Cholinoceptor blocking drugs

1. Cholinoceptor Blockers &
Cholinesterase
Regenerators
Dr.M.Usman Khalid
DPT,MS-NMPT

2. MUSCARINIC ANTAGONISTS
 Atropine is the prototypical nonselective muscarinic blocker.
 This alkaloid is found in Atropa belladonna and many other
plants.
 Lipid-soluble
 Readily crosses membrane barriers.
 The drug is well distributed into the CNS, the eye, and other
organs.
 It is eliminated partially by metabolism in the liver and
partially unchanged in the urine; half-life is approximately 2 h;
and duration of action of normal doses is 4–8 h except in the
eye.

3. Mechanism of Action
 muscarinic blocking agents act like competitive
(surmountable) pharmacologic antagonists; their blocking
effects can be overcome by increased concentrations of
muscarinic agonists.

4. Effects

5. Clinical Uses
 1. CNS—Scopolamine is standard therapy for motion
sickness, benztropine, biperiden, and trihexyphenidyl are
representative of several antimuscarinic agents used in
parkinsonism.
 2. Eye—Antimuscarinic drugs are used to cause mydriasis.
In descending order of duration of action, these drugs are
atropine (>72 h), homatropine (24 h), cyclopentolate (2–
12 h), and tropicamide (0.5–4 h).
 These agents are all well absorbed from the conjunctival sac
into the eye.

6. Clinical Uses
 3. Bronchi—Parenteral atropine has long been used to
reduce airway secretions during general anesthesia.
Ipratropium is a quaternary antimuscarinic agent used by
inhalation to promote bronchodilation in asthma and chronic
obstructive pulmonary disease (COPD).
 4. Gut—Atropine, methscopolamine, and propantheline
were used in the past to reduce acid secretion in acid-peptic
disease, but are now obsolete for this indication. Muscarinic
blockers can also be used to reduce cramping and
hypermotility in transient diarrheas.

7. Clinical Uses
 5. Bladder—Oxybutynin, tolterodine, or similar agents may
be used to reduce urgency in mild cystitis and to reduce
bladder spasms after urologic surgery. Tolterodine,
darifenacin, solifenacin, fesoterodine, and propiverine
are slightly selective for M3 receptors and are promoted for
the treatment of stress incontinence.
 6. Cholinesterase inhibitor intoxication—Atropine, given
parenterally in large doses, reduces the muscarinic signs of
poisoning with AChE inhibitors. Pralidoxime is used to
regenerate active AChE.

8. Toxicity
 A traditional mnemonic for atropine toxicity is “Dry as a
bone, hot as a pistol, red as a beet, mad as a hatter.” This
description reflects both predictable antimuscarinic effects
and some unpredictable actions.

9. Toxicity
 Blockade of thermoregulatory sweating may result in
hyperthermia or atropine fever (“hot as a pistol”). This is the
most dangerous effect of the antimuscarinic drugs in children
and is potentially lethal in infants.
 Sweating, salivation, and lacrimation are all significantly reduced
or stopped (“dry as a bone”). Moderate tachycardia is common,
and severe tachycardia or arrhythmias are common with large
overdoses.
 In the elderly, important toxicities include acute angle-closure
glaucoma and urinary retention, especially in men with prostatic
hyperplasia. Constipation and blurred vision are common
adverse effects in all age groups.

10. Toxicity
 CNS toxicity includes sedation, amnesia, and delirium or
hallucinations (“mad as a hatter”); convulsions may also occur.
 Other drug groups with antimuscarinic effects, for example,
tricyclic antidepressants, may cause hallucinations or delirium in
the elderly, who are especially susceptible to antimuscarinic
toxicity.
 At very high doses, intraventricular conduction may be blocked;
this action is probably not mediated by muscarinic blockade and
is difficult to treat.
 Dilation of the cutaneous vessels of the arms, head, neck, and
trunk also occurs at these doses; the resulting “atropine flush”
(“red as a beet”) may be diagnostic of overdose with these
drugs.

11. Treatment of toxicity—Treatment of
toxicity is usually symptomatic.

12. Contraindications
 The antimuscarinic agents should be used cautiously in
infants because of the danger of hyperthermia. The drugs are
relatively contraindicated in persons with glaucoma,
especially the closed angle form, and in men with prostatic
hyperplasia.

13. NICOTINIC ANTAGONISTS
 A. Ganglion-Blocking Drugs: Blockers of ganglionic
nicotinic receptors act like competitive pharmacologic
antagonists, although there is evidence that some also block
the pore of the nicotinic channel itself.
 These drugs were the first successful agents for the
treatment of hypertension. Hexamethonium (C6, a
prototype), mecamylamine, and several other ganglion
blockers were extensively used for this disease.
 The adverse effects of ganglion blockade in hypertension are
so severe (both sympathetic and parasympathetic divisions
are blocked) that patients were unable to tolerate them for
long periods.

14. Neuromuscular-Blocking Drugs
 Neuromuscular-blocking drugs are important for producing
marked skeletal muscle relaxation that is important in surgery
and in mechanical ventilation of patients

15. CHOLINESTERASE
REGENERATORS
 Pralidoxime is the prototype cholinesterase regenerator.
These chemical antagonists contain an oxime group, which
has an extremely high affinity for the phosphorus atom in
organophosphate insecticides.
 Because the affinity of the oxime group for phosphorus
exceeds the affinity of the enzyme-active site for phosphorus,
these agents are able to bind the inhibitor and displace the
enzyme if aging has not occurred. The active enzyme is thus
regenerated.