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International Post-Baccalaureate
PharmD. (IPBP) Program

Internal Assessment (IA) Exam

STUDY GUIDE

PHARMACOLOGY- II

© 2006

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TABLE OF CONTENTS FOR STUDY GUIDE NUMBER 2

1. Autonomic Nervous System

2. Drugs Used in Asthma
3. Drugs Used in Diabetes
4. Drugs Used in GI Diseases
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AUTONOMIC NERVOUS SYSTEM

• The nervous system is made up of:

o Afferent (sensory) fibers
o Efferent (motor) fibers
 The motor portion of the nervous system can be subdivided in:
• Autonomic Nervous System
• Somatic Nervous System

The Autonomic Nervous System (ANS):

 Activities of the ANS are not under conscious control

 The ANS is made of two fibers (Preganglionic and Postganglionic fibers)

 The ANS is primarily concerned with visceral functions necessary for life
o Heart beat
o Smooth muscle contraction/relaxation
o Exocrine & certain endocrine secretion

Somatic Nervous System

 Activities of the somatic nervous system are under conscious control

 The somatic nerve is a single motoneuron
 The somatic nervous system is primarily concerned with voluntary functions
o Movement and posture
o Respiration
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Another difference between the ANS and somatic nervous system is that the somatic
nervous system is a single motoneuron; whereas, the ANS is made of two fibers (one
pre- and one post-ganglionic fiber) except adrenal medulla, where only one
preganglionic fiber innervates the adrenal medulla

From an anatomical point of view, the ANS is divided into

 Craniosacral (parasympathetic) division

 Thoracolumbar (sympathetic) division

The sympathetic and parasympathetic divisions of the ANS originate within the nuclei in
the CNS, i.e., the neurons are coming out of the spinal cord (Sympathetic) or the medulla
and the spinal cord (parasympathetic). Thus, the terms thoracolumbar and craniosacral,
respectively, denote the sympathetic and parasympathetic division of the ANS,
Adrenergic and Cholinergic fibers

o Depending the neurotransmitter released at the synaptic terminal, the fibers can be
adrenergic or cholinergic
 If the neurotransmitter is nor-adrenaline, the fiber is adrenergic
 If the neurotransmitter is Acetylcholine (Ach), then the fiber is
cholinergic
 All preganglionic fibers are cholinergic because Ach is the
neurotransmitter
 All postganglionic fibers for the parasympathetic system are
cholinergic because Ach is the neurotransmitter
 Most of the postganglionic sympathetic fibers are adrenergic
because the neurotransmitter is nor-adrenaline (NE); but, few
postganglionic sympathetic fibers could be cholinergic as well
(e.g., sweat gland; please above, the very first figure).
 All somatic motoneurons are cholinergic because Ach is the
neurotransmitterChemical neurotransmission

 Chemical transmission takes place through the release of

neurotransmitters from the nerve terminal (presynaptic membrane)
into the synaptic cleft
 The neurotransmitter crosses the cleft by diffusion and activates the
receptors on the postsynaptic membrane

Adrenergic Receptors

o There are two types (alpha and beta) of adrenergic receptors based on the affinity
of isoproterenol, epinephrine and norepinephrine for these receptor
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o The α-adrenergic receptors have a rank order of potency of: epinephrine >
norepinephrine >>> Isoproterenol
o The β-adrenergic receptors have a rank order of potency of: isoproterenol >
epinephrine > norepinephrine
o Recently, subtypes of each receptor have been cloned.
o Activation of each subtype of the receptor will lead to different physiological
responses

Cholinergic neurotransmission

• Choline, the presursor for synthesis of Ach, is transported from extracellular

region to the presynaptic nerve by a sodium-dependent carrier
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• Acetycholine (Ach) is then transported by carrier B and stored in vesicles

• When an action potential reaches the nerve terminal, a voltage-sensitive calcium
(Ca2+) channel is opened
• Increased Ca2+ influx causes fusion of vesicles with the surface membrane
through interaction of:
o Vesicular-associated membrane proteins (VAMPs; synaptotagmin and
synaptobrevin, etc.)
o Synaptosomal-associated membrane proteins (e.g., SNARE complex:
SNAP-25 and syntaxin)
o Calcium influx will lead to an interaction between vesicular- and
synaptosomal-associated membrane proteins and thus fusion of the
vesicles to the synaptic membrane (exocytosis)

Receptor Activation

Acetylcholine released at the synaptic cleft will bind to postsynaptic receptors.

Termination of Action

Acetylcholine is hydrolyzed by the enzyme acetylcholinesterase (AChE) to acetate and

choline, which can be transported back to the nerve terminal for future use.

Adrenergic neurotransmission

Synthesis

• Tyrosine is transported by Na+-linked carriers into cytoplasm

• Tyrosine is hydroxylated to dihydroxyphenylalanine (DOPA) by the enzyme
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tyrosine hydroxylase (TH)

o Methyl-tyrosine (metyrosine) inhibits the rate-limiting enzyme and
therefore prevent or, at least reduces adrenergic neurotransmission
• Used for treatment of hypertension associated with Pheochromocytoma
• DOPA is then converted to dopamine by the enzyme DOPA decarboxylase
o Alpha-methyldopa (aldomet) deceives the dopa-decarboxylase and being
converted to alpha-methyl-dopamine and then being converted to alpha-
methyl-NE by the action of dopamine-beta-hydroxylase and stored into
the vesicle as a false neurotransmitter; therefore, the drug reduces
adrenergic neurotransmission since the false neurotransmitter, released
into the synaptic cleft instead of NE, cannot activate the receptors

Potential targets for drugs

 Presynaptic membrane
o Synthesis (e.g., hemicholinum interferes with the transport of choline)
o Storage (e.g., vesamicol interferes with storage of acetylcholine)
o Release (e.g., botulinum toxin interferes with the release of acetylcholine)

 Postsynaptic membrane
o Receptor activation (e.g., atropine blocks the muscarinic receptors)
o Termination of action (e.g., organophosphates inhibit acetylcholineesterase
and prolong neurotransmission at the cholinergic fibers)

For further details of the drugs affecting the cholinergic system, please see Dr. Arias’s
section.

Storage

• Dopamine is converted to norepinephrine by the enzyme dopamine-beta-

hydroxylase (DBH) and transported into the storage vesicles and/or dopamine can
be transported into the storage vesicles and converted to norepinephrine inside the
storage vesicles by the enzyme DBH
• The carrier that transports the neurotransmitter (dopamine or norepinephrine)
inside the vesicles is called vesicular transporter
o The drug Reserpine blocks the vesicular transporter
o In the presence of reserpine, the neurotransmitter will not be transported
into the storage vesicles and therefore oxidized by the enzyme monoamine
oxidase (MAO) and will be excreted
o Thus, reserpine reduces adrenergic neurotransmission

Release
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• Arrival of an action potential at the nerve junction triggers an influx of calcium

ions
• Increased intracellular calcium promotes an interaction between vesicular- and
synaptosomal-associated proteins which ultimately leads to fusion of the vesicles
to the cell membrane and release of NE (exocytosis)
o Sodium channel blockers (e.g., tetrodotoxin), calcium channel blockers
(e.g., verapamil) can attenuate or block neurotransmitter release
o Guanethidine and Bretylium also block NE release

Receptor Activation

• Norepinephrine released at the synaptic cleft will bind to postsynaptic (please see
Figure 13) or presynaptic (also known as autoreceptors) receptors
• Activation of the autoreceptors leads to a decrease in further neurotransmitter
release
• This action is mediated by inhibition of the enzyme adenylyl cyclase (A.C.) that
leads to a decrease in cAMP formation

Termination of Action

• Norepinephrine is recaptured by reuptake mechanism back into the presynaptic

neuron (also known as NE transporter or uptake-1).
• NE transporter involves a Na -K+-linked–ATPase which can be inhibited by TC
antidepressants such as imipramine, or by cocaine
• Norepinephrine may diffuse out of the synaptic space and enter the general
circulation (Uptake 2)
• As stated above, NE is oxidatively deaminated by the enzyme MAO which leads
to excretion of NE at the presynaptic site, where the neurotransmitter is
synthesized
• MAO also exists at the postsynaptic site and oxidizes the released NE that reaches
the postsynaptic site
• At the postsynaptic site, NE can also be metabolized the enzyme catechol-O-
methyl-transferase (COMT)

