderly

Side Effects of MAO Inhibitors Common

Marplan Nardil

Daily dose 45-90 mg


10-30 mg 10-30 mg

Constipation,Dizziness, Dry mouth

Hypotension, Nausea, Weight gain Insomnia

Sexual difficulties

Less common Blurred vision ,Agitation, Headache

Hypertension, Hypomania, coordination, Impaired muscle Muscle cramps

• Adverse effects

• Tricyclic antidepressants routinely produce adverse autonomic

responses, in part related to their relatively potent antimuscarinic effects.

• These include dry mouth and a sour or metallic taste, epigastric distress, constipation, dizziness, tachycardia, palpitations, blurred vision (poor accommodation with increased risk of glaucoma), and urinary retention.

• Cardiovascular effects include orthostatic hypotension, sinus tachycardia, and variable prolongation of cardiac conduction times with the potential for arrhythmias, particularly with overdoses.

• In the absence of cardiac disease, the principal problem associated with imipramine like agents is postural hypotension, probably related to anti-a1 adrenergic actions. Hypotension can be severe, with falls

• jaundice, leukopenia, and rashes, but these are very infrequent. Weight gain is a common adverse effect of many antidepressants, but is less likely with the SSRIs, and is rare with bupropion

• Most antidepressants appear to be generally safe during pregnancy, in that proposed teratogenic associations in newborns exposed to several tricyclic antidepressants and some newer antidepressants (particularly fluoxetine) are not convincing .

• Antidepressants are commonly prescribed with other psychotropic and nonpsychotropic agents. There is potential for drug interactions with all antidepressants, but the most serious of these involve the MAOIs and to a lesser extent the TCAs.

• Bupropion : Dizziness, dry mouth, sweating, tremor, aggravation of psychosis, potential for seizures at high doses

• Fluoxetine and other serotonin reuptake inhibitors : Anxiety, insomnia, gastrointestinal symptoms, decreased libido, sexual dysfunction, teratogenic potential with paroxetine

• Suicide attempts are a common and unfortunate consequence of major depression. The lifetime risk of completing suicide in patients previously hospitalized with MDD may be as high as 15%.

• Overdose is the most common method used in suicide attempts, and antidepressants, especially the TCAs, are frequently involved. Overdose can induce lethal arrhythmias, including ventricular tachycardia and fibrillation.

• In addition, blood pressure changes and anticholinergic effects including altered mental status and seizures are sometimes seen in TCA overdoses.

• A 1500 mg dose of imipramine or amitriptyline (less than 7 days’ supply at antidepressant doses) is enough to be lethal in many patients drugs, including alcohol.

• Management of overdose with the newer antidepressants usually involves emptying of gastric contents and vital sign support as the initial intervention.

Side Effects of MAO Inhibitors


Less common

Agitation, Blurred vision Headache, Hypertension Hypomania, Impaired muscle

oordination , Muscle cramps

• Constipation, Dizziness

• Dry mouth, Hypotension

• Insomnia, Nausea

• Sexual difficulties,Weight gain c

Foods & Drugs to be avoided


Aged cheeses ,Caffeined beverages Beer, Canned figs , Broad-bean pods

Drugs Amphetamine, Cocaine,

Epinephrine ,L-dopa,decogestant

Drug Interactions with Cyclic Antidepressants


Possible effect

Antidepressant blood level  Antidepressant blood level 

Sedation  Antidepressant blood level ,

Fluoxetine(Prozac) Phenobarbitol Sedatives

64 26 Sep 2019


Signs and sympotms of Hypertensive Crisis on MAOIs

• Warning Sign – BP↑; palpitations; Headache

• Symptoms – sudden BP↑;

• Explosive occipital headache

• Head and face are flushed & feel full,Palpitation, chest pain

• Sweating, fever, nausea, vomiting,Dilated pupils, photophobia TX of Hypertensive Crisis on MAOIs

• Hold MAOIs doses,Do not lie down (elevates BP in head)

• IM chlorpromazine 100mg, repeat if necessary (to block


• IV phentolamine, (to bind with norepinephrine receptor sites, blocking

norepinephrine),Manage fever by external cooling techniques

• Evaluate diet, adherence, and teaching

Common Side effects of TCAs:Mechanism – blockade of acetylcholine:

Drowsiness, dizziness, tachycardia, skin rashes, dry moth, constipation, and urinary retention, Risk of mortality with overdose is high 388

Mechanism for the Delay in Onset of the therapeutic Effect of Antidepressant Medications.

• •

• •


Psychotic features also occur in major mood disorders, particularly mania and severe melancholic depression. Psychotic illnesses are characterized by disordered thought processes (as inferred from illogical or highly idiosyncratic communications) with disorganized or irrational behavior and varying degrees of altered mood that can range from excited agitation to severe emotional withdrawal.

Treatment with Lithium ideally is conducted in cooperative patients with normal Na+ intake and with normal cardiac and renal function. Occasionally, patients with severe systemic illnesses are treated with Lithium, provided that the indications are compelling.

Treatment of acute mania and the prevention of recurrences of bipolar illness in otherwise healthy adults or adolescents currently are the only uses approved by the FDA, even though the primary indication for Li+ treatment is for long-term prevention of recurrences of major affective illness, particularly both mania and depression in bipolar I or II disorders


• The cause of the mood swings characteristic of bipolar affective disorder is

unknown, although a preponderance of catecholamine-related activity may be present. Drugs that increase this activity tend to exacerbate mania, whereas those that reduce activity of dopamine or norepinephrine relieve mania. Acetylcholine or glutamate may also be involved. Bipolar disorder has a strong familial component. Genetic studies have identified at least three possible linkages to different chromosomes.

• Bipolar affective (manic-depressive) disorder occurs in 1–3% of the adult population. It may begin in childhood, but most cases are first diagnosed in the third and fourth decades of life.

• The key symptoms of bipolar disorder in the manic phase are excitement,hyperactivity, impulsivity, disinhibition, aggression, diminished need for sleep, psychotic symptoms in some (but not all) patients, and cognitive impairment

• Until recently, lithium carbonate was the universally preferred treatment for bipolar disorder, especially in the manic phase. With the approval of valproate, aripiprazole, olanzapine, quetiapine,risperidone, and ziprasidone for this indication, a smaller percentage of bipolar patients now receive lithium.

65 26 Sep 2019


• Molecular mechanisms of antimanic agents

• Chemistry. Lithium is the lightest of the alkali metals (group Ia); the salts of this monovalent cation share some characteristics with those of Na+ and K+. Li+ is readily assayed in biological fluids and can be detected in brain tissue by magnetic resonance spectroscopy

• Antipsychotic-antimanic agents antagonize the neurotransmitter actions of dopamine in the forebrain, suggesting a possible state of functional overactivity of dopamine in the limbic system or cerebral cortex in schizophrenia or mania

• The most successful alternatives or adjuncts to lithium to date are the anticonvulsants carbamazepine, lamotrigine, and valproic acid. Atypical antipsychotic agents also appear to be useful

• The treatment of mania and recurrences of mania and depression in bipolar disorder have long relied on the use of lithium. Lithium has a low therapeutic index and its safe use requires close control of serum concentrations

• Therapeutic concentrations of lithium ion (Li+) have almost no discernible psychotropic effects in normal individuals. It is not a sedative, depressant, or euphoriant, and this characteristic differentiates Li+ from other psychotropic agents.

