Cholinergic Antagonists:

(Cholinergic blockers or anticholinergic drugs)

They block the various types of cholinergic

receptors.
Antimuscarinic Drugs:

1.

2.

They block the action of Acetylcholine at muscarinic receptors

and also effects of parasympathetic nerve stimulation.

Ganglion Blocking drugs:

3.

They block the action of Acetylcholine at autonomic ganglia.

(Nicotinic receptors).

Neuromuscular blocking drugs:

They block the effect of Acetylcholine at N.M junction.

Antimuscarinic Drugs
They are also called Parasympatholytic drugs Or
Anticholinergics.
They reduce or abolish (block) the muscarinic receptor
mediated effects of parasympathetic nervous system.
The dosed required to block the responses to
parasympathetic stimulation are greater than those
required to block effects of exogenously administered
drugs. It is due to the fact that by nerve stimulation the
acetylcholine is liberated very close to the receptors,
where higher concentrations of antagonist are required.
Antimuscarinic drugs include naturally occuring
Belladonna Alkaloids (Atropine, Hyoscine) and a large
number of semisynthetic and synthetic drugs.

Classification:
Natural alkaloids:
Atropine
Hyoscine
Semisynthetic compounds:
Atropine methonitrate
Hyoscine methobromide
Hyoscine butylbromide
Homatropine methylbromide
Synthetic compounds:
Mydriatic and
Cycloplegics:
Cyclopentolate
Tropicamide
Homatropine

Spasmolytics
(antispasmodics)
Propantheline
Isopropamide
Ipratropium (anti
asthmatics)
Glycopyrrolate
Pirenzepine
Dicyclomine

Anti-Parkinsonism
Agents:
Trihexyphenidyl
Benztropine
Biperiden

ANTIMUSCARINIC DRUGS

These drugs, for example atropine and hyoscine,

block muscarinic receptors. In addition these
drugs block the sympathetic neurons that are
cholinergic, such as those innervating sweat
glands.
ATROPINE (Prototype)

Source
Plant

Alkaloid

Atropa
Belladonna

Atropine

Datura
stramonium

Atropine

Atropa
Acuminata

Atropine

Hyoscyamus

Hyoscine

Atropine
Chemistry: Atropine is an alkaloid ester of tropic
acid with an organic base, tropine. Hyoscine is an
ester of tropic acid with an organic base, scopine.

Mechanism of Action: Atropine is a

competitive antagonist of acetylcholine at
muscarinic receptors. The action of atropine is
reversible and can be overcome by increasing the
concentration of acetylcholine or any other
muscarinic agonist or by the use of
anticholinesterase.

Atropine
Pharmacokinetics: Atropine is lipid
soluble. Rapidly absorbed from GIT and
mucous membranes (conjunctiva). It can
cross BBB (Blood-Brain Barrier) and
placental barrier, and is secreted in milk.
Its half- life is about 4 hrs. It is metabolized
in liver. About half of the dose is secreted
unchanged in urine.

Atropine
Pharmacological Actions
Eye: Atropine blocks muscarinic receptors of circular muscles,
causing their relaxation. The unopposed action of dilator pupillae
(radial) muscles causes mydriasis. Light reflex is abolished and
this caused photophobia.
The ciliary muscle is relaxed with paralysis (loss) of
accommodation; the lens becomes flat and fixed for far (distant)
vision. This is called cycloplegia.
There is increase in the intra-ocular pressure because the iris
crowded back into the anterior chamber of the eye interferes with
the drainage of aqueous humor.
In elderly patients with shallow anterior chamber, atropine can
precipitate acute congestive glaucoma. Effects of atropine can
occur after local or systemic administration. After applying locally,
the mydriatic effect remains for 5-7 days and cycloplegic action
for 6-10 days.

Atropine
Gastrointestinal Tract:
Atropine markedly reduces salivary secretions. Mouth
becomes dry and swallowing becomes difficult. Gastric
secretion is reduced in volume but H+ concentration
remains unaltered.
Pirenzepine, a M1 muscarinic antagonist, does reduce
gastric acid secretion in doses that do not antagonize
other systems.
Atropine markedly reduces motility of the GIT. Its motor
activity is inhibited. There is decrease in the tone as well
as amplitude and frequency of peristaltic contractions.

Atropine
Gall Bladder:
Atropine has a mild antispasmodic effect on bile
ducts and gall bladder, but it cannot overcome
the spasm of bile ducts induced by morphine.
Urinary Tract:
Atropine decreases tone and amplitude of
contractions of ureter and urinary bladder.
Detrusor muscle is relaxed and sphincter
contracts. It causes urinary retention especially
in elderly males with enlarged prostate.

