Adrenergic System Adrenoceptors

Adrenergic receptors:
• Alpha 1
– Most vascular smooth muscles
– Activate PLC => ca++ =>
contraction
• Alpha 2
– Mostly presynaptic Alpha Beta
– Inhibit adenylate cyclase
• Beta 1
– Mostly heart Generally Excitatory Generally inhibitory
– Activate adenylate cyclase
• Beta 2 Exception: intestinal Exception: beta1 in
– Respiratory and uterine smooth
muscle smooth muscle the heart
– Activate adenylate cyclase
• Beta 3
– Mostly adipocytes
– Activate adenylate cyclase =>
lipolysis
• (Dopamine)

Mechanisms of Action and Effects Mechanisms of Action and Effects

Adrenergic or sympathomimetic drugs have three
mechanisms of action
1. Direct adrenergic drug action. Adrenergic drugs interact directly
with postsynaptic alpha1 and beta receptors on target effector
organs, activating the organ like norepinephrine does.
2. Indirect adrenergic drug action occurs by stimulation of
postsynaptic alpha1, beta1 and beta2 receptors by adrenergic
medications. These drugs increase the release of norepinephrine
into the synapse from storage sites in nerve endings or inhibit the
reuptake of norepinephrine from the synapse.
3. Mixed action. Is a combination of direct and indirect receptor
stimulation.
• Drugs that activate alpha 2 receptors on presynaptic
nerve fibers do not produce a sympathetic effect. In fact,
these drugs inhibit the release of the neurotransmitter
norepinephrine.
• Stimulation of alpha2 receptors in the CNS (central) is
helpful in treating hypertension but peripheral
stimulation has no effect. Exact mechanism not clear.
• Most body tissues have both alpha and beta receptors so
the effect produced depends on the type of receptor
activated and the number of affected receptors in a
particular body tissue.
 Adrenergic Agonist = Sympathetic Affinity of the Adrenergic Agonist
Indirect Acting Direct Acting Mixed Action

MOA= ↑ NE Release MOA= ++ α & β MOA= Both

Amphetamine Alpha Beta Ephedrine

Tyramine
Beta 1 Beta 2
Alpha 1 Alpha 2
Isoproterenol < EPI < NE
NE < EPI < Isoproterenol
Dobutamine Albuterol
Clonidine
Denopamine Salbutamol
Phenylephrine Guanfacine
Xameterol Terbutaline
Methxamine Guanabenz
Methylnorepin Clenbutarol
Midodrine
ephrine
Metaraminol
α-methyldopa

Receptor Selectivity Clinical Aspects of Adrenoceptor

α1 adenoceptor effects
• Eye ------------------------ Mydriasis.
• Arterioles --------------- Constriction.
• Uterus ------------------- Contraction.
• Skin ---------------------- Sweat.
• Platelet ------------------ Aggregation.
• Male --------------------- Ejaculation.
• Bladder Sphincter---- Contraction.
• Hyperkalaemia.

α2 adrenoceptors on nerve endings mediate negative

feedback which inhibits noradrenaline release.