Adrenergic Receptors

o There are two types (alpha and beta) of adrenergic receptors based on the affinity
of isoproterenol, epinephrine and norepinephrine for these receptor
o The α-adrenergic receptors have a rank order of potency of: epinephrine >
norepinephrine >>> Isoproterenol
o The β-adrenergic receptors have a rank order of potency of: isoproterenol >
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epinephrine > norepinephrine

o Recently, subtypes of each receptor have been cloned.
o Activation of each subtype of the receptor will lead to different physiological
responses

 Physiological responses associated with receptor activation

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 Receptor localization and biochemical responses

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Coupling mechanisms
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Adrenergic receptor agonists

Catecholamines
 have high potency in activating α and β receptors
 are metabolized by MAO at the presynaptic level
 are metabolized by COMT at the postsynaptic level as well as in the liver and
gut walls
 have a brief period of action when given parenterally but are ineffective
orally
 do not readily penetrate the CNS since they are polar molecules but have
some detectable actions on the CNS: anxiety, tremor, and headaches

Non-catecholamines
 drugs that lack the catechol hydroxyl groups, are not metabolized by COMT and
therefore have longer half-lives
 lack of the hydroxyl groups increases lipid solubility and therefore increases
CNS permeability

Mechanisms of Action

These drugs are divided into:

(1) direct acting (bind to the receptor and produce their actions
epinephrine
norepinephrine
dopamine
isoproterenol
dobutamine
albuterol
clonidine
metaproterenol
methoxamine
ritodrine
terbutaline

(2) indirect acting (these drugs do not bind to the adrenergic receptors but cause
release of NE or epinephrine
amphetamine
tyramine
cocaine
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(3) direct & indirect acting work via both mechanisms

ephedrine
metaraminol

Epinephrine

 is an endogenous catecholamine formed by the actions of a methyltransferase

enzyme in the adrenal medulla
 can also be administered exogenously
 has a rapid onset but brief duration of action;
 can be given i.v. in emergency situations, can also be administered s.c., by
endotracheal tube, by inhalation, or topically; not given orally due to inactivation
by intestinal enzymes; only metabolites of epinephrine are excreted in the urine

Pharmacological Actions

1. Actions on the cardiovascular system

o At low doses, it will produce vasodilation (β2 effects on vasculature)
o At high doses, it will produce vasoconstriction (the α effects )
o Positive ionotropic effect, i.e., it increases contractility of the heart (positive
inotropic) - β1
o Positive chronotropic, i.e., it increases rate of contraction - β1
o the net effect is an increase in cardiac output - β1
o Other actions include constriction of arterioles in the skin mucous membranes,
and viscera (α1 receptors)
o Dilation of the vessels going to the liver and skeletal muscle (via β2 receptors)
o The overall effect is an increase in systolic pressure and a slight decrease in
diastolic pressure that can result in a reflex slowing of the heart (via activation of
baroreceptors)

2. Actions on the respiratory system

o Epinephrine causes bronchodilation by acting on bronchial smooth muscle

(via β2 receptors)
o The result is an increase in the tidal volume (volume of gases inspired and
expired)
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3. Actions on pancreatic hormones

o Increases in glycogenolysis in the liver (via β2 receptors)

o Increases in the release of glucagon (via β2 receptors)
o Decreases the release of insulin (via α2 receptors)
o The resultant effect will be hyperglycemia (increase in blood glucose)

4. Actions on lipid metabolism

o Initiates lipolysis by acting on β receptors of adipose tissue which activate a

hormone-sensitive lipase which hydrolyzes triacylglycerols to free fatty acids
and glycerol

5. Actions on the eyes

o Epinephrine reduces production of the aqueous humor by vasoconstriction of the

ciliary body blood vessels reduces intraocular pressure in open-angle glaucoma

Therapeutic Effects

o Epinephrine is the drug of choice for the emergency treatment of respiratory

distress where there is bronchoconstriction resulting in diminished respiratory
exchange (e.g., in asthma and anaphylactic shock)
o selective β2 agonists are favored for the treatment of asthma because they have
longer duration of action and minimal cardiac stimulatory effects

o Epinephrine reduces production of the aqueous humor by vasoconstriction of the

ciliary body blood vessels; 2% epinephrine solution may be used to reduce
intraocular pressure in open-angle glaucoma

o Epinephrine is often used in local anesthetic solutions to produce local

vasoconstriction which allows the anesthetic to remain at the site longer before
being absorbed systemically and metabolized

Adverse Effects

 CNS related side effects include anxiety, fear, tension, headache, tremor, may
cause cerebral hemorrhage due to the elevated blood pressure
 Cardiac arrhythmias possible when patient is taking digitalis (which increase
cardiac output)
 Pulmonary edema
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Interactions

 Epinephrine may have enhanced cardiovascular actions therefore, the dose of

epinephrine must be reduced (may involve increased numbers of adrenergic
receptors on the vasculature of the hyperthyroid individual)

 Cardiovascular actions of epinephrine are exaggerated in the presence of cocaine

since cocaine inhibits the re-uptake of catecholamines into the adrenergic neuron;
the result is that epinephrine remains at the receptor site for longer periods of time

Norepinephrine (NE)

• activates both α and β receptors

• no therapeutic uses; can be used to treat shock but dopamine is better
Dopamine

• dopamine is the drug of choice for shock and is given by continuous infusion
• dopamine stimulates β1 receptors on the heart to strengthen contractility and
increase rate of contraction
• at very high doses, dopamine can activate α receptors on the vasculature and
cause vasoconstriction
• dopamine dilates renal and splanchnic arterioles by activating dopaminergic
receptors (D1 and D2)
• this increases blood flow to the kidneys and other viscera and is not affected by α-
or β- receptor blocking drugs
• the increased blood flow to the kidney enhances the glomerular filtration rate and
causes sodium diuresis which contrasts with the effect of NE, which causes
diminished blood flow to the kidney and thus kidney shutdown
• however, dopamine overdose produces effects similar to sympathetic stimulation
but the adverse effects are short-lived due to rapid metabolism of dopamine to
homovanillic acid (HVA)

Phenylephrine

 is a synthetic drug that selectively activates α1 receptors

 is not a catecholamine so is not a substrate for COMT
 is used as a nasal decongestant, in ophthalmic preparations for mydriasis, and also
used to treat hemorrhoid
 it causes vasoconstriction of blood vessels

Clonidine

 is a synthetic drug that is a selective α2 agonist

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 used to treat essential hypertension

 acts on sympathetic nerves to reduce NE release
 is well absorbed orally with bioavailability near 100%; half-life is about 12 hours
 can produce side effects such as dry mouth and sedation, which occur in about
50% of patients

Guanfacine and guanabenz

 are selective α2 agonists and used for the treatment of essential hypertension like
clonidine

Apraclonidine

 is a selective α2 agonist and used to reduce intraocular pressure

 given locally in the eye but may have adverse effects similar to clonidine

Isoproterenol

 is a synthetic catecholamine that acts primarily on β1 and β2 receptors

 is non-selective for β receptors so it can have cardiovascular actions via β1 and
pulmonary actions via β2 receptors
 is used in chronic bronchitis, emphysema, asthma as an inhaler so the
cardiovascular actions are limited
 the effect on the bronchioles is Bronchodilation
 duration of action is about 1 hour
 its adverse effects are similar to epinephrine

Selective beta-2 receptor agonists

o are used as bronchodilators for the treatment of bronchospasm and asthma

o are not substrates for COMT; varied onset and duration of action

 Metaproterenol
 Terbutalin
 Albuterol
 Pirbuterol
 Bitolterol
 Salmeterol

Indirect-Acting Adrenergic Agonists

Amphetamine
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 it acts indirectly to enhance catecholamine release from adrenergic nerve

terminals
 stimulates the CNS (an action noted by drug abusers and pilots)
 also has α1 agonist (vasoconstriction) and β1 agonist (increased heart rate)
actions

