Woyesa Elema

Specific objectives:

 At the end of this lesson students will be able to:

 Describe functional differences and receptors of

Parasympathetic and Sympathetic NS

 Identify cholinergic, cholinergic blocker, adrenergic,

adrenergic blocker and ganglionic blocker drugs

 Describe therapeutic use, adverse drug reactions and

possible drug interactions of the above mentioned
groups of drugs
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 NS
• The NS is divided in to CNS and PNS
• The PNS consists of
– all afferent (sensory) neurons, which carry nerve
impulses into the CNS
– all efferent (motor) neurons

• The peripheral efferent (motor) system is further

divided into the somatic nervous system and the
autonomic nervous system.
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 PNS
• The ANS is largely autonomous in that its activities
are not under direct conscious control.
– It is concerned primarily with visceral functions : cardiac
output, blood flow to various organs, digestion etc
• The function of the ANS is to maintain the constancy
of the internal environment (homeostasis).
• The somatic division is largely concerned with
consciously controlled functions such as movement,
respiration, and posture.

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 PNS
• Peripheral nervous system provides a double
set of nerve fibers:
 Sympathetic (adrenergic) fight or flight
• Exit from thoracic and lumbar regions
•
 Parasympathetic (cholinergic) rest and
sleep
• Exit from cranial and sacral portions
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 Comparison

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 Neurotransmitter Chemistry
• Neurotransmission in the PNS occurs at 3 major sites:

1. Preganglionic synapses in both parasympathetic and

sympathetic ganglia,
2. Parasympathetic and sympathetic postganglionic
neuroeffector junctions
3. All somatic motor end plates on skeletal muscle

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 Neurotransmitter…
• Ach(acetylcholine) is the transmitter released at all of
these sites except for the majority of sympathetic neuro
effector junctions and released from cholinergic
neurons.
• NE(norepinephrine) is the transmitter released at most
sympathetic postganglionic neuro effector junctions and
released from adrenergic or noradrenergic
neurons.
• Two NTs have particular clinical importance.
– Both are synthesized and stored primarily in the
nerve terminals
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 Neurotransmitter…
• Dopamine is a very important transmitter in the CNS
and released by some peripheral sympathetic
fibers.
• Adrenal medullary cells release a mixture of E & NE.
• Drugs that mimic the actions of Ach are termed
cholinomimetic or parasympathomimetic
drugs.
• Drugs that block the actions of Ach are known
as cholinoreceptor antagonists
– The receptors are called cholinoreceptors

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 Neurotransmitter…
• Drugs that mimic Epinephrine(E) or NE are
adrenomimetic or sympathomimetic and drug that
antagonize NE are known as adrenoceptor
antagonists
• Many visceral organs are innervated by both divisions

• When, mostly, an organ receives dual innervation, the

two systems work in opposition to one another.

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 Blood Vessels

• Most vascular smooth muscle is innervated by SNS

• Some blood vessels in the face, tongue, and urogenital
tract (especially the penis) are innervated by parasymp
and symp neurons.
• The parasympathetic innervation of blood vessels has
only regional importance
– In salivary glands, causes vasodilation that
supports salivation.
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 Blood Vessels
• There is a continuous outflow of noradrenergic
impulses to the vascular smooth muscle
– therefore some degree of constant vascular
constriction is maintained.
• An increase in impulse outflow causes further
contraction of the smooth muscle
– resulting in greater vasoconstriction.

• A decrease in impulse outflow permits the smooth

muscle to relax, leading to vasodilation.
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 The heart
• The heart is innervated by both symp. and parasymp.
neurons; however, their distribution in the heart is dt.
• Postganglionic noradrenergic fibers innervate the
sinoatrial (S-A) node and myocardial tissues of the
atria and ventricles.
• Activation of the parasympathetic outflow to the
heart results in -ve chronotropic effect and -ve
dromotropic effect.
• Effect of a drug on the heart depends on the balance
of SP and PSP activity at the time the drug is given

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 The heart
• During rest or mild activity, the heart is predominantly
under the influence of the vagal parasympathetic
system.
• Blockade of the autonomic innervation of the heart by
the administration of a ganglionic blocking agent
accelerates the heart rate.
• Conversely, if sympathetic activity is dominant, as in
exercise, ganglionic blockade will decrease the heart
rate and also reduce ventricular contractility.
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 Cardiovascular Reflexes

• Any sudden alteration in the mean arterial BP tends to

produce compensatory reflex changes in heart rate,
contractility, and vascular tone, which will
– oppose the initial pressure change and restore the
homeostatic balance.
• The injection of a vasoconstrictor, which causes an
increase in mean Arterial BP
– results in activation of the baroreceptors
– increased neural input to the CV centers in the medulla.
 The reflex compensation includes an ↑se in parasym. nerve
activity and a ↓se in symp. nerve activity.

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 The Eye
• Two sets of smooth muscle in the iris control the
diameter of the pupil.
 One set of muscles, which is arranged radially (dilator
pupillae), is innervated by sympathetic fibers
– Stimulation of them causes contraction of the radial smooth
muscle cells, leading to dilation of the pupil (mydriasis).
 The other set of smooth muscle cells in the iris
(constrictor pupillae) is circular and is innervated by
parasympathetic neurons.
– Stimulation of these cholinergic neurons causes contraction
of the circular smooth muscle of the iris and constriction of
the pupil (miosis).
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 The Eye
• Naturally elastic, the lens thickens, and the eye
accommodates for near vision.
– Drugs that block accommodation(adjustement of the shape
of the lens to change the focus of the eye) are called
cycloplegic.
• Since the parasympathetic system is dominant in the
eye, blockade of this system by atropine or of both
autonomic systems by a ganglionic blocking agent
will result in pupillary dilation and a loss of
accommodative capacity.