Clinical Aspects of Adrenoceptor β2

Direct acting; Epinephrine
Adrenoceptor Effects
• Epinephrine: interacts with both alpha and beta
• Low dose: mainly beta effects (vasodilation)
• High dose: alpha effects (vasoconstriction)
• Bronchi -------------- Relaxation.
• Pharmacological effects include:
• Arterioles ----------- Dilatation. • Increased BP
• Vasoconstriction in peripheral blood vessels which allows for
• Uterus --------------- Relaxation. shunting of blood to heart and brain
• Increased heart rate
• Skeletal Muscle -- Tremor. • Relaxation of GI smooth muscle
• Relaxation and dilation of bronchial smooth muscle
• Increased glucose, lactate, and fatty acids in the blood due to
• Hepatic ------------- Glycogenolysis. metabolic effects
• Inhibition of insulin secretion
• Hypokalaemia. • Increased leukocyte count and increased coagulation
 Direct acting; Epinephrine
• Therapeutic Effects
• Bronchospasm (emerg TX of asthma)
• Glaucoma
• Anaphylactic shock
• Promotes vasoconstriction
Da – Phenylephrine (α1)
• Therapeutic effects:
• Used in hypovolaemic shock as pressor agent.
• Sinusitis & Rhinitis as nasal decongestant.
• Mydriatic in the form of eye drops and lowers
intraocular pressure.
• Does not cross BBB, so no CNS effects.
• Actions qualitatively similar to noradrenaline.
• Postural Hypotension (Midodrine)
• To prolong spinal anesthesia
Mixed Action; Ephedrine
• Therapeutic Effects:
– Treatment of bronchial asthma
– As a nasal decongestant
– As a mydriatic agent
Da – Phenylephrine (α1)
Phenylephrine: Selective, synthetic and direct α1–agonist
• Long duration of action.
• Resistant to MAO and COMT.
• Administered parenteraly & topically (eye, nose)
Pharmacological effects include:
• To produce vasoconstriction
• It decreases cardiac output and renal perfusion
• No activation of beta1 or beta2
• Used to raise blood pressure in hypotension and shock
• Longer lasting than epinephrine
• May cause a reflex bradycardia
• Produces mydriasis and nasal decongestion.
Mixed Action; Ephedrine
Ephedrine: Plant alkaloid, directly act on adrenoceptor &
(indirectly) release of stored cathecolamine
•Effects appear slowly but lasts longer (t1/2-4h)
• Tachyphylaxis on repeated dosing
• Pseudoephedrine is similar.
• It resistant to COMT & MAO
• It has a high bioavailability
•A long duration of action
Pharmacological Effects include:
•Centrally – Increased alertness, anxiety, insomnia, tremor and nausea
in adults. Sleepiness in children.
•Used as bronchodilator, mydriatic, in heart block,mucosal vasoconstriction
& in myasthenia gravis.
α2 Agonist - Clonidine
Clonidine - Agonist to postsynaptic α2
adrenoceptors in brain, stimulation suppresses
sympathetic outflow and reduces blood
pressure.
– High dose activates peripheral presynaptic autoreceptors on
adrenergic nerve ending mediating negative feedback
suppression of noradrenaline release.
– Onset may be rapid (a few hours) or delayed for as long as 2
days and subsides over 2-3 days.
– Treatment is to reinstitute clonidine, i.m or treat for
phaeochromocytoma (is a tumor that produces norepinephrine and
epinephrine and is equivalent to overfunction of the adrenal medulla)
– Never use Clonidine with β-adrenoceptor blockers.
Pharmacological Effects Include:
– Clonidine reduces blood pressure.
 Adrenergic System - Agonists
b1 - receptors
• Mostly in heart
• Increase contractility = “positive inotrope”
• Increase heart rate = “positive chronotrope”

b2 - receptors
• Respiratory system – located in bronchial smooth muscle
• Short acting : Salbutamol, Metaproterenol,
Terbutaline,pirbuterol.
• Used for acute inhalational treatment of bronchospasm.
– Onset of action within 1 to 5 minutes.
– Bronchodilatation lasts for 2 to 6 hours.
– Duration of action longer on oral administration.
– Directly relax airway smooth muscle.
– Relieve dyspnea of asthmatic bronchoconstriction

β1 Agonists - Dobutamine β2 Agonists - Isoproterenol

Isoproterenol : β1=β2>> α
Dobutamine
• Resembles dopamine & it is directly activates β1-receptor.
Pharmacologic effects:
– (ß1) Increased cardiac contractility and heart rate
Pharmacologic & Therapeutic effects:
• Strong inotropic effect with little chronotropic effect => – (ß2) Vasodilation in peripheral (skeletal muscle, Renal and
increase in cardiac output without significant increase in heart rate mesenteric vascular beds ) Slight decrease in mean BP, marked
(Minimal changes in HR and systolic BP) drop in diastolic BP.
• Short-term treatment of impaired cardiac function after cardiac – (ß2) Muscle relaxation (Bronchial and GI smooth)
surgery, MI etc. – (ß2) Inhibit antigen-mediated histamine release
• Also used in “Dobutamine Stress Test” = Heart sonogram: – Adverse effects: Palpitations, Tachycardia,Coronary
Dobutamine mimics exercise insufficiency
• Adverse effects: Increases atrioventricular conduction, Atrial – Therapeutic uses: As a bronchodilator & cardiac stimulant for
fibrillation, Increased myocardial oxygen demand that may worsen heart block or severe bradycardia, ventricular arrhythmia)
post-infarct myocardial damage

β2 Agonists - Albuterol β2 Agonists - Albuterol

• Albuterol: • Albuterol:
– Effective following inhalation. – Effective following inhalation.
– Onset within 15 minutes, – Onset within 15 minutes,
– Duration last about 3-4 hours. – Duration last about 3-4 hours.