Tyramine

 not clinically useful

 found in fermented foods such as ripe cheese and Chianti wine
 it enhances the release of norepinephrine from the vesicular pool (possibly an
acute increase in blood pressure)
 but after repeated administration causes a drop in blood pressure due to depletion
of NE stores, a phenomenon referred to tachphylaxis
 normally endogenous tyramine is oxidized by MAO and removed but if the
patient is taking MAO inhibitors (psychiatry) then the effect of tyramine could be
significant

Mixed-Action Adrenergic Agonists

Ephedrine

• can enhance release of NE from nerve terminals but can also have stimulatory
actions on α and β receptors similar to epinephrine
• ephedrine is not a substrate for COMT or MAO so it has a long duration of action
• is only used clinically in combination with other agents to treat bronchospasm and
cough

Metaraminol

o is also a mixed-acting adrenergic agonist but is not used clinically

Adrenergic receptor antagonists

The adrenergic antagonists typically have a preferential affinity for one type of adrenergic
receptor allowing for the inhibition of specific adrenergic effects

The only exception is labetalol, which blocks both alpha and beta receptors

Mechanisms of Action
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o Block alpha or beta adrenergic receptors

o Competitive
o Non-competitive

o Partial agonist

These drugs bind to alpha or beta adrenergic receptors and block the action of exogenous
as well as endogenous adrenergic receptor agonists by either competitive or non-
competitive or partial agonist action and used in many clinical conditions listed below:

Pheochromocytoma (tumor of chromaffin cells)

Phenoxybenzamine
Phentolamine

Glaucoma (increased intraocular pressure)

Timolol
Carteolol

Migraine Prophylaxis

Propranolol
Timolol

Hypertension

Prazosin
Propranolol
Acebutolol
Pindolol
Terazosin
Nadolol
Atenolol
Labetalol
Doxazosin
Timolol
Metoprolol

Long-term Management of Angina

Propranolol
Atenolol
Nadolol
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Metoprolol

Benign Prostatic Hyperplasia

Terazosin

Competitive alpha adrenergic antagonists or blockers

o bind to adrenergic receptors but do not trigger a cellular response

o these drugs act by reversibly binding to the receptor (competitive) and preventing
activation by endogenous catecholamines or agonists
o prazosin and phentholamine can be examples of such drugs

Non-competitive antagonists

 binds covalently to α receptors, e.g., phenoxybenzamine which is a prodrug so it

requires metabolic activation to become active and produce its pharmacological
effects
 is an alkylating agent that binds covalently to both α1 –postsynaptic receptors and
α2 –presynaptic receptors
 the blockade is irreversible and non-competitive; only synthesis of new receptors
will overcome the effects of the drug (which takes several days)
 blocks α1 receptors in peripheral vasculature; therefore, prevents vasoconstriction
 the decrease in blood pressure causes a reflex tachycardia (which can also occur
because of blockade of alpha-2 in the heart)
 does not block the actions of epinephrine on β-receptors in other vascular beds
(vasodilaion)
 also blocks reuptake of NE; blocks histamine, Ach, 5-HT receptors; thus,
phenoxybenzamine is a non-selective drug
 can produce the following side effects:

o Postural hypotension
o Nausea and vomiting
o Inhibition of ejaculation
o Miosis
o Nasal stuffiness
o Tachycardia (due to activation of baroceptors)
o Increase in blood volume after long-term use
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Phenotolamine

 competitively inhibits α1 and α2 receptors

 its duration of action is about 4 hrs
 is used in hypertension associated with pheochromocytoma
 produces side effects similar to phenoxybenzamine

Prazosin and related drugs

o Prazosin
o Terazosin
o Doxazosin

o selectively block α1 receptors

o used for treatment of hypertension
o the first dose of the drug produces an exaggerated hypotensive response which
can cause fainting, so the drug is usually taken at bedtime and at 1/3 to 1/4 of the
normal dose
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Adverse Effects

o Dizziness
o Lack of energy
o Drowsiness
o Postural hypotension (but to a lesser degree than
o phenoxybenzamine or phentolamine)

Caution

o prazosin is often given with either a diuretic or β blocker which will necessitate
an adjustment in dose since there will be an additive antihypertensive effect

Yohimbine

o blocks alpha-2 receptors; therefore, it prevents binding of the endogenous NE to

the autoreceptors
o also reverse the antihypertensive effects of clionidine and other alpha-2 receptor
agonists
o although not proven clinically, it is thought to improve male sexual function
o there has been experimental interest for the development of selective alpha-2
receptor antagonists for use in diabetes type II as well as in depression

Beta-adrenergic Receptor Blockers

 the names of all β blockers ends in “-olol” except for labetalol which also has
some α1 blocking activity
 are all competitive antagonists with some also acting as partial agonists
 non-selective blockers inhibit both β1 and β2 receptors while cardioselective
agents will block β1 receptors
 although all β blockers lower blood pressure in hypertension, they do not induce
postural hypotension since the α adrenergic receptors remain functional
 are effective in treating angina, cardiac arrythmias, myocardial infarction, and
glaucoma, and in the prophylactic treatment of migraine headaches

Propranolol

 is a non-selective β blocker used in:

o Hypertension
o Chronic migraine therapy; propranolol decreases the incidence and
severity of attacks
o Angina pectoris
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 reduces the chest pain on exertion common in angina

 used for the chronic management not acute treatment of angina

 propranolol blocks β1 receptors on the heart and causes a negative ionotropic and
a negative chronotropic effects
 the drug directly depresses SA and AV activity
 in general, the β blockers are useful in attenuating supraventricular cardiac but not
ventricular arrhythmias
 the blockade of peripheral β2 receptors prevents vasodilation; the reduction in
cardiac output (beta-1) leads to a reflex peripheral vasoconstriction so there is
decreased blood flow to the periphery; the net effect is a gradual reduction in both
systolic and diastolic blood pressures
 no postural hypotension occurs because the α1 receptors are unaffected

Side Effects

Arrhythmias
 Cardiac arrhythmias may result if treatment with β blockers is stopped abruptly
 the chronic presence of the β blocker will cause upregulation of β1 receptors on
the heart; when the therapy is stopped abruptly, the endogenous catecholamines
have more receptors to bind to and the result could be angina, hypertension or
arrhythmia

Increased Na+ retention

 the drop in blood pressure increases Na+ retention and plasma volume, so these
drugs are often used in combination with diuretics to prevent Na+ retention

Bronchoconstriction

 blocking β2 receptors on the lungs causes contraction of the bronchiole smooth

muscle which can precipitate a respiratory crisis in patients with chronic
obstructive pulmonary disease or asthma
 therefore, β2 blockers are contraindicated in patients with asthma

Hypoglycemia

 blocking β2 receptors in the pancreas decreases glucagon secretion

 there is also decreased glycogenolysis; these effects are significant for an insulin-
dependent diabetic patient who should monitor blood glucose levels carefully
while taking propranolol because a pronounced hypoglycemia could occur after
the insulin injection
 cardioselective β blockers are preferred in diabetic patients

Cold Extremities
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 due to blockade of the peripheral β2 receptors and prevention of vasodilation,

there is reduced blood flow to the extremities and they may seem cold

Other non selective Beta-adrenergic Receptor Blockers

 Timolol and Nadolol

o are more potent than propranolol
o Nadolol has a long duration of action used to treat hypertension
o Timolol reduces production of aqueous humor in the eye and is used
topically to treat open-angle glaucoma; also used to treat hypertension

Selective beta-1 adrenergic receptor blockers

 Betaxolol
 Atenolol
 Metoprolol

o are selective β1 blockers (doses 50-100 times larger are needed to block
β2 receptors)
o produce similar cardiovascular effects like those mentioned for
propranolol
o lack unwanted bronchoconstrictor effects in asthma patients due to β1
blockade with propranolol
o are used to treat hypertension, especially in asthmatics and diabetics

