1. Cholinoceptor-blocking drugs

2. Overview
The cholinergic antagonists bind to cholinoceptors, but they do not trigger the usual receptor-mediated intracellular effects
Also called cholinergic blockers, parasympatholytics or anticholinergic drugs
Cholinoceptor antagonists are divided into muscarinic and nicotinic subgroups on the basis of their receptor affinities

3. Overview
Cholinergic antagonists are further subdivided according to their physiological site of action:
Muscarin antagonists (antamuscarinics, parasympatholytic drugs)
Ganglionic blockers
Neuromuscular-blocking drugs

4. Sympathatic innervation of adrenal medulla Neuromuscular blockers
Parasympathatic
Somatic
Ganglionic blockers
Neuromuscular junction
Ganglionic transmittion
NN receptor
Adrenal medulla
NN receptor
NN receptor
Neuroeffector transmittion
Neuromuscular blockers
antimuscarinics
Acetylcholine
Norepinephrine
Effector organ
α or β Adrenergic receptor
Effector organ
M receptor
Neuromuscular junction
NM receptor

5. I. Muscarinic antagonists (antimuscarinics)
These are reversible (surmountable) competitive antagonists that compete with ACh and other muscarinic agonists for a common binding site on the muscarinic receptor
These drugs block sympathetic neurons that are cholinergic innervating salivary and sweat glands
The antimuscarinics are beneficial in a variety of clinical situations, because they do not block nicotinic receptors

6. I. Muscarinic antagonists (antimuscarinics)
The class of drugs includes:
Naturally occurring alkaloids (atropine & scopolamine)
Semisynthetic derivatives of the naturally occurring alkaloids, which primarily differ from the parent compounds in their disposition in the body or their duration of action
Synthetic muscarinic antagonists (homatropine & tropicamide) , some of which show selectivity for particular subtypes of muscarinic receptors

7. I. Muscarinic antagonists (antimuscarinics) Pharmacokinetics
Natural alkaloids & tertiary antimuscarinic drugs
Absorption: well & rapidly absorbed from the gut and conjunctival membranes. When applied in a suitable vehicle, some (eg, scopolamine) are even absorbed across the skin (transdermal route)
Distribution: widely distributed in the body. Significant levels are achieved in the CNS within 30 minutes to 1 hour
Metabolism & excretion: hepatic metabolism accounts for the elimination of about half of atropine; the remainder is excreted unchanged in the urine
Quaternary antimuscarinic drug
Absorption: only 10–30% of a dose is absorbed after oral administration
Distribution: poorly taken up by the brain

8. I. Muscarinic antagonists Mechanism of action
Atropine (prototype) does not distinguish among the M1, M2, and M3 subgroups of muscarinic receptors
Few synthetic antimuscarinic drugs demonstrate selectivity for one or another of these subgroups:
M1 selective agents: pirenzepine, telenzepine
M3 selective agents: darifenacin, solifenacin

9. Dissociation constant (kd)M1 M2 M3
Atropine 1
Pirenzepine 25
300
500
AF-DX 116
2000 65
4000
Darifenacin 70 55 8

10. Effects of muscarinic blocking drugs
Organ
Effect
Mechanism
CNS
Sedation, anti-motion sickness action, antiparkinson action, amnesia, delirium
Block of muscarinic receptors, several subtypes
Eye
Cycloplegia, mydriasis
Block of M3 receptors
Bronchi
Bronchodilation, especially if constricted
GIT
Relaxation, slowed peristalsis, reduced salivation
Block of M1, M3 receptors
Genitourinary tract
Relaxation of bladder wall, urinary retention
Block of M3 and possibly M1 receptors
Heart
Bradycardia (at low doses)
Tachycardia (at high doses)
Block of presynaptic M1 receptors
Block of M2 receptors in the sinoatrial node
Blood vessels
Block of muscarinic vasodilation; not manifest unless a muscarinic agonist is present
Block of M3 receptors on endothelium of vessels
Glands
Marked reduction of salivation; moderate reduction of lacrimation, sweating; less reduction of gastric secretion

11. Dose-dependent effect of atropine
>10.0 mg
Hallucination and delirium; coma
Dose of atropine
Rapid heart rate; palpitation; marked dryness of the mouth; dilation of pupil; some blurring of near vision
5.0 mg
2.0 mg
Slight cardiac slowing; some dryness of the mouth; inhibition of sweating
0.5 mg

12. I. Muscarinic antagonists Clinical uses
Central Nervous System Disorders
Parkinson's Disease: Bezotropine, biperiden, and trihexylphenidyl
Motion Sickness: Scopolamine (injection or by mouth or as a transdermal patch)

13. I. Muscarinic antagonists Clinical uses
Ophthalmologic Disorders
Examination of the retina and optic disc and for the accurate measurement of refractive error administered topically as eye drops or ointment
Agents used: Atropine, scopolamine, cyclopentolate and tropicamide, homatropin
Short-acting drugs (e.g cyclopentolate and tropicamide) are favoured for ophthalmic application b/c complete recovery of accommodation occurs within 6 to 24 hours and 2 to 6 hours, respectively