• Pharmacologic effects: • Pharmacologic effects:

– (β2) Relax bronchial smooth muscle.
– (β2) Relax bronchial smooth muscle.
– Therapeutic uses: Chronic and acute asthma,
– Therapeutic uses: Chronic and acute asthma,
Bronchi asthma,Bronchospasm.
Bronchi asthma,Bronchospasm.
 β2 Agonists –
Metaproterenol & Terbutaline
Metaproterenol (β2>>β1>>>>α) Terbutaline
– ß2selective
– Terbutaline has a longer duration of action.
– Metaproterenol has less ß2 selective compared to terbutaline
and albuterol.
– Resistant to COMT metabolism
– Rapid onset and Long-duration
Pharmacologic effects:
– Relaxing effect on bronchial smooth muscle (β2)
– Show little effect on cardiac β1 receptors.
– Therapeutic uses: Bronchi asthma or bronchospasm
Indirect Sympathicomimetics -
Amphetamines
• Drug abuse: Generally teenagers,
seeking thrill/kick which obtained on
rapid IV infusion, high dose produce
Euphoria.
• The central actions of amphetamine are
largely mediated by release of nor-
adrenaline in the brain.
DOPAMINE
• It is alpha1 and beta1 agonist. When large
doses are infused it will produce
vasoconstrictions (alpha 1 action).
• At normal doses it raises cardiac output and
systolic blood pressure.
• Dopamine is used in patient of cadiogenic or
septic shock and severe congestive heart
failure, (CHF) where it increase the blood
pressure and urine outflow.
Indirect Sympathomimetics -
Amphetamines
– These are synthetic compound having the same pharmacological
profile as ephedrine.
– Orally active long duration of action 4-6hrs
– Displace norepinephrine in storage vesicle => forced epinephrine
release
– Also inhibit norepinephrine re-uptake and degradation by MAO
(“triple action”)
Pharmacological & Therapeutic effects
– On CNS: alertness, increase conc. Euphoria, talkativeness, increase
work capacity, Athletic performance is increased temporarily.
– Stimulated resulting in wakefulness and postponement of sleep,
they stimulate respiratory centre. Hunger is suppressed as result of
inhibition of hypertension feeding centre.
– They also week anticonvulsant, analgesic.
Indirect Sympathicomimetics
• Siburtamine
– This recently introduced anti-obesity drug inhibits the reuptake of both NA as
well as 5HT, but does not have clinically useful antidepressant property.
– It cans loss of 3-9 kg.wt.
– Side effects: dry mouth, constipation, anxiety, insomnia, chest pain
• Fenfluramine
– It affects food intake by enhancing serotonergic transmission in the
hypothalamus and has tranquillizing rather than stimulant property. Appetite
suppressant (now banned in US)
(combined with Phentermine = “FenPhen”)
– The plasma half life is 20hr.
– Treatment beyond 3 months are not recommended.
– Side effects: drowsiness, depression, loss of libido, dry mouth diarrhea.
• Metamphetamine/MDMA
– Effectiveness disappears due to catecholamine depletion
of vesicles => post-use depression
=> urge for re-administration!
Therapeutic Usage of Adrenergic
Agonist Drugs
1. Pressor agents: Nor adrenaline, Epedrine, Dopamine
2. Cardiac stimulants: Adrenaline, Isoprenaline
3. Branchodilators: Adrenaline, salbutamol, Terbutaline
4. Nasal decongestants: Xylometazoline, Pseudoehedrine
5. CNS Stimulants; Amphetamine, Dexamhetamine
6. Anorectics: Fenfluramine, Dexafenfluramine
7. Uterine relaxant: Ritodrine, salbutamol.
 Therapeutic Usage of Adrenergic
Contraindications to Use
Agonist Drugs
• Emergency drugs in treatment of acute cardiovascular, • Cardiac dysrhythmias, angina pectoris
respiratory and allergic disorders
– In children, epinephrine may be used to treat bronchospasm due
• Hypertension
to asthma or allergic reactions. • Hyperthyroidism
– Phenylephrine may be used to treat sinus congestion but
rebound congestion can occur. • Cerebrovascular disease
– Use in older adults. Used to treat asthma, hypotension, shock, • Narrow angle glaucoma—dilation increases IOP
cardiac arrest and anaphylaxis. Careful monitoring required as
elderly often have chronic cardiovascular conditions which may • In distal areas with a single blood supply such as
be aggravated by adrenergics. In ophthalmic preparations,
caution as systemic absorption can likewise increase BP. fingers, toes, nose, ears
– In shock as second line once volume has been replaced • In those with urinary retention
– In allergic disorders, used for vasoconstricting or decongestant
effects • In renal impairment
– Inhibition of uterine contractions
– For vasoconstriction and hemostatic effects