Atropine
Respiratory Tract:
Atropine acts on the bronchial glands and
bronchial smooth muscles. It reduces the
secretions of the respiratory tract and hence it
is used a preanesthetic medication.
Atropine causes bronchodilatation resulting in
increase in the rate and depth of respiration.
Ipratropium bromide, a synthetic quaternary
antimuscarinic compound is being used by
inhalation.

Atropine
Cardiovascular System:
Atropine has a biphasic action on the heart. It
causes transient bradycardia, especially
noticeable at low doses. This initial
bradycardia occurs due to:
Transient initial stimulation of dorsal nucleus
of Vagus Nerve.
Blockade of pre-synaptic M1 receptors on
post-ganglionic parasympathetic neurons.

Continued .
Large doses causes tachycardia due to blockade of
cardiac M2 receptors on SA node and AV node. Atropine
is used as pre-anesthetic medication as it may prevent
excessive vagal slowing of the heart during anesthesia.
Does not affect blood pressure unless there is
hypotension as a result of bradycardia e.g following acute
myocardial infarction,in which case atropine may return
the pressure to a normal value
In large doses there may be dilatation of cutaneous blood
vessels (atropine flush) in face and neck, which may be
due to direct action, unrelated to cholinergic innervation.

Atropine
Sweat Glands:
Sweat gland of the skin are innervated by sympathetic
cholinergic fibers, which play an important role in
thermoregulation. These are blocked by atropine resulting
in no sweating and no heat loss; there is rise in the body
temperature. Infants and small children are more sensitive
to this effect and suffer from Atropine fever.
Central Nervous System: Atropine stimulates CNS. Large
doses cause restlessness, irritability, hallucinations, and
delirium. Stimulation is followed by depression. Atropine
reduces tremors and rigidity in Parkinsonism, where there
is cholinergic activity.

Semisynthetic Derivatives
Atropine Methonitrate:
It is a quaternary derivative of atropine. It is used in
congenital hypertrophic pyloric stenosis and pylorospasm
in children.
Hyoscine Methobromide:
It is a quaternary derivative of hyoscine. It is used in
peptic ulcer, renal colic and cystitis.
Hyoscine Butylbromide:
It is used for esophageal and gastrointestinal spastic
conditions, peptic ulcer, spasm of ureter and bile duct.
Homatropine Methylbromide:
Used topically as mydriatic and cycloplegic. It is also
used orally to treat the spasm of GIT, bile duct and ureter.

Spasmolytics:
They are quaternary ammonium compounds. Given orally. Used for
gastrointestinal and genitourinary conditions. They reduce gastric
motility, pylorospasm and gastric secretion.
Ipratropium Bromide
It is used as a bronchodilator, by inhalation. It does not interfere with
the functions of ciliated epithelium of bronchial tree. So it can be
used in chronic obstructive pulmonary diseases (COPD).
Pirenzepine
It is a tertiary amine. It is selective antagonist of M1 receptors, which
are present in the intra-mural plexus of the stomach and reduced
gastric secretions without interference with M2 receptor. It is used in
the treatment of peptic ulcer.
Antiparkinsonism Agents
Have weak peripheral anticholinergic action, cross Blood-Brain
barrier and act on the basal ganglia.

THERAPEUTIC USES OF ANTIMUSCARINIC DRUGS

Eye Conditions:
Antimuscarinic drugs are used to produce mydriasis and
cycloplegia. When only mydriasis is required, a
sympathomimetic drug like phenylephrine is used.
Longer acting drugs like atropine may be used alternately
with a miotic agent to break the adhesions in uveitis and
iritis.
Also used topically for thorough examination of retina and
optic disk,for accurate measurement of refractive errors

Continued uses

Gastrointestinal System:
Antisecretory: Used in peptic ulcer
Antispasmodic: used in intestinal colic, biliary colic

Genitourinary System:
Used in ureteric colic, cystitis, incontinence of
urine. (nocturnal enuresis).
Central Nervous system
Parkinsonism
Motion sickness hyoscine butyl bromide prophylactically

Uses continued...

Cardiovascular and respiratory system:

Preanesthetic medication: useful in preventing:
Increased secretions of respiratory tract due to irritant effects of
anesthesia.
Vagal effects of some anesthetics

Bronchial asthma: Ipratropium is used by

inhalation.
Extreme bradycardia associated with:
-Acute M.I in whom excessive vagal tone causes
sinus or nodal bradycardia
-A V block

Uses continued

In the treatment of organophosphorus

compound Poisoning.
In treatment of mushroom poisoning.
To antagonize the muscarinic effects of
neostigmine.