• Lithium treatment also leads to consistent decreases in the functioning of protein kinases in brain tissue, including PKC, particularly subtypes a and b. Among other proposed antimanic or mood-stabilizing agents, this effect also is shared with valproic acid (particularly for PKC) but not carbamazepine

• Treatment with Li+ and valproate has been associated with increased expression of the regulatory protein B-cell lymphocyte protein-2 (bcl-2), which is associated with protection against neuronal degeneration

• Li+ is absorbed readily and almost completely from the gastrointestinal tract. Complete absorption occurs in about 8 hours, with peak plasma concentrations occurring 2 to 4 hours after an oral dose.

• Manic-depressive disorder (bipolar affective), emotional disorders • Biochemical bases: amine theory

Mania 5-HT↓ NE↑ Depression 5-HT↓ NE↓

“Mood-stabilizing” agent

1. Effects on neurotransmitters and their release.

↓NE and DA release from synapse in the brain, ↑those reuptake.

• Antipsychotic agents commonly are used to control acute mania, with

or without psychotic features; some agents (e.g., olanzapine) appear to have long-term mood-stabilizing effects. Potent sedative- anticonvulsant benzodiazepines, notably clonazepam and lorazepam are used adjunctively for rapid sedation in acute mania.

• Recurrent endogenous depression with a cyclic pattern is controlled by either lithium/imipramine, both of which are superior to placebo.

• management of manic, mixed, and depressive mood states in bipolar disorder best relies on lithium or other mood-stabilizing agents, notably the anticonvulsant lamotrigine, as the primary treatment. An antidepressant can be added cautiously and temporarily to treat bipolar depression

• The natural history of major depression (either as unipolar depression or depressive phases of bipolar disorder) is that individual episodes tend to remit spontaneously over 6 to 12 months; however, there is a high risk of relapse of depression for at least several months following discontinuation of a successful trial of antidepressant treatment.

• The benzodiazepines and the SSRIs are the most commonly employed medicinal treatments for the common clinical anxiety disorders

• The antihistamine hydroxyzine is an effective antianxiety agent, but only at doses (about 400 mg per day) that produce marked sedation . Propranolol and metoprolol, lipophilic b adrenergic receptor antagonists that enter the CNS, can reduce the autonomic symptoms (nervousness and muscle tremor) associated with specific situational or social phobias, but do not appear to be effective in generalized anxiety or panic disorder

• The occurrence of toxicity is related to the serum concentration of Li+ and its rate of rise following administration. Acute intoxication is characterized by vomiting, profuse diarrhea, coarse tremor, ataxia, coma, and convulsions.

• Symptoms of milder toxicity are most likely to occur at the absorptive peak of Li+ and include nausea, vomiting, abdominal pain, diarrhea, sedation, and fine tremor.

• The more serious effects involve the nervous system and include mental confusion, hyperreflexia, gross tremor, dysarthria, seizures, and cranial nerve and focal neurological signs, progressing to coma and death.

• Sometimes both cognitive and motor neurological damage may be irreversible. Other toxic effects are cardiac arrhythmias, hypotension, and albuminuria. Other adverse effects common even in therapeutic dose ranges include nausea, diarrhea, daytime drowsiness, polyuria, polydipsia, weight gain, fine hand tremor, and dermatological reactions including acne

• Li+ also has a weak action on carbohydrate metabolism, causing an increase in skeletal muscle glycogen accompanied by depletion of glycogen from the liver. The prolonged use of Li+ causes a benign and reversible depression of the T wave of the ECG, an effect not related to depletion of Na+ or K+.

• Li+ routinely causes EEG changes characterized by diffuse slowing, widened frequency spectrum, and potentiation with disorganization of background rhythm. Seizures have been reported in nonepileptic patients with therapeutic plasma concentrations of Li+. Myasthenia gravis may worsen during treatment with Li+

• Allergic reactions such as dermatitis and vasculitis can occur with Li+ administration. Worsening of acne vulgaris is a common problem, and some patients may experience mild alopecia.

• In pregnancy, maternal polyuria may be exacerbated by lithium. Concomitant use of lithium with natriuretics and a low-Na+ diet can contribute to maternal and neonatal Li+ intoxication.

66 26 Sep 2019


• Some tolerance to the sedative and autonomic effects of tricyclic antidepressants and to the initial nausea commonly associated with serotonin reuptake inhibitors tends to develop with continued drug use.

• The clinical successes of valproate and carbamazepine as antimanic agents, and of lamotrigine as a mood-stabilizing agent, have strongly encouraged exploration of the growing number of other anticonvulsants being introduced into neurological practice

• For bipolar disorder, a critical challenge is to develop safe and effective antidepressants that do not induce mania and mood- stabilizing agents that consistently out perform lithium in broad effectiveness, with improved safety

• Enuresis in children is an older labeled use for some TCAs, but they are less commonly used now because of their side effects. The SNRI duloxetine is approved in Europe for the treatment of urinary stress incontinence.

• Side Effects of Lithium Carbonate

• Common

• Confusion,Diarrhea

• Fatigue , Hand tremor

• Increased thirst

• Increased urination

• Muscle weakness

• Nausea/vomiting

• Weight gain*

Less common Potential serious (toxic)


Edema Hair loss Polyuria

Diarrhea(severe), Dizziness Drowsiness (severe), Slurred speech Muscle weakness Nausea/vomiting(severe)

Marked tremor/twitching


DM, hypo pastic movements in limbs -thyroid, or face muscles

Common causes for Li+↑

Decrease sodium intake

Fluid and electrolyte loss, sweating, diarrhea, dehydration, fever, vomiting

Exercise – marathons

Medical illness ie poor renal function

Overdose,Nonsteroidal anti-inflammatory drug therapy

• Signs of Lithium Toxicity

• Mild

Moderate Severe

• (1.5-2.0mEq/L)

• Abdominal pain

• Dry mouth

• Nausea/vomiting

• Dizziness

• Drowsiness

• Lethargy/ excitement

• Marked tremor/ twitching Slurred speech

2.0-2.5 mEq/L Anorexia

Blurred vision Convulsions

Coordination impairment

Delirium Stupor

Over 2.5 mEq/L Coma

Urination  kidney failure Convulsions

Side effects of other mood stabilizing med. Carbamazepine (Tegretol)

Confusion, memory disturbance Dizziness,WBC  (benign)

Nausea,Skin rash

Valproic Acid – used with Lithium-> additive

Hair loss; Nausea/vomiting; Sedation BW 


• After major depression, anxiety disorders represent the most

common application of antidepressants. A number of SSRIs and SNRIs have been approved for all the major anxiety disorders,including PTSD, OCD, social anxiety disorder, and panic disorder.