Partial Agonists
 Pindolol
 Acebutolol

o are able to weakly stimulate β1 and β2 receptors

o as a result of the partial agonist activity, these drugs are not as effective as
the cardioselective drugs without partial agonist activity (atenolol and
metoprolol)
o used for hypertension, especially in patients with modest bradycardia
o these drugs have fewer effects on lipid and carbohydrate metabolism so
they can be used in diabetic patients

Labetalol

 acts as both an α and β receptor blocker

 due to the α1 blockade there is peripheral vasodilation, in contrast to the other β
blockers
 used for hypertension in the elderly or in black patients (in general, black
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hypertensive patients are not well controlled with β blockers)

 used when increased peripheral vascular resistance is undesirable


Adverse Effects

 are associated with α1 blockade

 postural (orthostatic) hypotension
 dizziness
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Drugs Used in Asthma

What is asthma?
• Recurrent attacks of breathlessness, characteristically accompanied by wheezing
when breathing out
• Asthma is the most common chronic disabling respiratory disease
• Most people have their first attack when they are <5 years old. However, it could
occur in any age
• About 1 in 20 of the overall population is asthmatic; but in children 1 in 10
• Accounting for 1-3% of office visits; 500,000 hospital admissions
(children>adults)
• 5000 children and adults die of the disease each year
• More common in the US and other developed countries
• Bronchial asthma is the most familiar form of asthma and should be distinguished
from cardiac asthma caused by heart failure by the following characteristics:
o increased responsiveness of the trachea and bronchi to various stimuli
o widespread narrowing of the airway that changes in severity either
spontaneously or as a result of therapy

Pathophysiology of asthma

• Used to be viewed simply as reversible airway obstruction or “irritable airways”

• It is rather an inflammatory process since:
o increased number of inflammatory cells in the bronchoalviolar lavage
fluid of asthmatic (allergic and non-allergic) patients
o the number of these cells is further increased in allergic asthmatic patients
upon exposure to allergens
o in lung biopsies: increased airway thickness and increased influx of
inflammatory cells into the lung tissues

Pathogenesis

 Immunologic model
o bronchoconstriction upon exposure to antigens
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Re-exposure to antigen
(pollen, dust, etc)

Antigen and IgE

on mast cells

Mediators (histamine,
LTC4,PGD2, PAF, etc)

Early response Late response

(bronchoconstriction) (inflammation)
Mediators
Acute symptoms hyperreactivity

 Non-immunologic
o Not all asthmatic adults show bronchoconstriction upon an antigen
challenge
o Viral infection rather than antigen causes the attack
o Non-antigenic stimuli (dH2O, cold, exercise)

Mediators of Asthma
Please see Goodman & Gilman ((Figure 28-1 and tables 28-1, 28-2 (pp. 660-1))

Pathological features of asthma

• Contraction of airway smooth muscle
• Mucosal thickening from:
o Edema
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o Cellular infiltration
o Inspissation in the airway lumen of abnormally thick, viscid plugs of
mucus

Clinical signs of asthma

 Shortness of breath
 Wheezing
 Coughing
 Chest tightness

Forms of Asthma

 Mild (most asthmatics have a mild form of the disease: symptoms occurring
occasionally)
 Severe (more frequent attacks of wheezing dyspnea (night!); breathing becoming
increasingly difficult, causing sweating, rapid heart beat, and great distress and
anxiety; cannot lie down or sleep, may be unable to talk; even chronic limitation
of activity
 In a very severe attack, the low oxygen in the blood causes cyanosis of the face
(lips); fatal

FEV1

Pulmonary Function Tests are essential in diagnosing asthma (show obstructive pattern);
i.e., a decrease in forced expiratory volume in 1 sec (FEV1)
 Spirometry (confirmatory test)
 If spirometry normal, FEV1 is provoked by histamine or methacholine aerosole
 This exaggerated sensitivity of the airways appears to be fundamental to
pathogenesis of asthma since:
o it is nearly ubiquitous in asthmatic patients
o the degree of fall in FEV1 correlates well with the symptomatic severity of
the disease

Therapeutic Strategies

 Aimed to reverse or prevent airway obstruction, edema and cellular infiltration

 Airway obstruction (smooth muscle contraction) is easily reversed by
bronchodilators
 Reversal of edema and cellular infiltration require sustained treatment with anti-
inflammatory drugs (steroids)
 Thus, asthma therapies are sometimes divided into “short-term relievers” and
“long-term controllers”
 30

Short-term relievers

 Are aimed to control the symptoms (reverse or prevent airway obstruction)

o Bronchodilators consist of:

 beta-2 receptor agonists
 muscarinic receptor antagonists
 theophylline

 May have no significant effects on edema and cellular infiltration

 Not used for reversal of edema and cellular infiltration; therefore, “long-term
controllers” are needed

Long-term controllers

 Are aimed to reverse or prevent edema and cellular infiltration

o anti-inflammatory drugs consist of:
 corticosteroids
 mast cell stabilizers
 leukotriene antagonists

 Are not useful in control of acute symptoms

Bronchodilators

Useful in control of acute symptoms

o Beta-2 receptor agonists
o Muscarinic receptor antagonists
o Methylxanthines

I. Sympathomimetic drugs

o Activation of the sympathetic autonomic nervous system (mainly beta-2

adrenergic receptors) leads to muscle relaxation of bronchi
o Acts as physiological antagonist of bronchoconstrictor agents

Mechanism of action

These agents relaxes smooth muscle of bronchi via an increase in cAMP

production through activation of beta-2 receptors linked to activation of
adenylate cyclase
 31

ATP

Beta-2
drug Gs A.C.
receptor
cAMP

extracellular intracellular

Beta-2 receptor agonists

• useful in control of acute symptoms

• the only agents shown to be immediately effective in the setting of acute, severe
asthma
• regular use, as opposed to use limited to symptomatic treatment, is controversial
(corticosteroids preferable)
• exacerbated bronchial hyperresponsiveness, possibly owing to tachyphylaxis
involving decreased in the number of beta-2 receptors
• In clinical studies, regular use of fenoterol led to worse control of asthma than the
use of the drug in symptomatic basis only
• Intermittent use of these drugs is highly effective and safe for exercise-induced
asthma

o Isoproterenol (prototypic drug) beta-1 and beta-2 activity

• more selective drugs for the beta-2 receptor
o albuterol
o metaproterenol
• metered-dose inhaler for control of symptoms

• Toxicities include:

o Tremor
o tachycardia (beta-1 activity)

Muscarinic antagonists
 32

• Drugs with atropine-like anti-cholinergic activity (blocking muscarinic receptors)

are useful in control of acute symptoms (bronchoconstriction)
• However, these drugs may be effective in a smaller subset of patients with asthma
than the beta-2 receptor agonists
• Available in metered-dose inhaler

Mechanisms of action
These drugs block the muscarinic receptors and prevent the bronchcostrictor action of
acetylcholine

Phosphatidylinositol

M3
antagonist
ACh Gp/q PLC
receptor
IP3
Ca++
DAG
extracellular intracellular

Side effects
 Dry mouth
 Tachycardia
 Cycloplegia

Theophylline

o Is a methylxanthine related to caffeine and theobromine

o More effective than either
o Not active by the inhaled route; given orally

Mechanism of action

It elevates the level of cAMP by inhibiting the enzyme, phosphodiesterase, responsible

for conversion of cAMP to AMP.
 33

ATP

drug receptor Gs A.C.

cAMP

Phosphodiesterase
extracellular intracellular
AMP

Other proposed mechanisms

o Antagonizes cell surface receptor for adenosine (AC; direct

action on the airway smooth muscle; provoke histamine
release) Figure 20-3 of Katzung
o However, enprofyllin has no adenosine receptor antagonistic
action
o Anti-inflammatory action (low dose inhibits late response;
withdrawal from the drug causes worsening of asthmatic
symptoms, a fall in spirometry, and significant increases in
CD4 and CD8 lymphocytes in bronchial biopsies

Side effects

o GI disturbance
o Tremors
o Nervousness (high dose of aminophylline)
o Arrhythmias
o Convulsion (over-dosed)

Anti-inflammatory drugs

 Corticosteroids
 Mast cell stabilizers
 34

 Leukotriene receptor antagonists

 Corticosteroids

o used for treatment of asthma since 1950

o inhibit production of inflammatory cytokines
o Do not relax airway; but decrease bronchial reactivity
o Increase airway caliber and reduce the frequency of asthma exacerbation
(if taken regularly)
o Could potentiate the effect of beta receptor agonists
o But, main effects, inhibition of mediators of inflammatory cells
(lymphocytic and eosinophilic)

Clinical Considerations

 Mild asthma (occasional symptoms); inhaled beta-2 receptor agonists (p.r.n.)