Precautions with Atropine-like drugs

In patients over 40 years of age, with shallow anterior
chamber, systemic or topical administration of these
drugs may precipitate acute congestive glaucoma.
In patients with enlarges prostate there may be
retention of urine.
In coronary artery disease atropine may precipitate
angina.
In patients with partial pyloric stenosis, it may result in
complete stenosis.
In patients with gastric ulcer, if it is given alone, delay
in gastric emptying-time will expose the ulcer to acid
for longer time.

Poisoning of Antimuscarinic Drugs

Symptoms and signs: They are due to peripheral
blockade of muscarinic receptors and the actions on
CNS.
Peripheral muscarinic effects:
Dry mouth, dysphagia, thirst, constipation, pupils dilated,
loss of accommodation, photophobia.
Skin Dry, hot,

hyperpyrexia(atropine fevermost dangerous),

scarlet rash may appear, Atropine flush(face and neck)
Palpitations
Dysuria, retention of urine.

 Central nervous system effects:

They are:
Excitement, restlessness, delirium, disorientation,
hallucinations. This is followed by depression of
vasomotor center and respiratory center.
Dry as a bone(bec. sweating ,salivation,lacrimation,all
reduced
blind as a bat,
red as a beet,
mad as a hatter

Treatment

Treatment of hyperpyrexia ice bag,

artificial respiration, oxygen.
Removal of unabsorbed drug by gastric
lavage with KMnO4 or activated
charcoal.
To counteract excitement and
convulsions diazepam.
Specific treatment(Antidote)
Physostigmine I/V.

Sympatholytic pharmacology

Selective vs. Non-selective

Antagonist vs. Partial
Agonist
Reversible vs. Irreversible

Receptor agonists activate signal transduction

pathways
HO
NH3

HO

CH

CH2

NH2

OH

Norepinephrine
1 adrenergic
receptor

Gq

(+) Phospho-

lipase C
PIP2

COOH

IP3

Diacylglycerol

Increase Ca2+

Activate Protein
Kinase C

Response

Receptor antagonists block agonist binding to the

receptor
HO

HO

Antagonist

CH2

NH2

OH

NH3

Norepinephrine

Gq

What effect would an antagonist

alone have on receptor
activation?

CH

COOH

Phospholipase C

Clinical pharmacology of -adrenergic

receptor antagonists
Drug
Phenoxybenzamine
Phentolamine

Route of
Receptor admin.
Clinical uses

Prazosin

Terazosin

Doxazosin

Oral
Pheochromocytoma, hypertensive crisis
Parenteral Pheochromocytoma, hypertensive crisis,
male impotence
Oral
Hypertension, benign prostatic
hypertrophy
Oral
Hypertension, benign prostatic
hypertrophy
Oral
Hypertension, benign prostatic
hypertrophy

Side effects of 1 receptor antagonists:

Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia

Non-selective adrenergic receptor

antagonists
-Haloalkylamines
R
N CH2 CH2 X
R
R= aromatic, alkyl
X= Cl-, Br-, etc.

Non-selective adrenergic receptor

antagonists
-Haloalkylamines
CH3
O

Cl

Phenoxybenzamine (Dibenzyline)

Non-selective receptor
antagonist
Also blocks acetylcholine,
histamine, and serotonin
receptors
Irreversible antagonist
resulting from covalent
modification of receptor

Non-selective adrenergic receptor

-Haloalkylamines: Mechanism
of receptor inactivation
antagonists
R

R
N

R Cl-

R
N

R Cl-

Nu
Cl

Aziridinium ion

receptor

Nu

alkylated
receptor

Non-selective adrenergic receptor

antagonists
Imidazolines
HO
N
N

CH2
N
H

H3 C

Phentolamine (Regitine)

Non-selective receptor
antagonist
Competitive (reversible)
blocker
Potent vasodilator, but
induces pronouced reflex
tachycardia
Block of presynaptic 2
receptors may promote
release of NE
Also blocks 5-HT receptors,
and is a muscarinic and
histamine receptor agonist

-adrenergic receptor antagonists

O

Quinazoline ring
N
H3CO

N
N

Piperazine ring

H3CO
NH2

Prazosin: R =
(Minipres)
Terazosin: R =
(Hytrin)
Doxazosin: R =
(Cardura)