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 Pulmonary Smooth Muscle

• The bronchial tree is innervated by both NS

• Postganglionic parasympathetic neurons innervate
bronchial smooth muscle directly and produce
bronchoconstriction when stimulated.
• Sympathetic neurons appear to innervate vascular
smooth muscle and parasympathetic ganglion cells.
• The effect of noradrenergic fibers on ganglion cells is
to inhibit their firing.
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 GIT…

• The effects of symp and parasymp nerve stimulation are

superimposed on this local neural regulation.
• The myenteric and submucosal plexuses contain ganglion
cells giving rise to excitatory cholinergic fibers that
directly innervate the smooth muscle and gland cells of the
gut.
• The sympathetic fibers that enter the GIT are
postganglionic NArgic fibers, stimulation of which inhibits
gut motility and gland secretion and contracts sphincters.
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 Salivary Glands

• One exception to the generalization that the two systems

work in opposition to each other is secretion by the
salivary glands
– Both noradrenergic and cholinergic activation of these glands
leads to an increase in the flow of saliva.

• But its nature is different.

– That of symp. system is a sparse, thick, mucinous secretion
– That produced by parasym. activation is a profuse, watery
secretion.
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 The Adrenal Medulla

• The chromaffin cells are homologous with sympatheti

postganglionic neurons.
– The adrenal medulla may in fact be considered a modified
sympathetic ganglion.

• The adrenal medulla secretes 2 hormones: E and NE

• General activation of the sympathetic system (during
stress, fear, or anxiety)
– consist primarily of epinephrine in the human.

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 The Adrenal….
• Endogenous substances (such as histamine,
angiotensin, and bradykinin) can directly stimulate
the chromaffin cells to secrete epinephrine and NE.
• A variety of exogenously administered drugs (such as
cholinomimetic agents and caffeine) can directly
stimulate the secretion of adrenal hormones.
• The neuronally induced secretion of medullary
hormones is antagonized by ganglionic blocking
agents.

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 Steps In Neurochemical Transmission

• Regardless of the type of neuron, the fundamental

steps in chemical transmission are the same.
• Each of these steps is a potential site for p’cological
intervention in the normal transmission process:
1. Synthesis of the transmitter
2. Storage of the transmitter
3. Release of the transmitter by a nerve action potential

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 Steps In Neurochemical Transmission

4. Interaction of the released transmitter with receptors

on the effector cell membrane and the associated change
in the effector cell
5. Rapid removal of the transmitter from the vicinity of
the receptors
6. Recovery of the effector cell to the state that preceded
transmitter action
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 Cholinoceptors
• Cholinergic Receptors:
• Muscarinic (M):

M1-Stomach (HCl formation)

M2-Heart
M3-Smooth muscle (GI, bronchi, genito-urinary,
some BV) Exocrine glands
• Nicotinic (N):
– Nn-Autonomic ganglia , Nm-Skeletal muscle
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 adrenoceptors

Alpha (a1):Smooth muscle, GIT, bronchi, Genito-

urinary & most Blood vessels
• Alpha(a2): CNS (vasomotor center)
• Beta (b1): Heart
• Beta(b2): Some BV (Sk. muscle), bronchi, uterus

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 Receptor and Physiologic Responses
Alpha1
•Increases force of heart contraction; vasoconstriction increases BP;
mydriasis; salivary glands decrease secretions; bladder and prostate
capsule increases contraction and ejaculation
Alpha2
•Inhibits the release of nor epinephrine; dilates blood vessels;
produces hypotension
Beta1
•Increases heart rate and contraction; increases renin secretion----
increase BP
Beta2
•Dilates bronchioles; GI and uterine relaxation; increase in blood
sugar through glycogenolysis in the liver; increases blood flow in the
skeletal muscles
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PARASYMPATHOMIMETICS
(Classification)
• Direct Acting:
– Pilocarpine(natural alkaloid)
– Bethanechol, carbachol(synthetic)
– Acetylcholine
• Indirect Acting: (Anti-cholinestrases)
– Reversible
• Edrophonium(very short acting)
• Physostigmine, neostigmine, Carbamate(intermediate
acting)
• Pyridostigmine(long acting)
• Irreversible: echothiophate
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 Direct acting
• Acetylcholine :is the prototypical cholinergic
agent
• It functions as a neurotransmitter at all

cholinergic sites in the body

• because of its unique pharmacokinetic properties
has no clinical utility b/c it is easily hydrolyzed by
stomach acid and Acetylcholine esterase in
blood
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 pkinetics
• Acetylcholine is poorly absorbed from the gastric
mucosa;
• Ineffective if given orally

• The recommended to use parenteral

• In the blood it is rapidly hydrolyzed by the enzyme

cholinesterase into acetic acid and choline
• This makes its duration of action very short and
unreliable for therapeutic woyesa.E
purposes.
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 P dynamics

• It has two types of actions: nicotinic and muscarinic

• Cardiovascular system
– Heart: slow heart rate
– Blood vessels: vasodilator
– Blood pressure: falls because of the effect on the heart and blood
vessels

• Gastrointestinal tract
– It stimulates the tone and motility of the Gl tract but the sphincters will
be relaxed.
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 Cont..
• Urinary tract
– It stimulates the detrusor muscle and relaxes the internal
urethral sphincter resulting in evacuation of bladder
• Bronchioles
– It increase bronchial secretion and brings about
bronchoconstriction
• Eye
– It has two effects- miosis and accommodation for near
objects because of stimulation of the constrictor pupil and
ciliary muscles respectively.
• Exocrine glands- it stimulates salivary, gastric,
bronchial, lachrymal and sweat gland secretions
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 Cholinoceptor…..
• Unselective cholinoceptor stimulants in sufficient dosage
can produce very diffuse and marked alterations in organ
system function
– because Ach has multiple sites of action where it initiates both
excitatory and inhibitory effects.