 More frequent symptoms (chronic asthma or nocturnal asthma) need agents with a
longer duration of action; use anti-inflammatory agents to reduce and prevent
recurrence of inflammation
 Choose among the following agents depending on the symptoms:
o beta-2 receptor agonists; oral formulations for a longer duration of action
or inhaled preparations combined with another agents, e.g., oral
theophylline
o oral theophylline
o corticosteroids: maintain on lowest dose possible (alternate day therapy)
or use inhaled formulations
o cromolyn
o ipratropium
 Acute severe asthma: needs rapidly acting agents
o s.c. epinephrine; inhalation of beta-2 agonists
 Severe attacks resistant to treatment:
o I.V. aminophylline supplemented by treatment with oxygen,
corticosteroids, and beta-2 receptor agonists
 35

ANTI-DIABETIC DRUGS

Diabetes mellitus

-Approximately 14,000,000 people have diabetes in the USA

-Defects in insulin secretion or response or both
 Type 1 (insulin-dependent; IDDM)
 Type 2 (non-insulin-dependent; NIDDM)

Pancreatic hormones

Type 1 (IDDM)

• About 9% in the USA; in juveniles (<35) very common (b/w 10-16) more than in
adults
• Adults: non-obese; elderly when hyperglycemia first appears)
• Severe form of diabetes (in untreated states associated with ketosis)
• Resulting from destruction of pancreatic beta cell (immune-mediated (viral
infection) in most cases)
• Catabolic disorder (no insulin, high glucagon, no beta cell response to insulin
releasing stimuli)
• Exogenous insulin is therefore needed
 36

Insulin chemistry

• Insulin is a small protein (51 AA; MW = 5808)

• Arranged into two chains (A and B) linked by disulfide bridges
• Stored in beta-cells in crystal forms consisting of 2 Zn + 6 insulin molecules
• 1 mg = 28 units of insulin
• 1 unit = 1/28 mg insulin
• Pro-insulin is a long-chain; cleaved to yield insulin plus C-peptide (31AA)
• Pro-insulin has a mild hypoglycemic action
• C-peptide has no known function

Insulin secretion

• Insulin is released from pancreatic beta-cells; measured by radioimmunoassay

(RIA)
 37

• Basal versus stimulated (RIA; pmol)

• Basal = 5-15 micro units/mL (30-90 pmol/L)
• Peak rise = 60-90 micro units/mL (360-540 pmol/L) during meals
• Insulinogogue stimuli (glucose; mannose, AAs (Leu, Arg); vagal activity)

Figure 41-2 shows glucose uptake by beta-cells’ glucose transporter (GluT), provides
energy (ATP). When the level of ATP is increased, it causes closure of ATP-
dependent potassium channels which will depolarize the beta cells and leads to
opening of calcium channels and finally release of insulin.
 38

Insulin degradation
 Liver (60%) and kidney (35-40%)
 In diabetics, when exogenous insulin is administered, this ratio is reversed
 Half-life = 3-5 min
 Hydrolysis of S-S bonds b/w chains A and B by insulinase (glutathione insulin
transhydrogenase) followed by proteases

Insulin receptor
alpha Insulin

alphaInsulin
Outside

beta beta

Membrane

Tyr
ATP
Inside IRS-1 P

P P Tyr
IRS-1
P P
ADP

 Is made up of two alpha and two beta subunits; kinase activity is located in the
intracellular site
 Various hormonal agents affect the affinity of insulin receptor for insulin
o Hydrocortisone
o GH
• Insulin concentration: desensitization (4-24h)
• Elevated insulin levels cause receptor down-regulation
o Obesity
o Insulinoma
 39

Glucose transporters

 May play a role in etiology and manifestations of diabetes

 GluT4, lowering blood glucose, is inserted by insulin into the muscle membrane
and fat cells from intracellular vesicles
 Defects in GluT2-mediated transport of glucose into beta cells may contribute to
the reduced insulin secretion (type 2)
 40

Insulin’s Actions

 Promotes storage of fat as well as glucose in specialized cells

 Influences cell growth and the metabolic function of various tissues

Insulin’s actions on the liver

 Increases storage of glucose as glycogen

 Resets the liver in a fed state by reversing glycogenolysis, ketogenesis, and
gluconeogenesis

I. Direct Actions:
 Insulin produces these effects directly by phosphorylation which
activates
• Pyruvate kinase
• Phosphofructokinase
• Glucokinase

While it represses gluconeogenesis enzymes

• Pyruvate carboxylase
 41

• Fructose bisphosphatase
• Glucose-6-phosphatase

II. Indirect Actions:

 By reducing fatty acid flux to the liver through its antilipolytic
action on adipocytes, insulin reduces hepatic gluconeogenesis and
ketogenesis
 Decreases urea production, protein catabolism, cAMP in the liver
 Promotes triglycerides synthesis
 Increases K+ and PO4-2 uptake

Insulin’s actions on muscle

 Promotes protein synthesis by

o increasing AA transport
o increasing ribosomal activity
 Promotes glycogen synthesis to replace expended stores due to muscle activity
o These effects accomplished by
 increasing storage of glucose into muscle cells
 inducing glycogen synthase
 inhibiting phosphorylase

Insulin’s actions on adipocytes

 Storing energy in the form of triglycerides

 Reduces FFA and increase TG storage by
o induction of lipoprotein lipase
o hydrolyzes TG from circulating lipoprotein
o glucose transport into cells to generate glycerophosphate, which permits
esterification of FFA supplied by hydrolysis of lipoproteins
o Reduction of intracellular lipolysis of stored triglyceride by
 direct inhibition of intracellular lipase
 Suppression of cAMP and dephosphorylation of the lipase in the
fat cell

Summary insulin’s actions

Table 41-3; please see above.

Insulin Preparations

Insulin Preparations differ in

 Source
 Purity
 Concentration
 Solubility
 42

 Onset and duration of action

There are 4 different types of insulin

1) Ultra-short acting
2) Short-acting
3) Intermediated-acting
4) Long-acting

• Ultra-short and short acting clear solution at neutral pH; contains Zn++
• Other preparations modified to provide prolonged action and turbid at neutral
pH with
• protamine in phosphate buffer (NPH insulin)
• varying [Zn++] in acetate buffer (ultralenete and lente insulin)
• Conventional s.c. insulin therapy consists of split-dose injections of mixture of
• Short-acting and intermediate acting
• Multiple doses of ultra-short acting or short acting along with one of
the three insulin suspensions (NPH, lente, ultralente)

Ultra-short acting (Insulin lispro)

• Switch in position of proline (28) p and lysine (29)

• Advantage: to forms hexamers, unlike human insulin
• Rapidly breaks down into monomers and is absorbed very rapidly; peak 1
h
• Human insulin (takes 2-3 times more for the hexamers to breakdown)
• Duration of action 3-4 h (lispro) < regular

Short acting (Regular insulin)

• Onset is within 30 min and last for 5-7 h

• Only forms to be administered I.V.
• 30-40% less costly than lispro

Intermediated acting

• NPH (neutral protamine Hagedorn, or isophane)

• Onset is delayed by
o Combining appropriate amounts (1:10) of protamine and insulin

Long-acting
 43

• Lente is a mixture of 30% semilente (rapid onset) with 70% ultralente

(delayed onset and longer duration)
• Beef < pork and human (onset)
• Beef > pork and human (duration)