Toxicity of adrenergics
• Vasopressor action can affect renal perfusion
• Can induce cardiac dysrhythmias
• Increases myocardial oxygen consumption
• May decrease perfusion of liver w/resultant
damage
• Hyperglycemia, hypokalemia, and
hypophosphatemia 2ndary to B1 stimulation
• Tissue necrosis w/extravasation
• Do not give epinephrine and isoproterenol at the
same time or within 4 hours of each other. Could
result in serious dysrhythmias.

Organ System Effects

Adrenergic Agonist Drugs

What is the treatment of choice

for anaphylactic shock?
Epinephrine

Why?
It is the only drug that addresses the
most serious manifestations:
• β1 increases cardiac output
• β2 relaxes constricted bronchioles
• α1 constricts capillaries
Indirect Sympathicomimetics:
MAO - Inhibitors:
– Inhibition of MAO causes increase in free Norepinephrine
– In the CNS, MAO also metabolizes dopamine and serotonin => MAO
inhibitors trigger increase in these “happy hormones” => uses as
antidepressants
– Irreversible inhibition of MAO => long-lasting effect (weeks!)
• Tranylcypromine
• Moclobemide

Possibility of severe adverse interactions of MAO inhibitors with numerous

other drugs
=> fatal hypertension
 CHAPTER FOKUS
NEUROPHARMACOLOGY • This chapter describes the basic pharmacology of drugs that affect the
parasympathetic nervous system. It also explains how cholinergic drugs

SBD 3034 / SPH 3014 increase parasympathetic activity and anticholinergic drugs decrease it.

CHAPTER OBJECTIVES
• After studying this chapter, you should be able to :

Muscarinic Drug • describe the neuronal release and inactivation of acetylcholine

• list the three types of cholinergic receptors and the tissues where they are
located
• explain the effects of acetylcholine on the major internal organs and
glands of the body
• name two direct and two indirect acting cholinergic drugs and the effects
they produce
• name three anticholinergic drugs and the main effects they produce on
the major body system
• list the most frequently observed adverse effects of both cholinergic and
anticholinergic drug therapy

CHOLINOMIMETIC DRUGS • MUSCARINIC DRUGS

• Muscarinic receptors are present in the brain, in ganglia, and on some

cells such as those in blood vessels. Cholinergic agonists mimic the
effects of acetylcholine at these sites.
Direct Acting Indirect Acting
• Muscarnic receptor Agonists:
MAO=Receptor Agonist MAO= Cholinesterase inhibitors • Acetylcholine and several synthetic choline esters.
• Naturally occurring cholinomimetic alkaloids.
( Pilocarpine, muscarine)
Choline Esters Alkaloids Reversible/ Irreversible/
Carbamates Organophosphate
• Acetyl choline produces effects on many tissues include :
Acetylcholine Pilocarpine • dilation of blood vessels
Bethanecol Muscarine Physostigmine Isoflurophate • Contraction of spleen
Carbachol Nicotine Neostigmine Echothiophate • Contraction of smooth muscle
Methacholine Pyridostigmine Iodide,
Edrophonium Parathion • Acetyl choline and drugs that mimic its actions may combine with
muscarnic or nicotinic receptors or both
Malathion • Acetyl choline (20-100mg I.V) has found occasional therapeutic use to
terminate attacks of tachycardia.
 Cholinergic Response
Cholinergic Response
Responses Mediated by Nicotinic Receptors
Responses Mediated by Muscarinic Receptors
Type of Principle location Mechanism of Effect
Type of Receptor Principal Locations Mechanism of Effects Receptors Signal
Signal Transducer
Transduction Nm (In muscle) In somatic Increased sodium Contraction of
M1 – Neuron Autonomic ganglia, Increased inositol Modulation of neuromuscular influx muscle
presynaptic nerve triphosphate (IP3) neurotransmission junction
terminals and CNS and diacylglycerol
(DAG) Nn (In neurons) Autonomic Increased sodium Excitation of
ganglia influx postganglionic
M2- Cardiac Cardiac tissue (sinoatrial Increased potassium Slowing of heart rate
neurons
& efflux or decreased and conduction
atrioventricular nodes) cAMP
M3- Glandular Smooth muscle & gland Increased cGMP due Vasodilatation
to NO stimulation