• Fortunately, drugs are available that have a degree of

selectivity
– so that desired effects can often be achieved while avoiding or
minimizing adverse effectswoyesa.E
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 Mode of Action of Cholinomimetic Drugs

• Direct-acting cholinomimetic agents directly bind to

and activate muscarinic or nicotinic receptors
• Indirect-acting agents produce their primary effects by
inhibiting acetylcholinesterase.
– the excess Ach in turn stimulates cholinoceptors to
evoke increased responses.

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 Mode of Action of Cholinomimetic Drugs
• Some cholinesterase inhibitors also inhibit
butyrylcholinesterase (pseudocholinesterase).
– also known as plasma, and nonspecific cholinesterase
• Has a widespread distribution, with enzyme
especially abundant in the liver, where it is
synthesized, and in the plasma.
– Plays little role in the action of indirect-acting
cholinomimetic drugs
 Because this enzyme is not important in the physiologic
termination of synaptic Ach action.

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 Direct-Acting Cholinoceptor Stimulants
• Can be divided on the basis of chemical structure into
– esters of choline (including Ach)
– alkaloids (such as muscarine and nicotine).
• A few of these drugs are highly selective for the
muscarinic or for the nicotinic receptor.
– Many have effects on both receptors; Ach is typical.
• Some quaternary cholinesterase inhibitors also
have a modest direct action as well
– Neostigmine which activates NM nicotinic
cholinoceptors directly in addition to blocking
cholinesterase.
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 Direct-Acting…
• The therapeutic usefulness of ACh is limited by
– (1) its lack of selectivity as an agonist for different
types of cholinoreceptors and
– (2) its rapid degradation by cholinesterases.
• Development of three choline ester derivatives of ACh:
methacholin , carbachol and bethanechol (Urecholine).

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 Direct-Acting…
• Methacholine differs from ACh only in the
addition of a methyl group at the -carbon of
ACh.
– This modification greatly increases its selectivity for
muscarinic receptors relative to nicotinic receptors
– It renders methacholine resistant to the pseudo-ChE
in the plasma and
– Decreases its susceptibility to AChE
Thereby increasing its potencyand duration of action
compared to those of ACh.

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 Direct-Acting…

• Carbachol differs from ACh only in the

substitution of a carbamoyl group for the terminal
methyl group of ACh.
– makes carbachol completely resistant to degradation by
cholinesterases
– does not improve its selectivity for muscarinic versus
nicotinic receptors
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 Direct-Acting…
• Bethanechol combines the addition of the
methyl group and the substitution of the
terminal carbamoyl group Producing a drug
that is
– A selective agonist of muscarinic receptors
– Resistant to degradation by cholinesterases.
• All of these drugs are very hydrophilic and membrane
impermeable
– are poorly absorbed and poorly distributed into the CNS

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 Direct-Acting…

• Although all are hydrolyzed in the GIT, they differ

markedly in their susceptibility to hydrolysis
• The tertiary natural cholinomimetic alkaloids
(pilocarpine, nicotine, lobeline) are well absorbed
from most sites of administration.
• Nicotine, a liquid, is sufficiently lipid-soluble to be
absorbed across the skin.
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 Direct-Acting…
• Lobeline is a plant derivative similar to nicotine.
• These amines are excreted chiefly by the kidneys.
• Pilocarpine is a tertiary amine that crosses
membranes relatively easily.
– it is rapidly absorbed by the cornea of the eye, and it
can cross the blood-brain barrier.
– It is a pure muscarinic receptor agonist, and it is
unaffected by cholinesterases.

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 Basic Pharmacology of…
• Methacholine, bethanechol, and pilocarpine are selective
agonists of muscarinic receptors
• Carbachol and ACh can activate both muscarinic and
nicotinic receptors.
• At usual therapeutic doses, the effects of carbachol and ACh
are entirely due to the activation of M
– The greater accessibility and abundance of these
cholinoreceptors compared with the N
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 Basic Pharmacology of…
• Low doses of muscarinic agonists given IV relax
arterial smooth muscle and produce a fall in BP
– stimulation of M on vascular endothelial cells
• Activation of these receptors by directly acting
cholinomimetic drugs has major p’logical
significance
– As the potentially dangerous hypotension produced
by their activation is an important limitation to the
systemic administration of muscarinic agonists.