Please also see Table 41-4

 44

Mixtures of insulins

• Onset and duration of action

• When regular is used, NPH is preferred since increased proportions of
lente to regular insulin retards the rapid action of the mixture
• The excess Zn in lente and ultralente can precipitate and therefore retards
absorption and biological effect of the mixture
• Therefore, all mixtures contain NPH rather than lente
• Lispro can be acutely (prior to injection) be mixed with either NPH, lente
or ultralente without its rapid absorption being affected
• However, premixed preparations are not stable
 45

Sources of insulin

 Beef and pork

o Human = pork (except 1 AA)
o Human = beef (except 3 AAs) [2 Threo/2 Ala]
o Most preparations contained beef insulin
o Commonly prescribed in the USA beef (70%) and pork (30%)
 Production of these preparations has recently been terminated!
o Only purified pork insulin is still available
 Human
o Less expensive
o Less immunogenic (allergy and resistance)
o By recombinant DNA techniques
o Human proinsulin gene is inserted into
o E. coli (Humulin)
o Yeasts (Novolin)

Purity of Insulin

 Gel column
o Contaminants
 Proinsulin
 Partially cleaved insulin
 These are not biologically active but are immunogenic
 Chromatography (further purified)
o When <10 ppm of proinsulin (FDA, purified)

Concentration of Insulin

 100 U/mL (100U) in 10 mL vials

 Limited supply of 500U regular human insulin in rare cases of severe insulin
resistance

Insulin’s Analogs

 Formation of hexamers delays the absorption

 Therefore, analogs are made to change the aggregation characteristics of insulin
and thus its absorption
 Switch of proline (28) to lysine (29) and vice versa led to production of Lispro
 Glargine (HOE901) is a promising soluble and ultra-long-acting insulin
 2 arginine molecules attached to B chain to C-terminal and a substitution of
 46

glycine for asparagine (A21)

Insulin delivery systems

1. Subcutaneous injection is the standard method

2. Portable Pen Injectors (to facilitate multiple s.c. injections); portable pen-sized
injectors, better compliance
3. Infusion (CSII, insulin pump), programmable to deliver individualized basal and
bolus insulin replacement
4. Inhaled insulin (under clinical trials to evaluate safety and efficacy)

Treatment with Insulin

 Type 1 diabetes
 Most type 2 diabetic patients do not need exogenous insulin for survival, but
many need exogenous supplementation to achieve optimum health
 Tight hypoglycemic control with comprehensive self-management training
(except patients with renal disease, elderly and younger children (<7)

Complication of Therapy

1. Hypoglycemia
a. delay in taking a meal
b. physical exertion
c. large dose of insulin
d. tight control without frequent monitoring
e. Patients should carry an identification card, bracelet, or necklace

Signs

Hyperactivity of both sympathetic (tachycardia, palpitation, sweating, tremulousness)

and parasympathetic (nausea, hunger) that may progress to convulsion and coma

Treatment of hypoglycemia

 Mild hypoglycemia (patients are conscious and able to swallow)

 orange juice or any sugar-containing beverages

 More severe forms (unconscious)

 20-50 ml of 50% glucose solution (I.V.)
 If I.V. is not available, 1 mg of glucagon (s.c. or i.m.) will restore
consciousness within 15 min to allow ingestion of sugar
 If glucagon is not available; small amount of honey or syrup can be
inserted in the buccal pouch; oral feeding contraindicated in
unconsciousness
 47

2. Immunopathology of insulin
 Antibodies are produced (IgA, IgD, IgE, IgG, IgM) which could
produce
 Insulin allergy
 Insulin resistance
Insulin allergy

Immediate hypersensitivity; rare case in which local or systemic

urticaria from histamine release (IgE)
S.c. nodule appearing several hours later and lasting upto 24 h (IgG)
Purified insulin has reduced risk of allergy
Use of human insulin from the onset eliminates the risk
Allergy to beef insulin can be corrected by human or purified pork
Antihistamines, corticosteroids and even desensitization
Insulin resistance

Low titer of circulating IgG anti-insulin Abs

High titer of IgG Abs develops in patients with
Some degree of tissue insensitivity (obese diabetics)
A history of interrupted insulin therapy with preparation of less-
than-pure beef insulin
This results in extremely high insulin requirement
Switching to a less antigenic insulin is useful

3. Lipodystrophy at injection sites

a. Atrophy of s.c. fatty tissue
b. Use of highly concentrated and purified insulin preparations have reduced
this problem significantly
c. Hypertrophy
d. Liposuction

Oral Hypoglycemic Agents

 Used for treatment of type 2 diabetes

 Used in combination with insulin for treatment of type 1 as well as
type 2
 Sulfonylureas
o First generation
o Second generation
 Biguanides
 Thiazolidines
 Alpha-glucosidase inhibitors
 48

Type II diabetes

• 2% of adults may be affected

• Gradual onset mainly in people >40; occasionally in adolescents
• Milder form; in most cases, diagnosed during a routine medical examination
• Insulin is produced but not enough to meet the body’s need, especially overweight
people; often the body is resistant to the effect of insulin
• Thus, type 2 diabetes is ranging from:
o Predominantly insulin resistance with relative insulin deficiency
o Predominantly secretary defects with insulin resistance

• The tissue resistance to insulin and the impaired beta-cell response to glucose
appear to be further aggravated by increased hyperglycemia
• Thus, reducing hyperglycemia by various therapeutic strategies could ameliorate
these two defects
• Dietary attempts to reduce weight are usually helpful to correct hyperglycemia
• If dietary treatments fail, oral hypoglycemic agents should be used
Oral Hypoglycemic Agents

• Used for treatment of type 2 diabetes

• Used in combination with insulin for treatment of type 1 as well as type 2

 Type 1
o Although no clear indication for the combination therapy, in the
unusual case of significant concurrent insulin resistance
o In individuals with diets very high in starch, addition of alpha-
glucosidae inhibitors (?) GI in the USA (no)

 Type 2
o BIDS (bedtime NPH with daytime sulfonylureas)
o Multiple insulin injection
o Severe insulin resistance
o Recently, other oral hypoglycemic agents can be used as well
(biguanides; alpha-gucosidase inhibitors, etc)

 Sulfonylureas
o Mechanisms of Actions
 Sulfonlureas are insulinogogues (cause secretion of insulin)
 49

Please see figure 41-2

 Block potassium channel
 Ca channel blockers could affect the action of these drugs at very
high concentrations
 Diazoxide (thiazide-like) K channel opener
• Other actions
o Exocytosis of insulin (+)
o Synthesis of insulin (-)

• Other proposed mechanisms

 Reduction of serum glucagon (type 2)
 (?) indirect inhibition (increase release of insulin and
somatostatin which inhibit alpha cell secretion)
 In the absence of beta cells, (type 1), they increase
glucagons
 Extra-pancreatic effect to increase the effect of insulin
on its target tissues (upregulation)
 initial treatment for type 2
 not rapidly-acting, unlike meglitinides

 May cause cardiovascular problems

 Secondary failure & Tachyphylaxis
o Inability to dietary compliance
o refractoriness in responding beta cells
o progressive decrease in beta cell mass

• Classified, based on the potency, as

o First generation\
 Tolbutamide (safe in elderly)
 Chlorpropamide (t1/2 = 32 h!)
 Tolazamide (shorter duration; delayed onset)
o Second generation
 potent, efficacy (chorpropamide/?), fewer side effects;
liver, urine
 Should be used with caution in cardiovascular and
elderly patients
 Glyburide (renal insufficiency, hepatic X)
 Glipizide (shorter t1/2; food delays!; hepatic and renal
problems X)
 Glucotrol XL (24 h)
 Glimepride (once daily alone/w insulin)

 Meglitinides
 50

o Fast acting insulin secretagogues

o modulate beta cell insulin release by receptors located on the K channels
o unlike sulfonylureas, no direct effect on insulin exocytosis
 Repaglinide (FDA approval in 1998)
• very fast onset & short duration of action (peak in 1 h; liver
t1/2 = 1 h); thus, used for postprandial control
• used alone or/w biguanides (no sulfur)

