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 or anticholinergic drugs
Cholinoceptor antagonists are divided into muscarinic and nicotinic subgroups on the basis of their receptor affinities

3. OVERVIEW
Cholinergic antagonists are subdivided according to their physiological site of action:
Muscarinic antagonists / antimuscarinic / parasympatholytic
Ganglionic blockers
Neuromuscular-blocking drugs

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

8. 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. Scopolamine has the greatest CNS effects.
Metabolism & excretion: hepatic metabolism accounts for the elimination of about half of atropine; the remainder is excreted unchanged in the urine

9. I. Muscarinic antagonists (antimuscarinics) Pharmacokinetics
Quaternary antimuscarinic drug:
Absorption: only 10–30% of a dose is absorbed after oral administration
Distribution: poorly taken up by the brain. Free of CNF effects at low doses.

10. I. Muscarinic antagonists (antimuscarinics) Mechanism of Action
Atropine (prototype): highly selective for muscarinic receptors…does not distinguish among the M1, M2, and M3 subgroups
Much lower potency at nicotinic receptors
Few synthetic antimuscarinic drugs demonstrate selectivity for one or another of these subgroups (Table 8-1):
M1 selective agents: pirenzepine, telenzepine
M3 selective agents: darifenacin, solifenacin

12. Effects of muscarinic blocking drugs
Organ
Effect
Mechanism
CNS
Sedation (low doses), anti-motion sickness action, antiparkinson action, amnesia, excitement, agitation, hallucinations, coma
Block of muscarinic receptors, several subtypes
Eye (figure 6-9)
Cycloplegia, mydriasis, increase intraocular pressure, sandy eyes
Block of M3 receptors
Bronchi
Bronchodilation, especially if constricted, reduce secretions
GIT
Relaxation of GIT, reduced peristalsis, prolong gastric emptying time & intestinal transit time
Block of M1, M3 receptors
Genitourinary tract
Relaxation of ureters and bladder wall, slow voiding, no effect on the uterus
Block of M3 and possibly M1 receptors
Heart
Bradycardia (at low doses)
Block of presynaptic M1 receptors
Tachycardia (at high doses)
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 and thermoregulatory sweating (elevate temp.); less reduction of gastric secretion

13. Figure 6-9: Structures of the anterior chamber of the eye
Figure 6-9: Structures of the anterior chamber of the eye. Aqueous humor is secreted by the epithelium of the ciliary body, flows into the space in front of the iris, flows through the trabecular meshwork, and exits via the canal of Schlemm (arrow). Blockade of the β adrenoceptors associated with the ciliary epithelium causes decreased secretion of aqueous

14. Figure (8-5): Effects of subcutaneous injection of atropine on salivation, speed of micturition (voiding), heart rate, and accommodation in normal adults. Note that salivation is the most sensitive of these variables, accommodation the least. (Data from Herxheimer A: Br J Pharmacol 1958;13:184.)

15. Dose-dependent effect of atropine
>10.0 mg
Hallucination, delirium and 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

16. I. Muscarinic antagonists Clinical uses
Central Nervous System Disorders
Parkinson's Disease:
Parkinsonian tremor and rigidity seem to result from a relative excess of cholinergic activity due to deficiency of dopaminergic activity in the basal ganglia-striatum system
Blockage of cholinergic transmission produces effects similar to augmentation of dopaminergic transmission
Centrally acting agents such as benztropine, biperiden, and trihexylphenidyl play an adjuvant role in antiparkinsonism therapy combined with levodopa

17. + _ _ NEOSTRIATUM SUBSTANTIA NIGRA STIMULATORY Ach NEURONE GABAergic
Connection to muscle through motor cortex and spinal cord
Site of action of centrally acting antimuscarinic drugs
STIMULATORY Ach NEURONE + _
NEOSTRIATUM
Dopaminergic
GABAergic
Cell death results in less dopamine release in the neostriatum
SUBSTANTIA
NIGRA _

18. I. Muscarinic antagonists Clinical uses
Central Nervous System Disorders
Motion Sickness:
Vestibular disturbances appear to involve muscarinic cholinergic transmission
Scopolamine is used in the prevention of motion sickness. Can be given:
by injection
by mouth or
as transdermal patches
ADEs: cause significant sedation and dry mouth

19. I. Muscarinic antagonists Clinical uses
Ophthalmologic Disorders (eye drops or ointment)
Agents used: Atropine, scopolamine, cyclopentolate and tropicamide
Examination of the retina and optic disc and for the accurate measurement of refractive error administered topically (eye drops or ointment)
Short-acting drugs (e.g cyclopentolate and tropicamide) are favoured due to complete recovery of accommodation within 6 to 24 hours and 2 to 6 hours, respectively (table 8-2)
ADEs: may induced glaucoma in patients with a narrow anterior chamber angle, reduce lacrimal secretion

21. I. Muscarinic antagonists Clinical uses
Respiratory disorders
Atropine and synthetic analogues promote bronchocodilation and reduce secretion in both the upper and lower respiratory tracts
Ipratropium, tiotropium and aclinidium used in asthma & chronic obstruction pulmonary disease (COPD)…inhalational drug

22. I. Muscarinic antagonists Clinical uses
Gastrointestinal disorders:
Treatment of common traveler's diarrhea and hypermotility: in combination with an opioid antidiarrheal drug (e.g. atropine & diphenoxylate combination (Lomotil®)

23. I. Muscarinic antagonists Clinical uses
Urinary Disorders
In the treatment of urinary urgency caused by minor inflammatory bladder disorders
To relieve bladder spasm after urologic surgery
To decrease involuntary voiding in patients with neurologic disease (Oxybutynin, darifenacin, solifenacin, tolterodine, fesoterodine) (all are selective M3 antagonists), trospium (a nonselective antagonist)
Imipramine, a TCA with strong antimuscarinic actions, has long been used to reduce incontinence in institutionalized elderly patients. It is moderately effective but causes significant CNS toxicity.
Propiverine, a newer antimuscarinic agent, has been approved for this purpose.