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 Basic Pharmacology of…
• At low dose of a muscarinic agonist can sometimes
increase HR
• At higher concentrations of a muscarinic agonist, the
direct effects on cardiac muscarinic (M2) receptors in the
SA node and A-V fibers become dominant.
– marked bradycardia and a slowing of A-V conduction

• When these drugs are applied to the eye, they cause

miosis and allowing the lens to focus for near vision.
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 Basic Pharmacology of…
• Prominent effects within the digestive tract include
stimulation of salivation and acid secretion, increased
intestinal tone and peristaltic activity, and relaxation
of most sphincters.
• Bronchoconstriction and stimulation of secretions are
prominent effects in the respiratory system.
• evoke secretion from nasopharyngeal glands and
Urination is promoted
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 Clinical Uses

 Glaucoma ;Open-angle glaucoma ;But a spasm of

accommodation and miosis seriously disturb vision.
 Therefore, they have been replaced by β2-blockers
and carbonic anhydrase inhibitors, both of which
decrease the formation of aqueous humor without
affecting vision.
 Urinary Retention
• Bethanechol in postsurgical bladder dysfunction
associated with the retention of urine.
 Diagnosis of Bronchial Hyperreactivity

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 Adverse Effects

• Potentially severe adverse effects can result from

systemic administration of cholinomimetic drugs
– None should be administered by IM or IV
injection.
Nausea, abdominal cramps, Diarrhea
Salivation,Sweating and bronchoconstriction
Hypotension with reflex tachycardia
Cutaneous vasodilation
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 contraindication

• Mechanical obstruction of the bladder or

gastrointestinal tract
• Asthmatic pnt

• Hypotension

• Clossed angle glaucoma

• Brady cardiac arrthmia

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 CHOLINESTERASE INHIBITORS
• The indirect acting cholinomimetic are more
selective than direct acting cholinomimetics
b/c the inhibitors of AChE increase the activation of
cholinoreceptors only at active cholinergic synapses.
• At therapeutic concs, inhibitors of AChE do not
activate cholinoreceptors at sites that do not
receive cholinergic synaptic input, such as
endothelial M

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 CHOLINESTERASE INHIBITORS

• Inhibition of true AChE is most important for

potentiating the synaptic activity of Ac
• Several AChE inhibitors also inhibit the pseudo-ChE
in plasma.
– This can permit plasma concentrations of ACh to
rise markedly and activate endothelial muscarinic
receptors.
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 Quaternary Ammonium Agents

• Edrophonium and ambenonium quaternary

ammonium alcohols.
• Edrophonium has a very short duration of action,
lasting only 5 to 10 minutes
• Inhibition by ambenonium can last 4 to 8 hrs
• These drugs have direct agonist activity at N

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 carbamates
• Carbamate anticholinesterase agents are carbamic acid
esters
– hydrolyzed by AChE in a manner similar to that of ACh.

– The carbamates generally inhibit pseudo-ChE as well as true

AChE

• Their suicidal degradation by cholinesterases contributes

importantly to terminating their duration of effect.

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 carbamates
• Physostigmine ; inhibit AChE in the CNS, and used in
life-threatening antimuscarinic poisoning.
• Pyridostigmine is a quaternary ammonium with slightly
longer duration of action than neostigmine and it
causes fewer muscarinic side effects.
• Neostigmine and pyridostigmine also have direct
agonist activity at N on skeletal muscle.
• Rivastigmine is a carbamate cholinesterase inhibitor
with good penetration into the brain.
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 Organophosphates
• They are much less selective than are the
carbamates
• Parathion and malathion (insecticides) are
thiophosphates
• The organophosphates, except for echothiophate, are
very lipid soluble
– These agents are referred to as irreversible
inhibitors.????
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 Inhibitors targeted at AChE in the CNS

• Drugs have been developed for use in treating

Alzheimer’s disease: the drugs enter the CNS.
• Tacrine is and Donepezil
– Donepezil is a relatively specific inhibitor of AChE in the
brain with little effect on pseudo- ChE in the periphery.

• Galanthamine is a tertiary alkaloid

• phenanthrene derivative is a reversible competitive
inhibitor of AChE; it also acts on nicotinic receptors.
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 Absorption
• Most of the organophosphates are absorbed by all
routes of administration
– Because of their high lipid solubility and low MW
• Physostigmine and rivastigmine are tertiary amines
that are rapidly absorbed from the GIT as Tacrine,
donepezil, and galanthamine
• Quaternary ammonium (neostigmine and
pyridostigmine)are are poorly absorbed after oral
administration.
– They do not readily enter the CNS.

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 Basic Pharmacology
• Neuromuscular transmission in skeletal muscle is
enhanced by low concentrations of anticholinesterase
agents
– high concentrations result in cholinergic blockade.
– If ACh levels remain high, the nicotinic
cholinergic receptors can quickly become
desensitized.
– Muscarinic receptors do not exhibi comparable
desensitization.

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 Clinical Uses

 Myasthenia Gravis; Pyridostigmine and neostigmine

• Muscle weakness and rapid fatigue of muscles during
use are characteristics of the disease.
• Anticholinesterase agents help to alleviate the
weakness by elevating the concentration of Ach
while, plasmapheresis, and corticosteroid are directed
at decreasing the autoimmune response.
• In cholinergic crisis dx, edrophonium will briefly
cause a further weakening of muscles.