Cholinergic Receptor Agonists

Cholinomimetics = Parasympathomimetics

• Direct acting agonists

– bind and activate cholinergic receptors
- Act on the cholinergic receptors

• Indirect-acting agonists
– increase synaptic [ACh] by either inhibiting AChE or
increasing the release of ACh from terminals
- Act on the receptor of Ach
 Muscarinic
R emember!!!
Parasympathomimetics
• Cholinergic agonist => cholinomimetics
=> parasympatomimetics
The extremely short half-life of Ach makes
Organ system effects for cholinomimetics drugs it therapeutically useless
= parasympathetic effects
Ach is rapidly hydrolysed following oral
Adverse effects = SLUD/DUMBELS ingestion and rapidly metabolized
SLUD: salivation, lacrimation (crying), urination, defecation, true for all Ach
agonists following intravenous administration
DUMBELS - Diarrhea, Urination, Miosis, Bronchoconstriction, Excitation (of
skeletal muscle & CNS), Lacrimation, and Salivation and Sweating

*All symptoms can be blocked by ATROPINE

• PARASYMPATHOMIMETIC DRUGS:
Direct Acting- Choline Ester
• DRUGS that exert direct muscarinic actions or stimulate the muscarinic Drug Therapeutic Use Organ System Effects Others/ Adverse Effect
receptors.
Acetylcholine Eye: Intraocular – Eye: contraction of iris
• Pharmacological effects: -Miochol- Miosis during sphincter & ciliary muscle;
(N&M) opthalmic facilitate outflow of X= contraindication
AchE=Yes surgery. aqueous humor in canal of DX= Diagnose
• ON CVS: Ach has 4 effects on CVS : Cardio: schlemn decrease TX= Treatment
• vasodilation, Intracoronary – intraocular pressure ++= Stimulates
• Decreased in cardiac rate Coronary
• Decreased in the rate of conduction angiography
• Decreased in the force of cardiac contraction Bethanechol GU: Oral/ CNS: does not cross BBB GI: Salivary & gastric gland ++,
-Urecholine- Subcutaneuos/iv GI: increases tone & salivation, nausea, abdominal pain.
(M) – Postoperative/ motility Diarrhea: (X acid-pepsin disease-
• ON GIT: postpartum acid stimulation will aggravate)
AchE= No GU Contraction of
• All of the compounds of this class are capable of producing increasing in urinary retention- destrusor muscles of Resp: Bonchospasm (X asthma)
tone. Contraction of stomach and intestine. Promote bladder & relaxation of Skin: Sweating, flushing
emptying of trigone & sphincter
bladder Cardio: ↓BP (X coronary
• The enhanced motility may be accompanied by nausea, vomiting insufficiency & hyperthyroidism)
intestinal cramps.
Carbachol Eye: Topical CNS: does not cross BBB .
-Miostat- ocular – glaucoma Cardio& GI: Significant
• Urinary Tract:
(N&M) Intraocular – activity at N& M
• Ach contracts muscle of urinary bladder, increase the maximal voluntary Miosis during
voiding pressure, and decrease the capacity of the bladder. AchE=No
opthalmic surgery