• Panic disorder is characterized by recurrent episodes of brief overwhelming anxiety, which often occur without precipitant.

• The benzodiazepines provide much more rapid relief of both generalized anxiety and panic than do any of the antidepressants.

• OCD is known to respond to serotonergic antidepressants. It is characterized by repetitive anxiety-provoking thoughts (obsessions)or repetitive behaviors aimed at reducing anxiety (compulsions).

• Clomipramine and several of the SSRIs are approved for the treatment of OCD, and they are moderately effective.

Pathophysiology of anxiety

• •

Anxiety is a cardinal symptom of many psychiatric disorders and an almost inevitable component of many medical and surgical conditions. Indeed, it is a universal human emotion, closely allied with appropriate fear and presumably serving psychobiologically adaptive purposes.

A most important clinical generalization is that anxiety is rather infrequently a “disease” in itself. Anxiety that is typically associated with the former “psychoneurotic” disorders is not readily explained in biological or psychological terms; contemporary hypotheses implicate overactivity of adrenergic systems or dysregulation of serotonergic systems in the CNS.

Because of comorbidity between depression and anxiety disorders, it is advantageous for many patients to use a treatment that is helpful for both conditions. In some instances, because they are well tolerated and their clinical effects become evident promptly, benzodiazepines remain the preferred drugs for anxiety disorders despite the physiologic dependence associated with long- term use.

All benzodiazepines in clinical use have the capacity to promote the binding of the major inhibitory neurotransmitter g-aminobutyric acid (GABA) to the GABAA subtype of GABA receptors, which exist as multisubunit, ligand-gated chloride channels, thereby enhancing the GABA-induced ionic currents through these channels .

Pharmacological investigations have provided evidence for heterogeneity among sites of binding and action of benzodiazepines, whereas biochemical and molecular biological investigations have revealed the numerous varieties of subunits that make up the GABA- gated chloride channels expressed in different neurons.

The barbiturates were used extensively as sedative-hypnotic drugs. Except for a few specialized uses, they have been replaced largely by the much safer benzodiazepines. Barbituric acid is 2,4,6- trioxohexahydropyrimidine. compound lacks central depressant activity has sedative hypotic activity for anxiety relief.

67 26 Sep 2019


• Molecular mechanisms of antianxiety agents

• symptoms of anxiety commonly are associated with depression and

especially with dysthymic disorder (chronic depression of moderate severity), panic disorder, agoraphobia and other specific phobias, obsessive- compulsive disorder, eating disorders, and many personality disorders

• An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect. The degree of central nervous system depression caused by a sedative should be the minimum consistent with therapeutic efficacy. A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep.

• Benzodiazepines, barbiturates, and most older sedative-hypnotic drugs exert calming effects with concomitant reduction of anxiety at relatively low doses.

• Typically, the psychic awareness of anxiety is accompanied by enhanced vigilance, motor tension, and autonomic hyperactivity. Anxiety is often secondary to organic disease states—acute myocardial infarction, angina pectoris, gastrointestinal ulcers,

Anti-anxiety MedicationsBenzodiazepine group

• Drug





Dependence, withdrawal, tolerance

Daily dosage 0.5-6 mg

15-100 mg 2-60 mg 2-6 mg

* Most appropriate for the elderly

Trade Name Xanax Librium Valium


Adverse Effects of Anti-Anxiety Medication. Confusion,Dizziness,Drowsiness,Headache,

• Impaired muscle coordination,Irritability/restlessness Benzodiazepine Withdrawal Symptoms True withdrawal Delirium, Depression, Hypothermia, Impaired concentration Nausea , Paranoid ,Seizure.

Transient symtoms :agitation,anxiety,Blurred vision, Diarrhea,Dizziness, Headache, Insomnia

Vulnerable Populations:

At Most Risk for Adverse Drug Effects and Reactions

Reasons: The 5 “toos”

• Too few patients represented in studies to detect rare events

– 30,000 people in each category would need to receive the medication to detect 1 adverse reaction in a drug that affects 1:10,000

• Too simple: patients with multiple conditions excluded from trials

• Too median-aged: studies exclude patients at each end of the spectrum

2 More “Toos”

• Too narrow: indications for newly approved drugs are based on pre marketing clinical trials for ONE very specific condition

– Once marketed, the drug may be used for untested indications

• Too brief: most clinical trials are short

– Some adverse effects take years to manifest clinically

Drugs in Pregnancy • Treatment Goals

– Utilize appropriate resources to determine teratogenic risk and excretion in breast milk

– Assess the risk: benefit ratio of pharmacotherapy

– Utilize drug regimen that is safe, effective and minimizes risk to fetus or infant

– Minimize drug exposure to neonate/infant during lactation

68 26 Sep 2019



• ~35%ofwomentakesomemedicationsduring pregnancy

– Range/pregnancy = 1-15 medications (M=2.9)

• OTCmedicationsnotincluded

• WHOstudyshowedthatnon-white,unmarried,less educated women less likely to use medications

• Today ~60% of women breastfeed

• Over1,000drugsperyearareevaluatedfor teratogenic potential

– ~10% of children have abnormal physical or mental development

• Only 2-3% of these are associated with medications

Resources for Information

• Data on drugs in pregnancy and lactation are almost always POST marketing

– Constantly being updated-need for immediate access to drug updates

• 1979-FDA categories for Drug Use in Pregnancy

• FDA’s Adverse Drug Reaction reporting system underused

– MEDWATCH Program initiated in 1993

Lessons from the Past

• Thalidomide first appeared in Germany on 1st October 1957

– marketed as a sedative with few side effects

– Consideredsafe,usedformorningsickness

– Drug testing procedures were less rigorous

– limited testing failed to reveal tetragenic side effects

• Pre-marketing tests conducted on rodents which metabolize the drug in a different way to humans

– Subsequent tests on rabbits and monkeys produced similar SEs as in humans.

• Late 1950’s: post marketing reports

– Pharcomelia: babies born with flipper-like limbs • AKA: ‘Thalidomide Babies’


FDA Categories for Drug Use in Pregnancy

• CategoryA:

Adequate, well-controlled studies in pregnant women have not

shown an increased risk of fetal abnormalities

• CategoryB:

Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled studies in pregnant women.


Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus.

• CategoryC:

FDA Categories

Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women.


No animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women

• CategoryD:

Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk.

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FDA Categories

• Category X:

Studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities.

– The use of the drug is contraindicated in women who are or may become pregnant.