 Biguanides

o Mechanism of action is unclear

 direct stimulation of glycolysis in tissue, with increased removal of
glucose from blood
 reduced hepatic gluconeogenesis
 slowing glucose absorption from GI, with increased glucose to
lactate conversion by enterocytes
 reduction of plasma glucagon levels
 presence of beta cells is not necessary
 do not affect fasting but decrease postprandial glucose levels
(euglycemic versus hypoglycemic)
• Phenformin (lactic acidosis; no long-term beneficial
effects; X, USA)
• Buformin (X, USA), elsewhere (OK)

• Metformin (USA, clinical trials 1995); not metabolized,

excreted in urine; if renal failure exists, lactic acidosis will
occur since it blocks hepatic gluconeogenesis
 Prescribed in patients with refractory obesity
“insulin-resistant”
 It is advantageous over insulin and sulfonylureas in
these patients since
 it is an insulin-sparing agent
 does not increase weight
 does not induce hypoglycemia

• GI side effects, if higher doses are

not divided
o Anorexia
o Nausea
o Vomiting
o abdominal discomfort
o diarrhea (3-5%
discontinuation)
o decrease absorption of B12
 51

(chronic use)

Contraindicated in patients with renal or hepatic disease; alcoholism; hypoxia

 Thiazolidines

o Mechanism of action is unclear

 acute: post-receptor insulin-mimetic effect
 chronic: transcription of genes involved with glucose and lipid
metabolism

o Very effective drugs that enhance target tissue sensitivity to insulin so that
they reduce insulin resistance by increasing glucose uptake; euglycemic
drugs
 Troglitazone (hepatotoxicity; X, USA)
 Rosiglitazone
 Pioglitazone

 Alpha-glucosidase inhibitors

o inhibit the intestinal alpha-glucosidases; modulate postprandial digestion

and absorption of starch and disaccharides
o Only monosaccharides can be transported of the intestine to blood
o Disaccharides and polysaccarides (X); need to be digested by
 pancreatic alpha-amylase
 alpha-glucosidase
 also inhibit (sucrase; maltase; beta-glucosidases, etc)

 Weak anti-diabetic effects

 Acarbose
 Miglitol (6X > Acarbose)
o Side effects are annoying (GI)
 Flatulence
 Diarrhea
 Abdominal pain
o Used as adjunct therapy in patient who cannot
achieve glycemic goal by taking other medications
o Contraindicated in patients chronic or inflammatory
bowel disease
 52

Glucagon

• Synthesized in the alpha cells; 29 AA

• Degraded in the liver & kidney as well as in plasma and its receptor sites
• RIA, samples kept cold and enzyme inhibitors should be used
• Pharmacological effects
o metabolic effects (increases cAMP; facilitates catabolism of stored glycogen and
increases gluconeogeneis and ketogenesis)
o immediate action will be an increase in glucose at the expense of glycogen
o Cardiac effect (inotropic and chronotropic effect; cAMP-mediated)
o Smooth muscle (profound relaxation of intestine; not mediated by AC)

o Glucagon used for

 Severe hypoglycemia
 endocrine diagnosis (insulin antibody is formed in insulin-treated type 1; thus,
measure C-peptide by RIA after glucagon)
 beta-blocker poisoning (X in CHF)
 Radiology of bowel (relax the intestine)

Islet Amyloid Polypeptide

Amylin, IAPP
• A peptide; produced by beta cells
• About 1 molecule of IAPP is secreted along with 10
molecules of insulin
• no physiological function has yet characterized for this
peptide; however, it inhibit insulin-induced muscle uptake
of glucose
 53

Drugs used for the treatment of GI diseases

Acid-peptic disease

 Acid-peptic disease include

o Peptic (gastric & duodenal) ulcers
o GERD
o Pathologic hypersecretary states (Zollinger-Ellison syndrome)
 Pathogenesis is not fully understood
 Gastric acid and gastrin are necessary!
 Factors relating to mucosal resistance (protective factors) to acid
 Helicobacter pylori

Pathophysiology

 Imbalance between aggressive & defensive factors

o aggressive factors
 gastric acid
 Pepsin
 H. pylori infection
o defensive/cytoprotective factors
 Bicarbonate
 Mucus
 Prostaglandins

 Gastric acid secretion is controlled by:

o Gastrin
o Acetylcholine
o Histamine
 54

Risk factors
o Cooking
o Overindulgence
o Alcohol
o Tobacco
o NSAIDs and other drugs
o Stress
o Anxiety

Therapeutic strategies

To balance between aggressive factors and defensive/cytoprotective factors in order to

1. relieve pain associated with ulcer

2. promote ulcer healing
3. prevent recurrence

Drugs used in Acid-peptic Disease

• Antacids
• H2 receptor blockers
• Proton pump inhibitors
• Mucosal protective agents
• Antibiotics
 55

 Antacids

 Weak bases; used for centuries to neutralize acid and relief the pain (?) and
discomfort associated with hyperacidity
 Also, since pepsin is inactive in solutions with pH >4, can reduce peptic activity
 Mucosal protection, e.g., PG synthesis or binding of an unidentified substance (?)
 Most antacids contain Al or Mg (+OH) alone or as combination (Why? See the
attached PowerPoint file; table 63-1) and occasionally with NaHCO3 or calcium
salts
 56

Side effects

o Changes in bowel habits

o (constipating/cathartic)
o Cation absorption & systemic alkalosis (renal impaired patients)
o In patients with CHF, large doses of antacids containing Na!
o Little impact on GERD
o Addition of Alginic acid (Gaviscon)!

 H2 receptor antagonists
 57

 In mid 70s, Black and colleagues, developed H2 blockers

 Competing with histamine for the H2 receptors
 More specific class of inhibitors of gastric acid secretion
 These drugs are able to reduce basal and stimulated gastric acid (by 90%)
 Less effective in nocturnal secretion
 Promote healing of GI ulcers
 Prevent recurrence
 Also used for pathologic hypersecretory states (e.g., Z-E syndrome)
o Cimetidine
o Ranitidine
o Famotidine
o Nizatidine

Side effects

o All are generally well tolerated

o Cimetidine has antiandrogenic effect
o Causes gynecomastia (reversible) upon long-term high dose
o Rarely seen with ranitidine and famotidine
o Headache (34%) with famotidine and ranitidine
o Reversible hematologic abnormalities (blood testing!)
o Cimetidine inhibits hepatic microsomal enzymes and could affect metabolism of
o Theophylline, Warfarin, Diazepam, Phenytoin
o Rarely seen with ranitidine but not with famotidine

Combination therapy

 H2 blockers with antacids; little rationale

 Combination may not be beneficial
 58

 H2 blockers with omeprazole (loss of efficacy)

Refractory disease

 Lack of response to H2 blockers & antacids

o Elderly
o Cigarette smokers
 Can be overcome by
o Use higher dose (Z-E syndrome)
o Prolong treatment (Z-E syndrome)
o Switch to another H2 antagonist
o Switch to a proton pump inhibitor
o Addition of antibacterial (H. pylori)

OTC H2 blockers

• OTC products of all 4 H2 blockers

• Used for
o Heartburn
o Dyspepsia

 Antimuscarinic agents

o Decrease secretion due to inhibition of cholinergic input

o Now rarely used alone
o As adjunct therapeutic agents
o Pirenzipine (M1 antagonist) in Europe

 Proton Pump inhibitors

o Substituted benzimidazole compounds

o Irreversibly block parietal cell proton pump
o Prodrugs become active in acid
 59

 Omeprazole
 Lansoprazole
 Rabeprazole
 Pantprazole

o All drugs are effective for the short-time (up to 2 months) treatment of GI
ulcers and GERD
o At low doses, these agents are effective in preventing recurrence of GI
ulcers and esophagitis
o These drugs are superior to H2 blockers and misoprostol in the healing of
NSAID-induced GI ulcers
o also used for pathologic hypersecretory syndromes
o Z-E syndrome
o Multiple endocrine neoplasias
o Systemic mastocytosis
o used as combination therapy with clarithromycin for eradication of H.
pylori
 60