Acyl
moiety

O
O

Quinazolines
Vary in half-life:
Prazosin 3 hrs
Terazosin 12 hrs
Doxazosin 20 hrs

Undergo extensive metabolism,

excreted mainly in the bile
Vasodilators
Relaxation of smooth muscle in
enlarged prostate and in bladder bas
First-dose effect

Other adrenergic receptor antagonists

Ergot alkaloids

R'

N
O

NH
O

NCH3

N
H

Derivatives of Lysergic Acid

Product of the grain fungus
Claviceps purpura
5 Major alkaloids based on R and
R; Ergotamine the most common
Used in the treatment of migraine
Ergots possess strong oxytocic
action

-adrenergic receptor antagonists

N
N
H

H
H
H3CO2C

Yohimbine (Yocon)

OH

Indole alkaloid
Found in Rubaceae and
related trees. Also in
Rauwolfia Serpentina.
Blockade of 2 receptors
increases sympathetic
discharge
Folklore suggests use in the
treatment of male impotence

-adrenergic receptor antagonists

Aryloxypropanolamines

Note: non-carbon atom

in side chain

O
Ar

NH

OH

Ar = aromatic ring structure

R = bulky alkyl group (isopropyl or tert-butyl)

-adrenergic receptor antagonists

CH3
O
OH

Propranolol
(Inderal)

N
H

CH
CH3

Non-selective
Lipophilic
Local anesthetic
properties
Blockade is activitydependent

-adrenergic receptor antagonists

CH3
O
OH

Propranolol
(Inderal)

N
H

CH
CH3

Pharmacological effects
Decreased cardiac output and
heart rate
Reduced renin release
Increase VLDL, Decrease HDL
Inhibit lipolysis
Inhibit compensatory
glycogenolysis and glucose
release in response to
hypoglycemia
Increase bronchial airway
resistance

Therapeutic uses for -adrenergic receptor antagonists:

Hypertension, angina, cardiac arrhythmias, migraine, stage fright,
thyrotoxicosis, glaucoma, congestive heart failure (types II and III)

Non-selective -adrenergic receptor

antagonists
CH3
O
HO

HO

OH

N
H

CH
CH3

Less lipophilic than propranolol

Long half-life: ~20 hours
Mostly excreted unchanged in urine
Administered: Oral
Uses: Hypertension, angina, migraine

Nadolol (Corgard)

CH3
O
O

OH

N
H

CH3
CH3

N
N

Timolol (Timoptic, Blocadren)

Thiadiazole nucleus with

morpholine ring
Administered: Oral, Ophthalmic
Uses: Hypertension, angina,
migraine, glaucoma
How will -blockers affect
pupil size?

Non-selective -adrenergic receptor

antagonists
CH3
O
OH

N
H

CH

N
H

CH3

Possesses Intrinsic sympathomimetic

activity (ISA)
Partial agonist
Less likely to cause bradycardia and lipid
abnormalities
Administered: Oral
Uses: Hypertension, angina, migraine

Pindolol (Visken)

What would a pindolol dose-response curve look like?

Non-selective -adrenergic receptor

antagonists
CH3
O
OH
O

N C CH3
H
CH3

N
H
Carteolol (Cartrol, Ocupress)

Possesses Intrinsic sympathomimetic

activity (ISA)
Partial agonist
Less likely to cause bradycardia and lipid
abnormalities
Administered: Oral, Opththalmic
Uses: Hypertension, glaucoma

Selective -adrenergic receptor

antagonists
CH3
O
OH

N
H

CH
CH3

R
Metoprolol (Lopressor, Toprol)
R= CH2 O CH3
CH3
Bisoprolol (Zebeta)
CH
R= O
CH2
CH2
O
CH3

Cardioselective
Less bronchconstriction
Moderate lipophilicity
Half-life: 3-4 hours
Significant first-pass metabolism
Administered: Oral, parenteral
Uses: Hypertension, angina, antiarrhythmic,
congestive heart failure

Selective -adrenergic receptor

antagonists
CH
3
O
OH

N
H

CH
CH3

NH2
O

Atenolol (Tenormin)

Cardioselective
Less bronchconstriction
Low lipophilicity
Half-life: 6-9 hours
Administered: Oral, parenteral
Uses: Hypertension, angina

Selective -adrenergic receptor

antagonists
CH
3

N
H

OH

CH
CH3

O
O

CH3

Esmolol (Brevibloc)

Very short acting

Half-life: 9 minutes
Rapid hydrolysis by esterases found in red
blood cells
Administered: Parenteral
Note: incompatible
with sodium bicarbonate
Uses: Supraventricular tachycardia, atrial
fibrillation/flutter, perioperative hypertension