Excellent Website

• Ob.Gyn. News – Editorial

X-Rated Drugs

• Accutane

• Estrogen

• Isotrentinoin

• Vaccines: MMR, Varicella

– CDC Advisory Committee on immunization Practices

• Vaccinate all pregnant women with INACTIVATED influenza vaccine in the fall or throughout influenza season

Addressing Patients’ Concerns for Vaccine Safety

• TheUSFDAapprovedFluarix,aninactivated influenza vaccine for adults in 2005

• Fearofmercuryandthimerosal

– Spurred by media

– IOM (2004) released results of analysis of potential

link between thimerosal and neurobehavioral conditions and found no evidence of association

• BUT…urged“fullconsideration…toremovingthimerosal from any product given to infants, children or pregnant women”

Current Vaccines Available • Thimerosal-free or Thimerosal-reduced

– May be added at the end of manufacturing process to prevent bacterial or fungal growth

– Results in minute traces in final product Institute for Vaccine Safety – Thimerosal Table

• Thompson, et al, (2007). Early thimerosal exposure and neuropsychological outcomes at 7 to 10 Years. NEJM. 357 (13). 1281-1292.

– N= 1047 children between the ages of 7 and 10 years and administered standardized tests assessing 42 neuropsychological outcomes

– Findings: The detected associations were small and almost equally divided between positive and negative effects.

• • •

Higher prenatal mercury exposure associated with better performance on one measure of language and poorer performance on one measure of attentionand functioning.

Increasing levels of mercury exposure from birth to 7 months were associated with better performance on one measure of fine motor coordination and on one measure of attention and executive functioning.

Increasing mercury exposure from birth to 28 days was associated with poorer performance on one measure of speech articulation and better performance on one measure of fine motor coordination

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Pregnancy alters the Pharmacokinetics of Most Drugs

• Increase in total body water (~8L)

• Increase in total body fat

• Increase in GFR

• Decrease in gastrointestinal motility and changes in absorption and gastric acidity

• IncreaseinCO,bloodvolumeand plasma proteins

• Decreaseinplasmaalbumin concentration

– Changes in serum albumin effect the bioavailability of protein-binding

Pregnancy and Pharmacokinetics

• Pregnancy often accompanied by nausea and vomiting, which may prevent absorption of the medication, but…

• Increased plasma volume, fetal growth, and increased interstitial tissue result in a wider distribution of medications

Bottom Line

• Every woman requires thorough history of pregnancy complaints prior to pharmacologic treatment

• Dosages may need to be considered based on the stage of pregnancy

• Prescribing in pregnant patient requires more than just attention to FDA drug categories

In Translation…

• AbsorptionaffectedbydecreasedGItone

– Drug remains in stomach longer leading to increase in absorption through stomach and delayed in absorption of drugs

• Distributionaffectedbyincreasedplasmavolume causing prolonged half lives

– Fat soluble drugs stay longer in the body

– Drugs with high protein binding and lower lipid solubility

(such as anticonvulsants) have longer half lives

– Hormones (strongly protein bound) compete for available

binding sites-resulting in wide distribution of free, unbound drug in the body

Pregnancy and Pharmacokinetics

• Metabolism of drugs in liver relatively unchanged

– Drugs cleared through liver eliminated similar to non pregnant women

• Excretion-increased rates of clearance – Renal blood flow increases by 25-50%

– GFR increases by 50%

– Serum level of drug must fall to allow diffusion of drug from the fetus’s circulation

Placental Transfer

• Simplediffusion:molecularsizemay/notpermit transfer

• Activetransport:whereconcentrationofsubstancesare higher in fetus and transported back to the mother

• Pinocytosis:wheresolublemolecules(suchasviruses) cross membrane in small vesicles and are released

• Facilitateddiffusion:glucoseisrapidlytransferredto fetus

• Leakage:fetalcellsentermother’scirculationthrough small membrane breaks

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Properties of Medications that easily cross the placenta

• Small molecular size and weight (250-500d) – Most drugs have weights < 600d

• Non-protein bound • Non-ionized

• Lipophilic

Selecting a Drug for a Pregnant or

Nursing Mother

• Principlesofteratology:

– Timing of exposure in fetal development

• Based on fetal developmental stage when insult is applied can help predict the possible defect

• Exposure at time of conception and implantation may kill the fetus (all or nothing effect)

– If exposure occurs in first 14 days after conception when the cells can assume another cell’s function (totipotential), the fetus may not be damaged

• Most sensitive period: time from implantation to the end of organogenesis (days 18- 60)

– Damage to developing organs

– heart is most sensitive during the 3rd and 4th weeks of gestation, external

genitalia are most sensitive during the 8th and 9th weeks

– brain and skeleton are sensitive from the beginning of the 3rd week to the end of pregnancy and into the neonatal period.

Factors that Influence Teratogenicity of a drug

• Genotypes of the mother and fetus

• Embryonic stage at exposure

• Drug dose

• Duration of exposure

• Nature of the agent and mechanism by which it causes a defect

• Simultaneous exposure to other drugs and environmental agents that potentiate a drug

• Maternal and fetal metabolism of the drug

• Extent to which the drug crosses the placenta

• •

The safest pregnancy-related pharmacy is as little pharmacy as possible

However,womenwithahistoryofpsychiatric, seizure-related, or hematologic illnesses frequently require medication throughout pregnancy. Insuchpatients,caremusttobetakentoselectthe safest drug from the necessary class of medication.

Misri and Kendrick noted that prescribing drugs for women during the antenatal and postnatal period is a balancing act and that no risk-free alternatives exist

» Misri S, Kendrick K. Treatment of perinatal mood and anxiety disorders: a review. Can J Psychiatry. Aug 2007

• • •

The Male Partner…

Research is increasingly addressing the role of paternal exposure to medications before conception or during his partner’s pregnancy

Certain exposures may alter the size, shape, performance, and production of sperm

– suggests that drug exposure in the male may put the fetus at risk Animal studies have shown that paternal teratogenic

exposure may lead to pregnancy loss or failure of the embryo to develop

– unlike teratogenic agents affecting pregnant woman, teratogenic agents affecting the father do not seem to directly interfere with normal fetal development

– Animal studies showing that paternal teratogenic exposure may lead to pregnancy loss or embryonic failure.

• Austin, 1994; Chatenoud, 1998

For example:

• Colchicine

• Pregnancy category – D

• Trimester of risk – Unknown

• Associated defects and complications – potential chromosome aberrations

• Studies: Colchicine has been shown to cause birth defects in animals. The drug can lower sperm counts and cause sperm defects, resulting in birth defects.

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Current EB Recommendations

Inhumans,noevidenceofbirthdefectsafterpaternal exposures, but to minimize any possible risk, counseling in men exposed to radio and chemotherapy should delay conception ~ 3 months after the end of therapy.

Male patients treated with drugs with maternal teratogenic potential should be advised to practice effective birth control during therapy and up to one or two cycles of spermatogenesis and to avoid semen contact with vaginal walls during first trimester of pregnancy.