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 Clinical Uses
 Smooth Muscle Atony
• Neostigmine is most commonly used, and it can be
administered Sc and IM
 Antimuscarinic Toxicity
• A number of drugs in addition to atropine and
scopolamine have antimuscarinic properties.
– Tricyclic antidepressants, phenothiazines, and
antihistamines,
– Physostigmine…….
 Alzheimer’s Disease; used agent cross BBB
– tacrine, donepezil, rivastigmine, and galanthamine.
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 Clinical Uses
 Glaucoma;open-angle glaucoma
 Strabismus
• Long-acting anticholinesterase agents, such as
echothiophate or demecarium, are employed

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 Adverse Effects
• Excessive inhibition can ultimately lead to a
cholinergic crisis that includes
– GI distress , respiratory distress, CV distress,
visual disturbance, sweating, and loss of skeletal
motor function.
– CNS symptoms include dizziness, and mental
confusion.
– Death usually results From paralysis of skeletal
muscles required for respiration

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 Treatment of Anticholinesterase Poisoning

• The first step is atropine sulfate

– To block stimulation of muscarinic receptors.
• Mechanical respiratory support is required.
• If the poisoning is due to an organophosphate
– pralidoxime chloride will result in
dephosphorylation of cholinesterases in the
periphery.
– it will not enter the CNS and cannot reactivate
central cholinesterases.why???

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 P’LOGICAL ACTION
Antimuscarinic drugs are competitive
antagonists of the binding of ACh to muscarinic
receptors
• The tissues or systems affected will depend on
– the dose administered
– the drug’s p’kinetic properties (e.g. increased entry
into the CNS at higher conc.)
– the differential sensitivity of muscarinic receptors
in various organs to individual blocking agents.

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 CLINICAL USES
 Cardiovascular Uses
• Atropine is useful in pts with carotid sinus syncope.
• If sinus bradycardia is due to extracardiac causes,
atropine can generally elicit a tachycardic response.
 Uses in Anesthesiology
• Atropine or scopolamine
• Now this premedication is not routinely required due
to the less irritating new anesthetics.
 Use With Cholinesterase Inhibitors to prevent
excessive inhibition of AChE:

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 CLINICAL USES
 Uses in Ophthalmology
• Antimuscarinic drugs are widely used to
produce mydriasis and cycloplegia.
Uses in Disorders of the Digestive System
• Nonselective antimuscarinic drugs
– have been employed in the therapy of peptic ulcers
– as adjunctive therapy in the tt of irritable bowel
syndrome.
– They can decrease the pain associated with
postprandial spasm of intestinal smooth muscle.
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 CLINICAL USES
Uses in Urology
• Propantheline, oxybutynin, dicyclomine,
Tolterodine
– Have been used for uninhibited bladder syndrome,
bladder spasm, enuresis, and urge incontinence.
Uses in Respiratory Disorders
• for the tt of asthma, but displaced by the
adrenergic drugs
– due to low therapeutic index and impaired
expectoration
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 CLINICAL USES
• Dryness of the mouth, cough, and a bad taste may
occur but it does not appear to have other significant
adverse effects.
• It does not affect mucociliary transport or the volume
and viscosity of sputum.
• Its effectiveness in chronic obstructive lung disease is
equal or better than β2-adrenergic agonists
– less effective than β2-adrenergic agonists in asthma,
– it is useful when combined with other bronchodilators.

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 CLINICAL USES
 Uses in Parkinsonism
– since there is an apparent excess of cholinergic activity
– Antimuscarinics are sometimes employed for mild cases
– in combination with other agents (e.g., levodopa).
 Uses in Motion Sickness
• Scopolamine for very stressful and of short duration.
• When the motion is less stressful and lasts longer,
H1- antagonists are probably preferable
– especially for the prophylactic tt of motion sickness.

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CONTRAINDICATIONS AND CAUTIONS

• These agents are contraindicated in

– Glaucoma, Cardiac disease and hyperthyroidism,
prostatic hypertrophy,and reflux esophagitis
• Infants and children
• Elderly with impairment of memory.
• With Phenothiazines and tricyclic
antidepressants
• gastrointestinal infections

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 Adrenomimetic drugs
• The adrenomimetic (sympathomimetic )drugs
mimic the effects of adrenergic sympathetic
nerve stimulation on sympathetic effectors.
• The adrenergic transmitter NE and Epinephrin
• Their therapeutic importance
– can be used to maintain BP
– to relieve acute bronchial asthma.
– they constrict mucosal blood vessels and thus
relieve nasal congestion

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 Adrenomimetic drugs
• They can be divided into two major groups on
the basis of their chemical structure:
– The catecholamines and the noncatecholamines.
• The catecholamines include NE, Ep, and DA (are
naturally occurring) and several synthetic
substances, such as isoproterenol.
 Sympathetic effectors have activity at α1-, α2-,
β1-, or β2- or in some cases, combinations of
these adrenoceptors with vary affinities for each
receptors.
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 Adrenomimetic drugs

• Some have a high affinity for all of the adrenoceptors.

– like epinephrine,

• Others are relatively selective.

– Isoproterenol has a high affinity for β1- and β2-adrenoceptors
but a very low affinity for α-adrenoceptors;
– Isoproterenol is considered a nearly pure β-agonist.
– NE has a high affinity for α- and β1-adrenoceptors but a
relatively low affinity for β2-receptors.

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 Adrenomimetic drugs
• They can be divided into two based on their MOA
i. Directly acting adrenomimetic drugs
– NE, E, and others produce responses in effector cells by
directly stimulating adrenoceptors
ii. Indirectly acting adrenomimetic drugs
– like amphetamine do not themselves interact with
adrenoceptors, but releasing NE from neuronal storage.
• Some of these drugs act both directly and indirectly
– Such drugs are called mixed-action adrenomimetics.