Side effects

 Relatively safe drugs

o Nausea
o Itching
o Diarrhea
o Headache and dizziness
o Rash
o Inhibition of microsomal enzymes
o Long-term use can cause malignancy in rats (?)
o Prolonged complete suppression of the acid barrier to bacterial entry into
the body and to hypergastrinemia

 Octreotide

o Is a long-acting synthetic somatostatin analog, which activate the

somatostatin (ST2) receptor and decreases acid secretion

 Mucosal protective agents

o Sucralfate or aluminum-sucrose sulfate

 a sulfated disaccharide
 Acts as a barrier to acid, pepsin and bile through polymerization
and selective binding to necrotic ulcer tissue
 Also, may directly absorb bile salts
 May stimulate PG synthesis
 Poorly absorbed (rising blood levels in patients with renal failure);
fewer side effects
 Requires acidic pH to be activated; should not be given with agents
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that reduce or neutralize gastric acid

o Colloidal bismuth compounds

 Act by binding to an ulcer, coating it and protecting it from acid
and pepsin
 Other actions
• Inhibition of pepsin activity
• Stimulation of mucus production
• Increased PG synthesis
• May also have antimicrobial activity against H.
pylori (?)

 Bismuth subsalicylate (pepto-Bismol) USA

 Tripotassium dicitrato bismuth (Europe)

o Carbenoxolone
 Synthetic derivative of glycerrhizic acid (licorce)
 Effective in healing of both gastric and duodenal ulcers
 Mechanism of action is unclear
 thought to be due to increases in production, secretion and
viscosity of intestinal mucus
 Has an aldosterone-like side effects
• Hypertension
• fluid retention
• hypokalemia
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 Some diuretics prevent the side and beneficial (?) effects

 Not available in the USA; widely used in Europe

o Prostaglandins

Cell Membrane PL
Phospholipase
Arachidonic Acid
LOX
COX

PGI2 LTs
TXA2 PGs

Leukocyte modulation LTC4/D4/E4 LTB4

Vascular permeability Phagocyte attraction activation

Bronchial constriction
Increased secretion

 Although PGs are thought to be cytoprotective, the primary

mechanism might be inhibition of gastric acid secretion (please see
above Figure 37-1).

• Misoprostol
 A methyl analog of PGE1
 Approved for treatment of NSAID-induced ulcer
 Causes diarrhea and is oxytocic (pregnancy!)

Drugs promoting GI motility

 GI motility is controlled by cholinergic ANS

o Cholinomimetic drugs can cause increases in GI motility
 Bethanechol, a directly acting cholinomimetic drug
 Metoclopramide and cisapride
• In addition to cholinomimetic, metoclopramide is a
potent dopamine antagonist and enters the CNS
• Cisapride does not cross the BBB, but activates
peripheral 5HT4 receptor
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• Both drugs release ACh from cholinergic neurons

• They may also sensitize intestinal smooth muscle
cells to the action of Ach
• They do not increase gastric or pancreatic secretion

Side effects of metoclopramide and cisapride

 Cisapride causes ventricular arrhythmias (USA ?)

o Norcisapride, under trial
 Metoclopramide
o Somnolence
o Nervousness
o Dystonic reaction
o Parkinsonism (elderly)
o Tardive dyskinesia (elderly)
o Increases prolactin release, galactorrhea & menstrual disorders

 Other drugs that cause increase in GI motility

• Erythromycin, a macrolide antibiotic
• Allosetron, a 5HT3 receptor antagonist

Anti-emetic drugs

 The physiological mechanism responsible for nausea and vomiting is

not fully understood
 Vomiting center (medulla) receives from CTZ (DA or 5HT)
 Nausea and vomiting can occur as a result of
o Pregnancy
o Motion sickness
o GI obstruction
o Peptic ulcer
o Myocardial infarction
o Renal failure
o Hepatitis
o Cancer chemotherapy (CS!); drug refusal
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 Major categories of anti-emetic drugs include

o Antihistamines
o Phenothiazines
o Metoclopramide
o Ondansetron
o Marijuana
o Corticosteroids

 Antihistamines
• Diphenhydramine
• Hydoxyzine
o Possess anti-muscarinic as well as sedative
effects
o They also have H-1 receptor blockade
properties
o articularly effective against motion sickness
 Phenothiazines
• Promethazine
• Prochorperazine
 Block dopamine receptors (CTZ)
 Others have limited use due to production of a
greater degree of sedation
 Extrapyramidal side effects, especially dystonia
(large doses; during cancer chemotherapy)
 Dystonia can be reversed by diphenhydramine

 Metoclopramide
o Block dopamine receptors (CTZ)

 Serotonin receptor antagonists (5HT3)

o Ondansetron
o Granisetron
o Dolasetron
 Used for prevention of chemo-induced nausea and
vomiting
 Less effective against
• delayed emesis
• Induced by high-dose chemo
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 Marijuana derivatives
o THC (dronabinol)
 Mechanism of action is unclear but appears to involve
receptors in the CTZ

 Neurokinin receptor antagonists (under investigation)

 Corticosteroids
o Dexamethasone; mechanism of action is unknown

 Benzodiazepines
o Anticipatory nausea and vomiting

Pancreatic enzyme replacement products

 When lipase level reduces < 10% of normal, fat will appear in stool (steatorrhea)
 In the postprandial period, about 100,000 units of lipase are delivered in the
intestine; 10,000 units/h
 Problems with use of these products:
o Enzymatic degradation of exogenous lipase (only 8%)
o Addition of cimetidine to the regimen helps
o Uric acid stones; related to high purine content
o Also, contains lactose; in lactose-intolerant patients!
o Too expensive

Laxatives

 Generally classified by simplified mechanism of action

o Irritant or stimulant laxatives
o Bulking agents
o Stool softeners
 However, they have more complex mechanisms of action

• Irritant or stimulant laxatives

o Caster oil
 Become hydrolyzed in the intestine to ricinoleic acid
 Onset of action is immediate and last until it is out
o Cascara, Senna, Aloes
 Contain emodin alkaloids liberated after absorption from
the intestine and excreted in the colon, where peristalsis is
stimulated (onset is delayed; 6-8 h)

o Phenolphtalein and bisacodyl

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 Chemically similar; potent colonic stimulants; increased

duration of action due to enterohepatic circulation
• Bulking laxatives
o Hydrophilic colloids
 Made of ingestible part of fruits, vegetables & seeds
 Form gels within the colon; distending it
o Agar, psyllium seed & methylcellulose
 Work the same way as above
o Bran and other forms of vegetable fibers
 Work the same way as above
o Saline cathartics (Mg salts)
 Also distend the colon and stimulate peristalsis
o Isosmotic solutions containing PEG
 Work in the same manner
 Serve as colonic lavage solutions for removal of ingested
toxin and for radiological procedures
o Lactulose
 a synthetic disaccharide (galactose-fructose)
 Not absorbed
o Sorbitol
 Non absorbable

• Stool softeners
o Emulsified with stool
o Serve to soften the stool and make passage easier
 Mineral oil
 Glycerin suppositories
 Detergents (DDSSS, docusate)
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Antidiarrheal drugs

 Two most widely used

o Diphenoxylate (with atropine)
 A weak analog of meperidine
o Loperamide (OTC)
 Related to haloperidol
 Does not cross BBB
 Thus, less sedating and addicting
o Difenoxin (not OTC)
 An active metabolite of diphenoxylate (ACh(-)release)
 Should not be used in patients with severe ulcerative
colitis, since it may precipitate toxic megacolon
 May prolong the duration of diarrhea in patients infected
by Shigella or Salmonella
 Could be useful in patients with irritable bowel
syndrome, particularly when combined with
 Increased dietary fiber
 Anticholinergic drugs as antispasmodics
 Supportive counseling
o Kaolin and pectin
 Absorb toxins and drugs