– Reproductive Toxicology, 2008



Drug Exposure Options for Pregnant and Lactating women

Withhold the drug (e.g., headache medications)  E.g., Ergotamine: Pregnancy category – X

 Trimesters of risk – all

 Associated defects and complications: LBW, and

preterm birth, ergotamine-induced vasoconstriction

in the placenta of pregnant women.

 The effect of ergotamine most obvious in male

newborn infants, particularly after treatment in the third trimester.

Delay drug therapy (if woman is close to end of lactation)


• Choose drugs that pass poorly into placenta or breast milk- (e.g., some variations even within same class of drug)

• e.g., Benzodiazepines-Pregnancy category – D or X

• Trimesters of risk: The first, second, and third

trimesters are times or risk for flurazepam (dalmane), temazepam (restoril), and triazolam (Halcion) (category X).

• Avoid alprazolam (Xanax-cat D) during pregnancy

• Chlordiazepoxide(Librium) appears to be safest choice during pregnancy.


• Choosealternateroutesofadministrationwhen possible

• Avoidlongacting/medicationswithlonghalflives

• Adviselactatingwomentotimetheirmedications

before the infant’s longest sleep period • Temporarily withhold breast feeding

– Can safely resume after 1-2 half lives (50%-75% elimination)

• For drugs with high toxicity, must delay 4-5 half lives

• Discontinuenursingifmedicationisforlife threatening condition (e.g., chemotherapy)

Treatment of Select Conditions during Pregnancy

• Asthma:

– Asthma complicates approximately 4% of


– In some cases, asthma improves during pregnancy

– Those with poorly controlled asthma are at risk for:

• Hyperemesis, uterine hemorrhage, preeclampsia, placenta previa, hypertension and premature labor

IMPLICATIONS of Pregnancy on Asthma

• Pregnancy has a significant effect on the respiratory physiology of a woman

• Respiratory rate and vital capacity do not change in pregnancy, but there is an increase in tidal volume, minute ventilation (40%), and minute oxygen uptake (20%) with resultant decrease in functional residual capacity and residual volume of air due to elevation of the diaphragm

• Airway conductance is increased and total pulmonary resistance is reduced, possibly as a result of progesterone

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Improved Outcomes associated with controlled asthma

• CurrentEVIDENCESupportsTreatment

• Almostallanti-asthmadrugsaresafetousein

pregnancy and during breastfeeding.

– Under-treating is a frequent occurrence for the pregnant patient because patients are worried about the medication effects on the fetus

– With a few exceptions, the medications used to treat asthma during pregnancy are similar to the medications used to treat asthma at other times during a person’s life.

Choice of Asthma Medications

– The type and dose of asthma medications will depend upon many factors.

• inhaled drugs are recommended because there are limited body-wide effects in the mother and the baby.

• It may be necessary to adjust the type or dose of drugs during pregnancy to compensate for changes in the woman’s metabolism and changes in the severity of asthma.

Common Asthma medications

• Inhaled B2 Agonists – Albuterol-Category C

• Mild, infrequent episodic

• May cause maternal hyperglycemia, tachycardia,

hypotension or neonatal hypoglycemia

• Briggs, et al., 2002: study of 1090 infants exposed to albuterol in 1st trimester-possible association with polydactyly

• No congential defects link in 2nd, 3rd trimester

• No adverse effects during lactation

– Possible B2Choice-Brethine (category B)

Theophylline (Cat C)

• Can be used along with inhalation therapy

• Preferred treatment for patients requiring long term therapy

• Must monitor levels throughout pregnancy to avoid toxicity

– Especially important in 3rd trimester d/t decrease in theophylline clearance and increase in volume of distribution

– Keep maternal plasma concentrations as low as therapeutically possible

• Crosses placenta in equal concentrations to mother

• Not associated with congenital defects but can cause jitteriness, cardiac arrythmias, hypoglycemia, feeding

difficulties in infants

– Neonates more likely affected

Corticosteroids (Cat C)

• Systemic corticosteroids are reserved for patients who require more urgent treatment.

• Conversely, cromolyn and nedocromil (Cat B) inhibit antigen- and exercise-induced asthma.

– They can be indicated as the first-line anti- inflammatory medication for the treatment of asthma

– Does not have systemic absorption – ?crossing of placenta

Corticosteroids (cat C)

• CanbegivenIV,PO,orinhaled

• 2reportscongenitalcataractsininfantsexposedto prednisone throughout gestation

– No association found in other studies

• Spontaneousabortion,prematurity,cardiac

abnormalities reported in one study

( Greenberger,1983)

• Prednisone<20mg/daysafeinlactation

– In larger doses, delay nsg 3-4hours after dose

74 26 Sep 2019



• > 1 million women of childbearing age have epiliepsy

• <1% of pregnancies are complicated by seizures

• 25% of women will have an increase in seizures during


• Women with epilepsy (with or without medication) have a

higher incidence of delivering an infant with congenital malformations and mental retardation

– Rates of major malformations affecting the heart, skeletal or nervous system in children born to women on anticonvulsants are at least double the rate in the general population

• Occurrence: 4–6 per hundred births vs the 2-3 per hundred births risk that all pregnant women face

• Benefits v risk are overwhelmingly important to consider

Epilepsy in Pregnancy

• AAP recommends that a patient who is seizure free for 2 years undergo trial medication withdrawal before becoming pregnant

• Suggested waiting period of 6 months after d/cing medication

• Anticonvulsant pharmacokinetics change during pregnancy:

– Lower serum concentrations due to increased renal and hepatic clearance

– Decreasedprotein-bindingcapacity – Increasedvolumedistribution

• despite lower serum concentrations, seizures may not increase due to increased free drug concentrations

– Must monitor concentrations of anticonvulsants closely

Newborns exposed to anticonvulsants

• Hemorrhagic disease in newborns in first 24 hours can be fatal

– Due to deficiency in Vit K clotting factors as a result of anticonvulsant exposure

• All infants should be treated with Vit K at birth

• Some physicians recommend Vit K for mother in last 2-

4 weeks of pregnancy

– Anticonvulsants also causes folate deficiencies

• Prophylactic folic acid during gestation recommended to prevent megaloblastic anemia and/or neural tube defects

Fetal Anticonvulsant Syndrome • Can occur with all antiepileptic drugs

• Phenytoin (cat D) can cause fetal hydratoin syndrome

– School, learning and developmental problems, craniofacial abnormalities, growth retardation, limb defects, cardiac lesions, hernias, distal digital and nail hyoplasia

• 10% risk for all of above (FHS)

• 30% risk of partial expression of syndrome

Phenobarbital (cat D)

• Lessteratogenicthatphenytoinbutcancause heart defects and cleft palate

• Canalsocausecoagulopathiesandfolate deficiencies

– Also has potential to cause neonatal addiction

• Foundinbreastmilk-causesnewborn

drowsiness, feeding difficulties, and infantile spasms after weaning

Carbazamine and Valproate (Cat D)

• At first, thought to be less harmful to fetus

• Associated with the same congenital abnormalities plus spina bifida (1%)

• Can be used with caution in lactation

75 26 Sep 2019


Lamotrigine (Lamictal), Gabapentin (Neurontin) and Oxcarbazine (Trileptal)= Cat C

• Recent results encouraging

• Appear to be less teratogenic or associated

with fetal loss in 1st trimester • Caution: more data needed

• • •

So…the jury is still out…

Althoughthereappearstobeapredispositionfor congenital malformations in the offspring of women treated for epilepsy, it is hard to establish a causal effect with the medication

It may be a complex interaction of the medication, the nature of their disease, and genetics rather than just the medication alone

» Samuels, 2002 Thethreemostcommonmalformationsnotedin

children of women treated for epilepsy are cardiac malformations, facial clefts, and genital/renal malformations.