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 CLINICAL USES
• The clinical uses of catecholamines are based
on their actions on bronchial smooth muscle,
blood vessels, and the heart.
• Ep is also useful for the tt of allergic reactions
like anaphylactic shock, urticaria, angioneurotic
edema, and serum sickness.
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 CLINICAL USES
• Ep and NE have been used to prolong the action of
local anesthetics
– Due to their vasoconstrictor actions
• Ep has been used as a topical hemostatic agent
for the control of local hemorrhage.
• NE is infused IV to combat systemic hypotension
during spinal anesthesia or other hypotensive
• Dopamine is used in the treatment of shock like
(cardiogenic shock, septic shock), due to MI or CHF.

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 Adverse Effects
• Produce rapid HR.
– Tachycardia(ep) and bradycardia(NE.
• Headache, tremor, anxiety, fear, and nervousness.
• Overdosage with Ep and NE are cardiac arrhythmias,
excessive hypertension, and acute pulmonary
edema.
• Isoproterenol produce excessive cardiac stimulation
• Tissue sloughing and necrosis due to local ischemia
may follow extravasation
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 OTHER ADRENOMIMETIC AGENTS

• non catecholamines.
– Some directly acting cpds, such as phenylephrine and
methoxamine, activate α-adrenoceptors almost
exclusively,
– Others, like albuterol and terbutaline, are nearly
pure β- adrenoceptor agonists.
 Some of the indirectly acting amines are used
primarily for their vasoconstrictive properties.
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 OTHER ADRENOMIMETIC

• Many noncatecholamine adrenomimetic amines

– Resist enzymatic destruction
– Have prolonged actions
– Are orally effective
• The indirectly acting drugs are effective only when
given in large doses, and they often produce
tachyphylaxis.

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 Directly Acting Adrenomimetic Drugs

Phenylephrine, Metaraminol, and Methoxamine

• These drugs are directly acting amines that exert

their effects primarily through an action on α.
– These agents have little or no direct action on the
heart.

• All three drugs increase both systolic and

diastolic BP through their vasoconstrictor action.
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 Directly Acting ….

• Phenylephrine is not a substrate for COMT and has

20 minutes duration of action.
• Metaraminol and methoxamine are not metabolized
by either COMT or MAO.
 Their duration of action is 60 minutes longer than NE.
 They are potent vasoconstrictor

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 Directly Acting ….

• Phenyephrine should not be given to pts with closed-

angle glaucoma before iridectomy
– Increases in intraocular pressure may result.

• Apraclonidine and brimonidine are α2-selective

agonists that also lower IOP(approved for glaucoma)
• In dentistry, phenylephrine is used to prolong the
effectiveness of a local anesthetic and nasal decongestant.

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 Directly Acting …

 Xylometazoline and oxymetazoline

• Are direct-acting α-agonists.

• These drugs have been used as topical decongestants

because of their ability to promote constriction of the
nasal mucosa.
• When taken in large doses, oxymetazoline may cause
hypotension, presumably because of a central
clonidine-like effect
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 Directly Acting …
 Dobutamine

• Dobutamine, in contrast to dopamine, does not produce a

significant proportion of its cardiac effects through the
release of NE from adrenergic nerves
– Dobutamine acts directly on β1-adrenoceptors in the heart.

• Dobutamine exerts a greater effect on the contractile force

of the heart relative to its effect on the heart rate than does
dopamine and more useful for cardiogenic shock.
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 Directly Acting …
 Terbutaline and Albuterol

• Both are relatively selective β 2 agonists.

• Both have a longer duration of action than
isoproterenol
– because they are not metabolized by COMT.

• Like isoproterenol, they are not metabolized by MAO

and are not transported into adrenergic neurons
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 Directly Acting …

• Both are effectively given either orally or sc.

• They produce less cardiac stimulation than

does isoproterenol. why???/
– but are not completely without effects on the
heart.

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 Directly Acting …
• Therapeutical, Uses
 Bronchial asthma and bronchospasm
Bronchitis and emphysema
• Side effects include nervousness, tremor,
tachycardia, palpitations, headache, nausea,
vomiting, and sweating.
• adverse effects is minimized by giving through
inhalation. how????
• β2-selective agents used as tocolytic. How???
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 Indirectly Acting Adrenomimetic Drugs

 Ephedrine

• Ephedrine is a naturally occurring alkaloid that can

cross the BBB and exert a strong CNS-stimulating
• The peripheral effects are primarily due to its indirect
actions and depend largely on the release of NE
• It may cause some direct receptor stimulation,
particularly in its bronchodilating effects.
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 Indirectly Acting….

• Its duration of action is longer than that of

NE.why?
– It is much less potent than NE

– Tachyphylaxis develops to its peripheral actions.

• Unlike Ep or NE, ephedrine is effective when

administered orally.
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 Indirectly Acting….

• Ephedrine increases systolic and diastolic BP

• HR is generally not increased.
• Contractile force of the heart and CO are 
• It produces bronchial smooth muscle relaxation of
prolonged duration (asthma tt)
• It has little effect on the eye (aside from pupillary
dilation ).
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 Clinical Uses of Ephedrine
• Its bronchodilator action is weaker than that of
Isop.
– Its oral effectiveness and prolonged duration of
action make it valuable in the tt of these
conditions.
• Terbutaline and albuterol are replacing
ephedrine for bronchodilation
– Their oral effectiveness and greater bronchiolar
selectivity,.

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 Adverse effects of Ephedrine

• Adverse effects include

– tachycardia, premature systoles, insomnia,
nervousness, nausea, vomiting, and
emotional disturbances may develop.

• It should not be used in patients with ......