Side effects of -blockers:

Bradycardia, AV block, sedation, mask
symptoms of hypoglycemia, withdrawal
syndrome

Effect of chronic -receptor blockade

Na+

Presynaptic neuron
Tyrosine

Na+
Dopamine
Tyrosine
Action Potential

H+

O
MA

DA
NE

NE

Ca2+

Uptake 1
Na+, Cl-

NE
NE

NE

Effector organ

NE

Effect of chronic -receptor blockade:

Na+

Receptor up-regulation

Tyrosine

Na+
Dopamine
Tyrosine
Action Potential

H+

O
MA

DA
NE

NE

Ca2+

Uptake 1
Na+, Cl-

NE
NE

NE

Effector organ

NE

Side effects of -blockers:

Bradycardia, AV block, sedation, mask symptoms
of hypoglycemia, withdrawal syndrome
Contraindications:
Asthma, COPD, congestive heart failure (Type IV)

Mixed adrenergic receptor antagonists

OH

H
N 1'
CH3

HO

Non-selective receptor antagonist

1 receptor antagonist
Two asymmetric carbons (1 and 1)
(1R, 1R)-isomer possesses -blocking activity
(1S, 1R)-isomer possesses greatest 1 receptor blocking
activity
-blocking activity prevents reflex tachycardia normally
associated with 1 receptor antagonists
Administered: Oral, parenteral
Uses: Hypertension, hypertensive crisis

CONH2

Labetalol (Normodyne, Trandate)

Mixed adrenergic receptorOCHantagonists

3
O
OH

N
H

Non-selective receptor antagonist

1 receptor antagonist
Both enantiomers antagonize 1
receptors
Only (S)-enantiomer possesses blocking activity

N
H

Carvedilol (Coreg)

-blocking activity prevents reflex

tachycardia normally associated
with 1 receptor antagonists
Administered: Oral
Uses: Hypertension, congestive
heart failure (Types II and III)

Pharmacologic manipulation of the adrenergic system

Na+

Presynaptic neuron
Tyrosine

Na+

Dopamine

Tyrosine

Action Potential

H+

O
MA

DA
NE

NE

Ca2+
NE
NE

NE

Effector organ

Uptake 1
Na+, Cl-

NE

HO

CH2

CH

NH2 TYROSINE

COOH

Inhibition of
norepinephrine
synthesis

HO
HO

tyrosine hydroxylase

Metyrosine
CH2

CH

NH2 DOPA

COOH
aromatic L-amino acid decarboxylase

HO
HO

CH2

CH2

NH2 DOPAMINE

dopamine -hydroxylase
HO
HO

CH

CH2

NH2 NOREPINEPHRINE

OH
phenylethanolamineN-methyltransferase

HO
HO

CH
OH

CH2

NH
CH3

EPINEPHRINE

Drugs that reduce storage or release of NE

Na+

Tyrosine

Na+
Dopamine
Tyrosine

Reserpine
Guanethidine

Action Potential

O
MA

H+

NE

NE

Ca2+
NE
Guanethidine,
Bretylium

Effector organ

Guanethidine

Catecholamine depleters
N

H3CO
N
H

O
H

H3CO2C

OC
OCH3

Reserpine (Serpasil)
Indole alkaloid obtained from
the root of Rauwolfia
serpentina
Block vesicular monoamine
transporters
Deplete vesicular pool of NE

OCH3
OCH3
OCH3

Slow onset of action

Sustained effect (weeks)
Used in the treatment of
hypertension
May precipitate depression

Drugs that reduce storage or release of

NE
N

H
N

NH2

NH

Guanethidine (Ismelin)

Possess guanidino moiety

(pKa > 12)
Resonance stabilization of cation spreads
positive charge over the entire four atom
system
Almost completely protonated at physiological
pH
Pharmacologic sympathectomy
Effects can be blocked by transport blockers
Uses: Hypertension

Drugs that reduce storage or release of NE

Na+

Tyrosine

Na+
Dopamine
Tyrosine

Guanethidine
Action Potential

O
MA

H+

NE

NE

Ca2+
NE
Guanethidine,

Effector organ

Guanethidine

Drugs that reduce storage or release of

CH3 NE
CH

CH2CH3

O3S

CH3
Br

Bretylium tosylate (Bretylol)

Aromatic quaternary ammonium
Precise mechanism unknown
Displace and release NE and prevent
further release (depletion)
Local anesthetic
Administered: Parenteral
Uses: Antiarrhythmic (ventricular
fibrillation)

CH3