Ocular Effects Direct Acting- Alkaloids

Drug Therapeutic Use Organ System Effects Others/ Adverse Effect

Pilocarpine Skin: Oral – xerostomia CNS: Cross BBB Skin: Profuse sweating,
-Isoptocarpine- Eye: ↓intraocular Eye: Rapid miosis cutaneous vasodilation
(M>N) pressure in narrow contraction of iris Resp: bronchoconstriction
AchE= No /wide angle glaucoma sphincter & ciliary GI: Profuse salivation
GI: ↑Salivary secretion muscle; facilitate
to ease swallowing outflow of aqueous
&hydration of oral humor in canal of
Muscarinic receptor agonist cavity schlemn decrease
Pilocarpine intraocular pressure
Miosis-Pupillary constriction Muscurine None
(M)
AchE= No
Nicotine Oral or transdermal – CNS: ++ Ganglia CNS: Convulsions, followed
Muscrinic receptor antagonist smoking cessation initially- high doses by coma & respiratory arrest
(N)
Atropine AchE= No programme produces ganglionic Cardio: Hypertension &
Mydriasis - Pupillary dilatation blockade. cardiac arrythmia
(desensitization of N)
Cardio:↑ HR &BP
GI: ↑ tone& motility
 Precautions, Toxicity, and
CHOLINOMIMETIC DRUGS
Contraindications
•ACh and its agonist analogs should be administered only by the oral or Direct Acting Indirect Acting
subcutaneous route for systemic effects; they also are used locally in the
eye.
•Antidote - atropine. MOA=Receptor Agonist MOA= Cholinesterase inhibitors
•Epinephrine may be used to overcome severe cardiovascular or
bronchoconstrictor responses. Choline Esters Alkaloids Reversible/ Irreversible/
•Among the major contraindications to the use of the choline esters are Carbamates Organophosphate
asthma, hyperthyroidism, coronary insufficiency, and acid-peptic disease.
•Bronchoconstrictor action could precipitate an asthmatic attack Acetylcholine Pilocarpine
•Hyperthyroid patients may develop atrial fibrillation. Bethanecol Muscarine Physostigmine Isoflurophate
•Hypotension induced by these agents can severely reduce coronary blood Carbachol Nicotine Neostigmine Echothiophate
flow, especially if it is already compromised. Methacholine Pyridostigmine Iodide,
•The gastric acid secretion produced by the choline esters can aggravate the Edrophonium Parathion
symptoms of acidpeptic disease.
Malathion
•Other possible undesirable effects of the cholinergic agonists are flushing,
sweating, abdominal cramps, a sensation of tightness in the urinary
bladder, difficulty in visual accommodation,headache, and salivation.

Indirect Acting Cholinergic

• Reversible inhibitors : Agonists = IRREVERSIBLE
- to reverse the effects of drugs that block cholinergic and nicotinic
receptors (excessive anticholinergic blockade)
Drug Therapeutic Use Organ System Effects Others/ Adverse Effect
- water soluble
Isoflurophate Eye: TX of glaucoma Eye: Intense miosis Generalized cholinergic
(Floropryl) (long acting) stimulation, paralysis of
• Irreversible inhibitors motor function (causing
- long duration because form irreversible bonds with the AchE enzyme breathing difficulties) &
convulsions.
- lipid soluble
Echothiphate Eye: TX of glaucoma
- cross skin, BBB and membrane. (Phosphline) (long acting & low lipid
solubility); reserved for
cases when intraocular
pressure cant be
controlled by other drugs
Malathion An insecticide that is Cannot be detoxified in
Parathion converted in the body of vertebrates
insects & fish to acive
compound

ANTICHOLINESTERASE DRUG
• These agents inhibit acetylcholinesterase, which is concentrated in
synaptic regions and is responsible for the rapid hydrolysis of
acetylcholine. Anticholinesterase agents have therapeutic utility in the
treatment of glaucoma and other ophthalmologic indications.
• Antidotal therapy of the toxic effects of cholinesterase inhibitors used as
insecticide and chemical warfare agents is directed to blocking the effects
of excessive acetylcholine stimulation.
• The function of AchE in terminating the action of Ach at the junctions of
various cholinergic nerve endings with the effector’s organs. Drugs that
inhibit AchE are called anticholinesterase (anti-ChE) agents.
Pharmacological Properties:
The anti- ChE agents potentially can produce the following effects.
• Stimulation of muscarinic receptor response autonomic effect or organs
• Stimulation followed by depression of all autonomic ganglia and skeletal
muscle.
• Stimulation with occasional depression of cholinergic receptor sites in
the CNS
• The main action of anti-ChE agents are of therapeutic importance
are concerned with eye, the intestine and neuromuscular junction
of skeletal muscle and other actions of toxicological interest.
• EYE :
• When applied locally on eye it will produce miosis. It will become
pinpoint in size, it generally contracts further when exposed to
light.
• GIT :
• Neostigmine enhances gastric contractions and increases the
secretion of gastric acid. The drug tends to counteract the
inhibition of gastric tone motility induced by atropine.
• SKELETAL NEUROMUSCULAR JUNCTION :
• Treatment of Myasthenia Gravis
• The anti-ChE agents will reverse the antagonism caused by competitive
neuromuscular blocking agents. Neostigmine can be used for the skeletal
muscle paralysis.
• Action on other sites : Anti-ChE agents cause contraction of smooth
muscle fibers of the bronchioles and ureters.
 • Treatment :

• ABSORPTION, FATE AND EXCRETION :

• Atropine in sufficient dose effectively antagonizes the action at
muscarinic receptors sites.
• Physostigmine is absorbed readily from the g. i. t., subcutaneous • Pralidoxime 1 – 2g infused intravenously is recommended.
tissues and mucous membranes.