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 Indirectly Acting….
Amphetamine
• It is an indirectly acting agent
• Its p’logical effects are similar to those of
ephedrine
– Its CNS stimulant activity is somewhat greater.
• Both systolic and diastolic BP are increased by
oral dosing with amphetamine.

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 Indirectly Acting….

• The HR is frequently slowed reflexively.

• CO may remain unchanged in the low- and moderate-
dose
• The therapeutic uses of amphetamine are based on its
ability to stimulate the CNS.
• It has been used in the tt of obesity. How??
• It overcomes fatigue

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 Indirectly Acting….

Amphetamine is useful in certain cases of

narcolepsy or minimal brain dysfunction.
• Methylphenidate and pemoline are
amphetamine variants which appear to have
efficacy in some children with ADHD.
• It is no longer recommended for these use. b/c??
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 Indirectly Acting….
Tyramine
• Is a by-product of tyrosine metabolism in the
body
• Is also found in high conc. in fermented foods
• It is readily metabolized by MAO in the liver
– Is normally inactive when taken orally because of
a very high first-pass effect.
• If administered parenterally, it has an indirect
sympathomimetic action (by the release of
NE)
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 Indirectly Acting….
• So, its spectrum of action is similar to that of NE.

• In pts. treated with MAO inhibitors, this effect of

tyramine may be greatly intensified, leading to
marked increases in BP.
• Pts. taking MAO inhibitors must be very careful
to avoid tyramine-containing foods. Why?

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 Adrenoceptor Antagonists
• Agents that inhibit responses mediated by
adrenoceptor activation.
• These drugs compete with adrenomimetic substances
for access to the receptors.
– These agents reduce the effects produced by both
sympathetic nerve stimulation and by exogenously
administered adrenomimetics.

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 Adrenoceptor Antagonists
• α-receptor mediates responses for which the
adrenomimetic order of potency is EpNEIsop
– Is susceptible to blockade by phentolamine and
phenoxybenzamine.
• It follows from this definition that
phentolamine and phenoxybenzamineare
called α-adrenoceptor antagonists or α -
blocking agents.

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 Adrenoceptor Antagonists

• β-receptor mediates responses for which the

adrenomimetic order of potency is Isop,
– is susceptible to blockade by propranolol.
• Propranolol is, therefore, called a β
adrenoceptorantagonist or β -blocking agent.

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 α- adrenoceptor Antagonists

• There are differences between the α receptors on

nerves (presynaptic receptors) and those on
effector cells (postsynaptic receptors).
– Some α–agonists and antagonists exhibit selectivity

• α- receptors classified as either 1 or 2.

– α1- exist on postsynaptic α - of smooth muscle
– α2-exist on presynaptic α–receptors of peripheral
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 α- adrenoceptor…

• The designation of receptors as either α1 or α2

cannot be categorized strictly by anatomical
location (i.e., presynaptic or postsynaptic)
• Evidence now indicates that α2-receptors
occupy a variety of sites including smooth
muscle, adrenal medullary cells, the brain, and
melanocytes.
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 α- adrenoceptor…
• Phentolamine is a disappointing antihypertensive
drug because its administration results in a reflex
increase in both HR and contractile force
• Prazosin is an effective antihypertensive drug
because the reflex cardiac stimulation it induces is
much less.
– Effects produced appear to be related to their relative
selectivity for α1- and α- 2

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 α- adrenoceptor…
• Phentolamine is a relatively nonselective α receptor blocking
agent
– Block postsynaptic α1 and presynaptic α 2
– Blocking of presynaptic α 2-receptors enhances release of
NE, hence augments HRand contractile force.
• Prazosin is relatively selective for α1-receptors
– Without having a substantial effect on presynaptic α2
• Prazosin stimulates the heart less than phentolamine.

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 α- adrenoceptor…

• The clinically important α -blockers fall primarily

into three chemical groups:
√ the haloalkylamines ( e.g., phenoxybenzamine)
√ the imidazolines (e.g., phentolamine)
√ the quinazoline derivatives (e.g., prazosin).

• Of these three classes, the quinazoline cpds. are of

greatest clinical utility
– The other two have diminished in recent years because they
lack selectivity for α -receptors.
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 Quinazoline…..

• The use is in the mgmt of primary hypertension.

– Prazosin, trimazosin, terazosin , and doxazosin

• The antagonism is of the equilibrium-competitive

• Most of the p’logical effects are directly attributable
to α1-antagonism
– At high doses the drug can cause vasodilation by a direct
effect on smooth muscle independent of α-receptors
– related to an inhibition Phosphodiesterase.

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 Clinical Uses
• Prazosin is effective in reducing all grades of
hypertension.
– It use alone in mild (mainly) and moderate
hypertension.
– It is given in combination with a thiazide diuretic
and a β-blocker in moderate or severe hypertension
 Prazosin may be particularly useful when
– Pts cannot tolerate other classes of HTN drugs
– BP is not well controlled by other drugs.

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 Clinical Uses
• It can be used in hypertensive patients whose
condition is complicated DM or gout.
– Since prazosin does not significantly influence
blood uric acid or glucose levels
• Prazosin and other α-antagonists use in the mgmt
of BPH (in pts who are not candidates for
surgery)
– Blockade of α-adrenoceptors in the base of the
bladder and in the prostate apparently reduces the
symptoms of obstruction & the urinary urgency
that occurs at night
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 Adverse Effects

• Less of a problem (postural hypotension) than

phenoxybenzamine or phentolamine
• Symptoms of postural hypotension(PH) (dizziness and
light-headedness) common with prazosin therapy.
– These effects occur most frequently during initial treatment and
when the dosage is sharply increased.
– PH is more pronounced during Na+ deficiency, as may occur in
patients on a low-salt diet or being treated with diuretics, β-
blockers, or both.
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 β- Blocking Agents

• Propranolol was the first to be introduced

– Is the prototypical drug with which others are compared.