14. I. Muscarinic antagonists Clinical uses
Ophthalmologic Disorders
Prevent synechia (adhesion) formation in uveitis and iritis: homatropine

15. I. Muscarinic antagonists Clinical uses
Respiratory disorders: Ipratropium, tiotropiumis, and aclidinium used as an inhalational drug in asthma & chronic obstruction pulmonary disease (COPD)
Gastrointestinal disorders
Treatment of traveler's diarrhea: in combination with an opioid antidiarrheal drug (e.g. atropine & diphenoxylate combination (Lomotil®)

16. I. Muscarinic antagonists Clinical uses
Urinary Disorders
Symptomatic relief in the treatment of urinary urgency caused by minor inflammatory bladder disorders
Relief bladder spasm after urologic surgery eg. prostatectomy: Oxybutynin, darifenacin, solifenacin, tolterodine, fesoterodine (all are selective M3 antagonists), trospium (a nonselective antagonist)

17. I. Muscarinic antagonists Clinical uses
Cholinergic poisoning
Used for the treatment of poisoning caused by anticholinesterase organophosphorus insecticides or by the ingestion of mushrooms of Inocybe genus
Atropine is used to antagonize/reverse the central and parasympathomimetic effects of the organophosphate anticholinesterase inhibitors

18. I. Muscarinic antagonists Toxicity
Predictable toxicities
Antimuscarinic adverse effects depend on the dose
Antimuscarinic agents may cause dry mouth, blurred vision ‘sandy eyes’, tachycardia, and constipation
Children, especially infants, are very sensitive to the hyperthermic effects of atropine (Atropine fever)
Elderly are especially susceptible to antimuscarinic toxicities including the eye and the bladder especially those with a history of prostatic hyperplasia

19. I. Muscarinic antagonists Toxicity
CNS toxicities: sedation, amnesia, and delirium or hallucinations; convulsions may also occur
Cardiovascular Effects
At very high doses, antimuscarinic can cause:
Intraventricular conduction block
Atropine flush: dilation of the cutaneous vessels of the arms, head, and neck

20. I. Muscarinic antagonists Contraindications
Contraindications to the use of antimuscarinic drugs are relative, not absolute
Antimuscarinic drugs are contraindicated in patients with glaucoma and elderly patients with a history of prostatic hyperplasia
Because the antimuscarinic drugs slow gastric emptying, they may increase symptoms in patients with gastric ulcer (nonselective antimuscarinic agents should never be used to treat acid-peptic disease)

21. II. Ganglion-Blocking Drugs
Agents: hexamthonium, mecamylamine, trimethaphan
Ganglionic blockers competitively block the action of ACh and similar agonists at nicotinic receptors of both parasympathetic & sympathetic autonomic ganglia
These drugs block the entire output of the ANS: the responses observed are complex and unpredictable (rarely used therapeutically)
The lack of selectivity confers such a broad range of undesirable effects that limit their clinical use

22. II. Ganglion-Blocking Drugs
In any given tissue, the magnitude of the response produced by ganglionic blocking drugs depends largely on the quantity and relative proportion of the total autonomic input coming from sympathetic and parasympathetic nerves at the time of drug administration

23. Effects of ganglion-blocking drugs
Organ
Effects
CNS
Antinicotinic action may include reduction of nicotine craving and amelioration of Tourette's syndrome (mecamylamine only)
Eye
Moderate mydriasis and cycloplegia
Bronchi
Little effect; asthmatics may note some bronchodilation
Gastrointestinal tract
Marked reduction of motility, constipation may be severe
Genitourinary tract
Reduced contractility of the bladder;impairment of erection (parasympathetic block) and ejaculation (sympathetic block)
Heart
Moderate tachycardia and reduction in force and cardiac output at rest; block of exercise-induced increases
Vessels
Reduction in arteriolar and venous tone, dose-dependent reduction in blood pressure; orthostatic hypotension usually marked
Glands
Reductions in salivation, lacrimation, sweating, and gastric secretion
Skeletal muscle
No significant effect

24. II. Ganglion-Blocking Drugs Clinical uses
Mecamylamine blocks central nicotinic receptors and has been advocated as a possible adjunct with the transdermal nicotine patch to reduce nicotine craving in patients attempting to quit smoking

25. II. Ganglion-Blocking Drugs Toxicity
Mild untoward ADRs: visual disturbances, dry mouth, conjunctival suffusion, urinary hesitancy, decreased potency, subjective chilliness, moderate constipation, occasional diarrhea, abdominal discomfort, anorexia, heartburn, nausea, eructation, and bitter taste and the signs and symptoms of syncope caused by postural hypotension
Severe ADRs: marked hypotension, constipation, syncope, paralytic ileus, urinary retention, and cycloplegia