The Teratogenicity of Anticonvulsant Drugs

• Holmes,etal:NEJM2001-

• Methods:screened128,049pregnantwomenatdeliveryto identify three groups of infants: those exposed to anticonvulsant drugs, those unexposed to anticonvulsant drugs but with a maternal history of seizures, and those unexposed to anticonvulsant drugs with no maternal history of seizures (control group). The infants were examined systematically for the presence of major malformations, signs of hypoplasia of the midface and fingers, microcephaly, and small body size.


• The combined frequency of anticonvulsant embryopathy was higher in 223 infants exposed to one anticonvulsant drug than in 508 control infants (20.6 percent vs. 8.5 percent; odds ratio, 2.8; 95 percent confidence interval, 1.1 to 9.7).

• The frequency was also higher in 93 infants exposed to two or more anticonvulsant drugs than in the controls (28.0 percent vs. 8.5 percent; odds ratio, 4.2; 95 percent confidence interval, 1.1 to 5.1).

• The 98 infants whose mothers had a history of epilepsy but took no anticonvulsant drugs during the pregnancy did not have a higher frequency of those abnormalities than the control infants


• A distinctive pattern of physical abnormalities in infants of mothers with epilepsy is associated with the use of anticonvulsant drugs during pregnancy, rather than with epilepsy itself

Coagulation Disorders

• Pregnancy is a hypercoagulable state – Incidence for DVT is still low: 0.2-0.4%

• Current recommendations for prophylaxis based on risk factors:

– Hereditary factors (protein C deficiencies/leiden factors)

– Hx of DVT/PE

– Age >35

– Multiple miscarriages

76 26 Sep 2019


Heparin: anticoagulant of choice (Cat C)

• Doesnotcrossplacenta

• Notassociatedwithcongenitaldefects

• Late pregnancy may be associated with increased heparin doses

• Perinatal mortality rates significantly improved for patients on heparin v. coumadin (3.6% v. 26.1% mortality)

• LMWH (Lovenox) safe and effective

– Less bleeding potential and less risk of osteoporosis – Does not cross fetal circulation

– Not excreted in breast milk

Coumadin (cat D)

• Exposure during 6-8th weeks can cause fetal warfarin syndrome

– Defects in CNS and skeletal system

• Exposure throughout pregnancy can cause:

– Stillbirths, spontaneous abortion, facial abnormalities

• Compatible with breast feeding

Treating Common Problems in Pregnancy

• Common Cold

• Nausea/Vomiting • Constipation

• Heartburn

• Hemorrhoids

Over the Counter Drug of Choice

Drug Class

During Pregnancy

During Lactation





Calcium carbonate

Calcium carbonate




Hemorrhoidal agents

Preparation H ointment

Preparation H ointment


Oxymetazoline nasal spray



Psyllium or docusate

Psyllium or docusate

The Common Cold

• No value in treating with medications

• If using medication, avoid combination products

• Limit duration of treatment

• Antihistamine of choice: chorpheniramine (cat B) or Loratidine

(cat B)

• Avoid brompheniramine (Dimetapp-Bromfed)

• Antihistamines excreted in breast milk

• Nasal cromolyn, beclomethasone useful alternative

• Clubfoot and inguinal hernias associated with first trimester

use of decongestants (e.g., Sudafed)

• Anti-tussives and expectorants all category C – No epidemiologic studies demonstrate fetal harm

Nausea and Vomiting

• 80% of women experience n/v during 1st trimester • Hyperemesisgravidarum-intractable,causeslyte

imbalances, weight loss, possible end organ damage – Occurs in 1:1000 births

– Requires hospitalization

• Causeunknown-txfocusedonsx

– Non pharmacologic measures not supported by evidence – OTC phosphorated carbohydrate (EMETROL) safe

– Meclizine (cat B) drug of choice

77 26 Sep 2019



• Etiology:increasedpressureoncolon,decreased peristalsis, increased progesterone, decreased motilin, increased colonic absorption of water

• Bulk-forminglaxatives(Metamucil)safeinpregnancy and lactation

– Increase fluids to prevent intestinal obstruction

• Surfactants/Stoolsofteners(docusate),mineraloil Cat c


• Affects 72% women in 3rd trimester

• d/trelaxationofLESanduterinedisplacement+ hormonal changes in gut motility

• Magnesium,calciumcarbonate,and/oraluminum hydroxides considered safe

• AvoidH2blockers

– If necessary-ranitidine preferred over cimetidine (has anti-

androngenic effects)

• Metoclopromide (Reglan) cat B


• OTC external preparations preferred

• Avoid suppositories d/t potential for systemic absorption across rectal mucosa

General Principles

Limitations of Drug Therapy in Children

• 75%ofFDAapprovedmedications lack indications in children

• Pediatricpractitionersactually prescibe “off label”

• FDAindicationsfordosingregimens are lacking

• Safety is based on post marketing reports of adverse events

Post Marketing Adverse Drug Reports

• MED WATCH – FDA medwatch-online.htm

78 26 Sep 2019


Important Legislation

• 1994: first FDA regulations regarding drug product labeling of known use and dosing

– Resulted in FDA approval of limited number of drugs in children

• 1997: Pediatric Exclusivity Provision of FDA Modernization Act passed

– Incentive for manufacturers to implement studies of their products on children

• 1999: Pediatric Rule developed

– Mandated that manufacturers perform trials and provide

safety and efficacy data

• 2003- Pediatric Research Equity Act-outlined FDA authority to enforce Pediatric Rule

Despite interest in pediatric drug therapy research, conducting clinical trials poses unique challenges


Recent reports of suicide with SSRI Treatment/ over treatment of ADHD Treatment of GERD

For Release: November 5, 2007,


A majority of infants taking anti-reflux drugs did not meet the diagnostic criteria for gastroesophageal reflux disease (GERD), according to a new study, “Are We Overprescribing Antireflux Medications for Infants With Regurgitation?” Researchers conducted esophageal pH monitoring (measuring the reflux or regurgitation of acid from the stomach into the esophagus) of 44 infants in a New Orleans medical center. Each of the children had persistent regurgitation and was referred to a specialty service for further management. The study showed that while only eight of the infants had abnormal pH levels indicating GERD, 42 of 44 infants were on antireflux medication. When medication was withdrawn from the infants who did not meet GERD criteria, reflux symptoms did not worsen. The study authors concluded that antireflux medications were unnecessary in the majority of infants who were prescribed such medication.