• Metoprolol was the first β1-selective and Timolol is

the first β-blocker approved for ophthalmic use
• All of them exert equilibrium-competitive antagonism
of the actions of catecholamines and other
adrenomimetics at β-receptors.
• Some are generally referred to as partial agonists
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 β- Blocking Agents…

• A comparison of the effects produced by propranolol,

with those of metoprolol, a relatively selective β1-
receptor blocker (clinical utility of such drugs)
• A pt., who is a candidate for β -blocker therapy , but
who also has obstructive airway disease
– should not receive a nonselective β-blocking agent because
of the possibility of aggravating bronchospasm.

• Metoprolol would be advantageous

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 β- Blocking Agents..
• The best recognized action of these cpds that is not
mediated by a β-receptor is depression of cellular
membrane excitability.
– This effect has been described as a membrane-stabilizing
action, a quinidinelike effect, or a local anesthetic effect.
• This action is due to the structural similarities
between β-blockers and local anesthetics.

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 β- Blocking Agents…
• With the usual therapeutic doses, the actions of the β
blocking agents appear to be almost entirely
accounted for by their β –receptor antagonism.
• β-receptors of the pulmonary and vascular smooth
muscle are β2 receptors
– β1-selective antagonists are frequently referred to as
cardioselective blockers.

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 β- Blocking Agents…
• The most important actions of these drugs are on
the CVS
• They decrease HR myocardial contractility, CO,
and conduction velocity within the heart.
– These effects are most pronounced when sympathetic
activity is high or when the heart is stimulated by
circulating agonists.
• Their action on BP are complex.
– After acute administration, BP is only slightly altered.
– This is because of the compensatory reflex increase in
PR
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 Clinical Uses
CV disorder
 Uses in the management of cardiac arrhythmias,
angina pectoris, and hypertension
 In long term mgmt of CHF
Glaucoma in open angle
– Decreased production of aqueous humor.
– Timolol has greater ocular hypotensive effect than
others.
• They use in the tt of acute angle-closure
glaucoma.
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 Clinical Uses
 Hyperthyroidism
 In hyperthyroid crisis,

 in the preoperative preparation for thyroidectomy

 during the initial period of antithyroid drugs

 Anxiety States

 Migraine

– A blockade of craniovascular β-receptors results in

reduced vasodilation
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 Contraindications
• In obstructive airway disease
• In asthmatics pts
• In hypoglycemic patients
• In Insulin dependent diabetics
• Cause burning or dryness of the eyes (e.g. timolol)
• Pts may have hallucinations, nightmares, insomnia,
and depression after high doses,
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 Drugs With Combined α- And
β -Blocking Activity
 bucindolol, carvedilol, and medroxalol
 Labetalol
• It possesses both α-blocking and β -blocking activity
• Is 1/3 as potent as propranolol as β -blocker and 1/10
as potent as phentolamine as an α -blocker.
• The ratio of β- to α-activity is about 3:1 when it is
administered orally about 7: 1 when it is administered
intravenously.
• Thus the drug can be most conveniently thought of as
a β-blocker with some α-blocking properties.
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 Drugs With Combined…
• Labetalol produces equilibrium-competitive
antagonism at β -receptors but does not exhibit
selectivity for β 1- or β 2-receptors.
• Like certain other β -blockers (pindolol & timolol), it
possesses some degree of intrinsic activity
– This partial agonism, especially at β2-receptors in
the vasculature, has been suggested to contribute
to the vasodilator effect of the drug.

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 Drugs With Combined…
• The membrane-stabilizing effect, or local anesthetic
action, of propranolol and several other β - blockers,
is also possessed by labetalol
– in fact the drug is a reasonably potent local anesthetic.
• The α-blockade produced by labetalol is also of the
equilibrium-competitive type.
• In a manner similar to prazosin, labetalol exhibits
selectivity for α1-receptors.
• Presynaptic α2-receptors are not antagonized by it

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 Drugs With Combined…
• Labetalol appears to produce relaxation of vascular
smooth muscle not only by α-blockade but also by a
partial agonist effect at β2-receptors.
– labetalol may also produce vascular relaxation by a direct
non–receptor-mediated effect.
• It can block the neuronal uptake of NE and other
catecholamines.
• This action, plus its slight intrinsic activity at α-
receptors, may account for the seemingly paradoxical
increase BP seen on its initial adm.
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 Clinical Uses

• Labetalol is useful for the chronic treatment of

primary hypertension.
• It can be used alone but is more often employed in
combination with other antihypertensive agents.
• Labetalol also has been used IVfor the tt of
hypertensive emergencies.
• Like conventional β-blockers, labetalol may be useful
for patients with coexisting hypertension and anginal
pain due to ischemia.

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 Clinical Uses

• Labetalol, because it possesses both α- and β –

blocking activity, is useful for the preoperative mgmt
of patients with a pheochromocytoma.
• Adverse Effects
• These include postural hypotension, GI distress,
tiredness, sexual dysfunction, and tingling of the scalp.
• Most of these effects are related to alpha -blockade,
Side effects associated with beta-blockade, such as
induction of bronchospasm and congestive heart
failure, may also occur,
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