• THERAPEUTIC USES :
• Poorly absorbed after oral administration. Following their
absorption, most organophosphorus compounds are excreted
almost entirely as hydrolysis product in the urine. • Used in Glaucoma – is a disease characterized by an increase in
intraocular pressure in eye leads to damage to the optic disc.
• Used in Myasthenia gravis – is a neuromuscular disease characterized by
• TOXICOLOGY :
weakness and marked fatigability of skeletal muscle.
• Used in the peripheral and central effects of poisoning by atropine and
• Organophosphorus compounds are used as agriculture related antimuscarinic drugs.
insecticides, these agents have been used frequently for homicidal
and suicidal purpose largely because of their accessibility.

• The broad spectrum of effects on the CNS includes confusion,

ataxia, slurred speech, convulsion, coma and death due respiratory
failure may occur less than 5 min- 24 hours depending upon the
dose, route, agent and other factors.

What is the difference between direct acting Cholinergic Antagonist

cholinergic agonists and indirect acting agonists? => Cholinolytics => Parasympatholytics
• Muscarinic receptor blockers:
Direct-acting agonist:
– Competitive antagonists
bind and activate cholinergic receptors – Widespread medical applications:
• Inhibition of bronchial and gastric secretion
• Relaxation of smooth muscles (Bronchii, pupillary sphincter…)
Indirect-acting receptors: • Cardioacceleration
• CNS-altering effects
Increase the synaptic concentration of Ach
• Nicotinic receptor blockers:
– Ganglion-specific blockers: no clinical applications
– Neuromuscular blockers: Muscle relaxants

Cholinergic Antagonist CHOLINERGIC ANTAGONISTS

=> Cholinolytics => Parasympatholytics
MUSCARINIC Ach Inhibitor NICOTINIC
• Muscarinic receptor blockers: ANTAGONISTS (Botulinum Toxin) ANTAGONISTS
– Competitive antagonists
– Widespread medical applications:
• Inhibition of bronchial and gastric secretion NEUROMUSCULAR GANGLIONIC
BLOCKING AGENTS BLOCKING AGENTS
• Relaxation of smooth muscles (Bronchii, pupillary sphincter…)
MOA = Interfere with postsynaptic
• Cardioacceleration Non- Depolarising Depolarising transmission of Ach
• CNS-altering effects MAO = Bind to NR MAO = Acts as
and competes with Ach nicotinic agonist - Mecamylamine
depolarization
• Nicotinic receptor blockers: Nicotine
Trimetaphan
– Ganglion-specific blockers: no clinical applications Short Long Duration
Duration (tubocurarine) (succinylcholine)
– Neuromuscular blockers: Muscle relaxants (vecuronium,
pancuronium)
 CHOLINERGIC ANTAGONISTS MUSCARINIC ANTAGONISTS
Blocks muscarinic receptors
MOA = Blocks MOA = Blocks
Muscarinic Receptor Release of Ach
Intermediate
Sensitive to
Responsiveness
MUSCARINIC
Ach INHIBITOR
Atropine
ANTAGONISTS

Atropine (Botulinum Toxin)

Scopolamine
Salivary, bronchial, Smooth muscle
Ipratropium & sweat glands & heart
Pirenzipine

ANTI MUSCARINIC DRUG (MUSCARINIC RECEPTORS ANTAGONISTS)