Developmental Pharmacology

• Pharmacokineticdifferencesinchildrenvarywithage • Drugsconsideredsafeinonegroupofpediatric

patients may be ineffective or toxic in another group – Hepatic enzymes and metabolic pathways mature at

different rates

• E.g., maturation of each pathway is asynchronous

– When a drug’s primary route of metabolism is immature, it may be shunted through an alternate pathway

– Drug dosing dilemmas can be avoided by using only those drugs with scientifically supported dosing

Key Points

• In infants, metabolism of most drugs is reduced

– GFR is 20-40% of adult capacity at birth and increases after the 1st week of life-reaches maximal level by 12 months

• In general, children over 10 years have organ development and metabolism similar to adults

– May require dosing adjustments based on body surface area

Key Points (con’t)

• GI tract acidity, enzymatic activity, and motility differences in infants and young children alter absorption of PO drugs

– Drugs that are weak bases increase drug absorption

– Drugs that are weak acids reduce drug absorption

– Reduced gastric transit in infants delays

absorption and peak plasma concentration time- but NOT the amount of drug absorbed

79 26 Sep 2019


Key Points

• Absorption from transcutaneous route is enhanced in infants-increased risk of adverse effects

– Caution with use of topicals in infants

• Thevolumeofdrugdistributionininfantsandyoung

children is increased due to increased body water

– Results in need for increased drug doses for water-soluble drugs (e.g., aminoglycosides)

– Drugs that are lipophilic (e.g., diazepam) may exhibit lower volume of distribution

Key Points

• Alterations in protein binding and tissue penetration of drugs may lead to reduced OR exaggerated response

Practical Tips for Pediatric Prescription Writing

1. Always obtain a weight at every pediatric visit

2. As a rule, start with smallest dose in neonates and


3. “round up” the dose if it falls between the given

choices UNLESS it is a toxic drug or has narrow

therapeutic window

4. With acetominophen, calculate dosage using

weight, not age

5. Always specify preferred formulation (e.g., chewable tabs, suspension, etc)

6. Stay current with literature!!!

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Geriatric Pharmacology

Baby Boomers and Beyond…

Medication Use Statistics

• People>65consume30%of prescription and 40% non- prescription drugs

– (Cohen, 2000)

• By2030,thepopulation>65will

double-with largest increases in 85-


• Adversedrugreactionsrankinthe

top 5 causes of mortality and

morbidity in elderly

• 28%ofelderlyhospitaladmissions are due to adverse drug reactions

80 26 Sep 2019


Adverse Drug Reactions

• About 15% of hospitalizations in the elderly are related to adverse drug reactions

• The more medications a person is on, the higher the risk of drug-drug interactions or adverse drug reactions

• The more medications a person is on, the higher the risk of non-adherence

Costs of Drugs

Average prescription drug cost for an older person is $500/year, but highly variable

• Nonprescriptiondrugsandherbalscanbequite expensive and dangerous when mixed with prescription drugs

• ManyMedicareManagedCarePlanshavedropped or severely limited drug coverage

• DrugscostmoreinUSthananyothercountry

– Many elderly patients look toward “bootlegged” drugs”

• Newdrugscostmore-notcovered

Non-prescription Drugs

• Surveysindicatethatelderstakeaverageof2-4

nonprescription drugs daily

• Laxativesusedinabout1/3-1/2ofelders-many who are not constipated

• Non-steroidal anti-inflammatory medicines, sedating antihistamines, sedatives, and H2 blockers are all available without a prescription, and all may cause major side effects

Prescription Drugs

• Elderlyaccountfor1/3ofprescription drug use, while only 13% of the population

• Ambulatory elderly fill between 9-13 prescriptions a year (new and refills)

• One survey: Average of 5.7 prescription medicines per patient

• Average nursing home patient on 7 medicines


• Decreaseintotalbodywater(duetodecrease in muscle mass) and increase in total body fat affects volume of distribution

• Water soluble drugs: lithium, aminoglycosides, alcohol, digoxin

– Serum levels may go up due to decreased volume of distribution

• Fat soluble: diazepam, thiopental, trazadone – Half life increased with increase in body fat


• Absorption: Not highly impacted by aging

• Variablechangesinfirstpassmetabolism due to variable decline in hepatic blood flow (elders may have less first pass effect than younger people, but extremely difficult to predict)

81 26 Sep 2019


Pharmacokinetics and the Liver

• Oxidative metabolism through cytochrome P450 system decreases with aging, resulting in a decreased clearance of drugs

• Hepatic blood flow extremely variable

Drugs with Cytochrome P450 Effects (partial)

Inhibitors Allopurinol Amiodorone Carbamazepine Azole antifungals Cimetidine

INH SSRIs Tacrine

Metronidazole Quinolones

Inducers Barbiturates

Phenytoin Rifampin Tobacco

Pharmacokinetics: Excretion and Elimination

• GFR generally declines with aging, but is extremely variable

• 30% have little change

• 30% have moderate decrease • 30% have severe decrease

• Serum creatinine is an unreliable marker • If accuracy needed, do Cr Cl

The Cockroft and Gault Equation

Cr Cl = 140-age(yrs) X wt (kg) X .85 for women Cr (mg/100ml)X72

May overestimate Cr Cl, especially in frail elders

Useful equation, but must be aware of its limitations

Pharmacodynamics: What the Drug does to the Body

• Some effects are increased

– Alcohol causes increase is drowsiness and lateral sway in older people than younger people at same serum levels

– Fentanyl, diazepam, morphine, theophylline

• Some effects are decreased

– Diminished HR response to beta -blockers



– Beta blockers – ASA

• Anticoagulation in AF

• HTN, especially systolic HTN • Pain

– Particular fear of narcotics in the elderly

82 26 Sep 2019


Drug-Drug Interactions

• Common cause of ADEs in elderly

• Almost countless – good role for pharmacist and computer or on-line programs

• Some common examples

– Statins and erythromycin and other antibiotics

– TCAs and clonidine or type 1Anti-arrythmics

– Warfarin and multiple drugs

– ACE inhibitors increase hypoglycemic effect of sulfonylureas

Drug-disease Interactions

• PatientwithPDhaveincreasedriskofdrug induced confusion

• NSAIDs(andCOX-2’s)scanexacerbateCHF

• Urinary retention in BPH patients on

decongestants or anticholinergics

• Constipation worsened by calcium, anticholinergics, calcium channel blockers

• Neurolepticsandquinoloneslowerseizure thresholds

The “Prescribing Cascade”