25. I. Muscarinic antagonists Clinical uses
Cholinergic poisoning: cholinesterase inhibitor insecticides, wild mushrooms and chemical warfare "nerve gases”
Used to treat poisoning caused by cholinesterase inhibitor insecticides / chemical warfare or by the ingestion of mushrooms of Inocybe genus
Atropine: used to antagonize/reverse the central and parasympathomimetic effects of anticholinesterase inhibitors
Cholinesterase Regenerator Compounds: to treat organophosphorus poisoning……pralidoxime (2-PAM) and diacetylmonoxime (DAM)

26. I. Muscarinic antagonists Clinical uses
Cholinergic poisoning:
Pretreatment with reversible inhibitors: “prophylaxis” to prevent binding of the irreversible organophosphate inhibitor
Pyridostigmine or physostigmine just in situations in which possibly lethal poisoning is anticipated, eg, chemical warfare (+ atropine)

27. I. Muscarinic antagonists Toxicity
“Dry as a bone, blind as a bat, red as a beet, mad as a hatter“
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

28. 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

29. I. Muscarinic antagonists Contraindication
Contraindications to the use of antimuscarinic drugs are relative, not absolute
Antimuscarinic drugs are contraindicated:
in patients with glaucoma
elderly patients with a history of prostatic hyperplasia
may increase symptoms in patients with gastric ulcer because the antimuscarinic drugs slow gastric emptying,
Never used to treat acid-peptic disease!!!

30. II. Ganglion-Blocking Drugs
Agents: hexamthonium, mecamylamine, trimethaphan
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

31. II. Ganglion-Blocking Drugs
The net effect depends on the relative proportion of the total autonomic input coming from sympathetic and parasympathetic nerves to the organ

32. Effects of ganglion-blocking drugs
Organ
Effects
CNS
Sedation, tremor, choreiform movements, and mental aberrations 
Eye
Moderate mydriasis and cycloplegia (parasympathetic tone dominates this tissue
Bronchi
Little effect; asthmatics may note some bronchodilation
Gastrointestinal tract
Marked reduction of motility and secretions, constipation may be marked
Genitourinary tract
Reduced contractility of the bladder; urinary retention, 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, thermoregulatory sweating, and gastric secretion
Skeletal muscle
No significant effect

33. II. Ganglion-Blocking Drugs
Response to Autonomic Drugs
Patients receiving ganglion-blocking drugs are fully responsive to autonomic drugs acting on muscarinic, α-, & β-adrenergic receptors because these effector cell receptors are not blocked
Responses may be exaggerated or even reversed? because of homeostatic reflexes, which normally moderate autonomic responses are absent

34. II. Ganglion-Blocking Drugs Clinical uses
Used infrequently because of complex and unpredictable and more selective agents available
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.

35. 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

36. Probable signs of atropine overdose include which one of the
following?
(A) Gastrointestinal smooth muscle cramping
(B) Increased heart rate
(C) Increased gastric secretion
(D) Pupillary constriction
(E) Urinary frequency

37. Which of the following is the most dangerous effect of
belladonna alkaloids in infants and toddlers?
(A) Dehydration
(B) Hallucinations
(C) Hypertension
(D) Hyperthermia
(E) Intraventricular heart block

38. Which one of the following can be blocked by atropine?
(A) Decreased blood pressure caused by hexamethonium
(B) Increased blood pressure caused by nicotine
(C) Increased skeletal muscle strength caused by neostigmine
(D) Tachycardia caused by exercise
(E) Tachycardia caused by infusion of acetylcholine

39. A 30-year-old man has been treated with several autonomic drugs for 4 weeks. He is now admitted to the emergency department showing signs of drug toxicity. Which of the following signs would distinguish between an overdose of a ganglion blocker versus a muscarinic blocker?
(A) Blurred vision
(B) Dry mouth, constipation
(C) Mydriasis
(D) Postural hypotension
(E) Tachycardia

40. Accepted therapeutic indications for the use of antimuscarinic drugs include all of the following except
(A) Atrial fibrillation
(B) Motion sickness
(C) Parkinson’s disease
(D) Postoperative bladder spasm
(E) To antidote parathion poisoning

41. Which of the following is an expected effect of a therapeutic dose of an antimuscarinic drug?
(A) Decreased cAMP (cyclic adenosine monophosphate) in cardiac muscle
(B) Decreased DAG (diacylglycerol) in salivary gland tissue
(C) Increased IP3 (inositol trisphosphate) in intestinal smooth muscle
(D) Increased potassium efflux from smooth muscle
(E) Increased sodium influx into the skeletal muscle end
plate

42. Which one of the following drugs causes vasodilation that can
be blocked by atropine?
(A) Benztropine
(B) Bethanechol
(C) Botulinum
(D) Cyclopentolate
(E) Edrophonium
(F) Neostigmine

43. Which one of the following drugs has a very high affinity for the phosphorus atom in parathion and is often used to treat life-threatening insecticide toxicity?
(A) Atropine
(B) Benztropine
(C) Bethanechol
(D) Botulinum
(E) Cyclopentolate
(F) Neostigmine
(G) Pralidoxime

44. Drug X caused a 50 mm Hg rise in mean blood pressure in the control animal, no blood pressure change in the ganglion blocked
animal, and a 75 mm mean blood pressure rise in the atropine-pretreated animal. Drug X is probably a drug similar to
(A) Acetylcholine
(B) Atropine
(C) Epinephrine
(D) Hexamethonium
(E) Nicotine