Muscarinic receptors antagonists prevents the effects of Ach by blocking its

EFFECTS OF ANTI-MUSCARINIC
binding to muscarinic cholinergic receptors at neuro effectors sites on smooth
muscle, cardiac muscle, and gland cells. DRUGS = Sympathetic
• In general muscarinic receptors antagonists cause little blockade of the effects of
Ach on nicotinic receptor sites, Atropine produces partial block only at relatively
• GLANDS Decrease of secretion
high doses. • HEART Initial bradycardia, then tachycardia
MECHANISM OF ACTION: • GU Relaxation of bladder wall, urinary
• Atropine and related compounds are competitive antagonists of the actions of Ach
and other muscarinic agonists; they compete with such agonists for a common
retention
binding site on the muscarinic receptors. • GI Relaxation, slowed peristalsis
• All muscarinic receptors are blocked by atropine.
• BRONCHI Bronchodilation
• NATURALLY occurring muscarinic receptors antagonist are the alkaloids of the
belladonna plants. The most important of these are atropine, and scopalamine • EYE Cycloplegia*, mydriasis, reduction of
lacrimal secretion (sandy eyes)
SOURCES:
• The belladonna drugs are widely distributed in nature in the solanaceae plants.
Atropa belladonna, yield the alkaloid atropine. The same alkaloid is found in
Datura stramonium. • Drowsiness, anti-motion sickness action, antiparkinson
action, amnesia, delirium CNS
CHEMISTRY:
• Atropine and scopolamine are organic esters formed by combination of an
aromatic acid, tropic acid, and complex organic bases either tropine or scopine.

Drug Therapeutic Use Others/ Adverse Effect

Ipratropium Resp: TX of asthma & chronic Aerosol targets bronchiolar tissue
(Atrovent)
Benztropine
obstructive pulmonary disorder

CNS: Effective against Parkinsons

locally to minimize systemic effects
Adverse Effects/Toxicity
(Cogentin) tremor (often taken with drugs
Trihexyphnidyl enhancing dopaminergic activity)
(Artane)
"DRY AS A BONE, RED AS A BEET, MAD AS A HATTER“
Scopolamine CNS: Motion sickness (p.o/iv), GI: Post-op urinary retention &
blocking short term memory. intestinal hypomobility
Eye: Mydriasis & cycloplegia 1. "Dry as a bone" is a result of decreased sweating,
Resp: Used prior to admin of inhalant salivation, and lacrimation.
anaesthetic to reduce secretions &
possibility of laryngospasm 2. "Red as a beet" is a result of dilation of cutaneous vessels
Methscopolamine GI: large doses required to treat peptic Such large doses-> of the arms, head, neck and trunk - "atropine flush".
(Pamine) ulcer disease (least sensitive to Eye: blurred vision
muscurinic blockade) GI: Dry mouth; usually
3. "Mad as a hatter" is a result of CNS effects, including
contraindicated in gastric peptic ulcer sedation, amnesia, delirium or hallucination.
disease because of slow gastric
emptying time, ↑exposure to acid
GU: urinary hesitancy
Flavoxate GU: overactive bladder: inappropriate
(Urispas) urination
Dicylomine GI: Irritable bowel syndrome; spastic
(Bentyl) colon
 ABSORPTION, FATE AND EXCRETION:

• Therapeutic uses:
Atropine rapidly absorbed from the g.i.t. Atropine has half life of 4 hrs. Half
• Muscarnic receptor antagonists were once the most widely used drugs for the
of a dose excreted unchanged in the urine.
management of peptic ulcer.

• Poisoning by muscarnic receptors antagonists like Atropine, and other • Although these drugs reduce the gastric motility and secretion of gastric acid it
antidepressants amitriptiline : does produced many side effects like dry mouth, loss of visual accommodation
For the treatment Physostigmine 1-4mg given slowly by I.V . usage of these drugs in peptic ulcer is poor.

• Belladonna alkaloids can induce bronchial dilation it was used in the treatment of
bronchial asthma.

• Atropine occasionally is useful in reducing the severe bradycardia.

• Belladonna alkaloids were used in the prevention of motion sickness.

• Uses in Anesthesia: The belladonna alkaloids commonly were used to inhibit

excessive salivation and secretions of the respiratory tract induced by
administration of general anesthetic agents.

• Anticholinestrase and Mushroom poisoning:

• Atropine is only useful as an antidote for the symptoms of mushroom poisoning
due to the cholinomimetic alkaloid muscarine found in certain mushroom species.
•

Classification of Blockers
Agent Pharmacological Onset time Duration Elimination
Properties (min) (min)
Succinylcholine Ultra short acting; Plasma
1-1.5 6-8 cholinesterase
Depolarizing
D-tubocurarine Long duration; Renal and
4-6 80-120 liver
Competitive
Atracurium Intermediate duration; Plasma
2-4 30-40 cholinesterase
Competitive
Mivacurium Short duration; Plasma
2-4 12-18 cholinesterase
Competitive
Pancuronium Long duration; Renal and
4-6 4-6 liver
Competitive
Rocuronium Intermediate duration; Renal and
1-2 1-2 liver
competitive