• Common cause of polypharmacy in elderly

• Some common examples

– NSAID ->HTN->antihypertensive therapy

– Metoclopromide ->Parkinsonism ->Sinemet – Dihydropyridine -> edema ->furosemide

– NSAID ->H2 blocker ->delirium ->haldol

– HCTZ ->gout->NSAID ->2nd antihypertensive – Sudafed ->urinary retention ->alpha blocker – Antipsychotic ->akithesia ->more meds


• AcetaminophenaseffectiveasNSAIDsinmild OA

• NSAIDssideeffects

– GI hemorrhage (less with COX-2)

– Decline in GFR (COX-2 as well)

• Decreasedeffectivenessofdiuretics,anti- hypertensive agents

• Indicationshouldjustifytheincreasedtoxicity of NSAIDs

Drugs and Cognitive Impairment

• Common cause of potentially reversible cognitive impairment

• Demented patients are particularly prone to delirium from drugs

• Anticholinergic drugs are common offenders (TCAs, benadryl and other antihistamines, many others)

• Other offenders cimetidine, steroids,


MedicalLetter2000 DrugSafety1999 DrugsandAging1999

Drugs and Falls

• Biggestriskdrugsarelongactingbenzodiazepines and other sedative-hypnotics

• BothSSRIsandTCAsassociatedwithincreasedrisk of falling

• BetablockersNOTassociatedwithincreasedriskof falling in published literature

• Mildincreaseinfallriskfromdiuretics,anti- arrythmics, and digoxin

Leipzig, 2008

83 26 Sep 2019


Drug-Food Interactions

• Interactionsbetweendrugsandfood

– warfarin and Vitamin K containing foods (remember

green tea, as well)

– Phenytoin & vitamin D metabolism

– Methotrexate and folate metabolism

• Drugimpactonappetite

– Digoxin may cause anorexia – ACE inhibitors may alter taste

Drugs And Dosages to Avoid in Most Instances

• Meperidine

• Diphenhydramine

• The most anticholinergic tricyclics: amitryptiline,

doxepin, imipramine

• Longactingbenzodiazepinessuchasdiazepam

• LongactingNSAIDssuchaspiroxicam

• Highdosethiazides(>25mg)

• Iron: 325 mg once daily is enough

Anticipate SE’s

• Narcotics

– Begin lactulose or sorbitol and a stimulant laxative – Colace is NOT sufficient in most instances

• Steroids

– Think about osteoporosis prevention – Remember steroid induced diabetes

• Levothyroxine

– Calcium interferes with absorption of levothyroxine

• ?Biphosphonatesand?Atrialfibrillation(NEJM, 2009)

• CalciumandMI??(BMJ,2010)

High Risk Situations

• Patient seeing multiple providers

• Patient on multiple drugs

• Patient lives alone and/or has cognitive impairment

• Discharge from hospital or any change in venue

Hospitalization: A High Risk Time

• At hospitalization:

• 40% of admission medications stopped

• 45% of discharge medications were started • Serious prescribing problems in 22%

• Other prescribing problems in 66% – Beers JAGS 1989, Lipton Medical Care 1992


• Lack of understanding of how to take

– High risk times: Hospital discharge, new meds added,

complex regimens • Unable to take

• Conscious nonadherence – Side effects

– Lack of understanding of benefits of drug – Financial

84 26 Sep 2019


Complementary Therapies

• Very commonly used in the elderly

• Somecommonherbsandalternativetherapies:

• “Anti-aging”

• Dementia


• OA


• Depression

DHEA,growthhormone Gingkobiloba Sawpalmetto,PC-SPES Chondroitonsulfate,


“Do No Harm?”

• California Department of Health Services, Food and Drug Branch

– screened 250 Asian herbal products

– collected from herbal stores in California

– assayed products using gas chromatography, mass

spectrometry, and atomic-absorption techniques

– Ko, NEJM 1998; 339; 847

• 32% contained unlabeled medications, 14% mercury, 14% arsenic, 10% lead

Herbals and Supplements: Regulation

• DemonstrationofsafetyisNOTrequiredpriorto marketing

• Manufacturingstandardsarenotrequired

• Canhavehealthclaims,butnotclaimsabout

treating, preventing, or curing

• For glucosamine/chondroitin, 1/3 of combinations did not contain listed ingredient


Herbals and Supplements:Potential interactions with Rx Drugs

• SAMemayincreasehomocysteine levels

• St.John’swortandOral contraceptives

• Ginkgomayincreaseanticoagulant effects of ASA, warfarin, NSAIAs, ticlopidine, and may interact with MAOIs

• Bottom line: Try to know what your patient is taking, and ask in a nonjudgmental way

Mr. W. is a 86 year old man with pulmonary HTN, COPD, CRI (creatinine of 2.2), CHF with an ejection fraction of 20%, mild dementia, depression, and severe anemia. He is frequently admitted to the hospital because of severe disease and poor adherence with his medical regimen. His discharge medications on last admission one month ago were aspirin 325mg, enalapril 20mg QD, furosemide 80mg BID, combivent, and sertraline 50mg. The inpatient team decided that he was undertreated, and added metoprolol 12.5mg BID, aldactone, FeSo4 325mg TID, and 3 inhalers. He was readmitted within a week. How might you approach his regimen?

Principles for Managing Drugs

• Completedrughistory,includingherbsand nonprescription drugs

• Avoidmedicationsifbenefitismarginalorifnon- pharmacologic alternatives exist

• Considerthecost

• Startlow,goslow,butgetthere!

• Keepregimenassimpleaspossible

• Writeinstructionsoutclearly

• Havepatientbringinmedicationsateachvisit

85 26 Sep 2019


Principles (continued)

• Considermedicationboxor“mediset”

• Ifthingsdon’tmakesense,considerahome visit

• Discontinuedrugswhenpossibleifbenefit unclear or side effects could be due to drug

• Becautiouswithnewerdrugs

• Considerifthebenefitofthe7thor8thdrugis sufficient to justify the cost, increase in complexity of regimen, and risk of side effects

Newer drugs

• Whatisuniqueaboutthiscompound?

• Whatclinicaldataisavailable?

• How does it compare with traditional therapy?

• How expensive is it?

• With third party payers cover this product?

• Does the potential advantage of this new drug justify the risk of using a new drug?


• The elderly take more medications than any other age group

• Pharmacokinetics and pharmacodynamics are altered

• Adverse drug reactions are common

• Risks go up with the number of

drugs used

• Nonprescription and herbal

therapies are common

• With care and common sense, we can probably do a better job

All this is possible because of our partners please support them for;

Health benefits: Motivation books:

Charity mission:

Financial wisdom:


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