Cholinergic Agonists and Antagonists

Question 1

Cholinergic Agonists

Answer 1

Direct-acting agents bind to and activate muscarinic and nicotinic receptors. Some activate both and others are selective for the muscarinic (pilocarpine and bethanecol) or nicotinic receptor. There are two types; Esters of Choline (Acetylcholine, carbachol, bethanechol, methacholine) and Naturally occurring alkaloids (Arecoline, muscarine, pilocarpine, nicotine, lobeline)

The indirect-acting agents inhibit acetylcholinesterase. These drugs are amplifiers of endogenous acetylcholine and act where acetylcholine is physiologically released.

Question 2

Acetylcholine Cardiovascular Effects

Answer 2

Vasodilation (M3 effect).

Decrease in cardiac rate (M2 effect) and decrease in rate of conduction in the SA and the AV nodes (M2 effect). There is also a decrease in force of contraction (M2 effect). Some of these cardiovascular direct effects can be obscured by the baroreceptor reflexes.

The IV injection of a small dose of acetylcholine produces a fall in blood pressure due to vasodilation (M3 effect) usually accompanied by reflex tachycardia. Larger doses of acetylcholine cause hypotension (M3 effect) and bradycardia (M2 effect).

Question 3

Acetylcholine Systemic Effects

Answer 3

Vasculature (endothelial cells): Release of NO and vasodilation; Decrease in BP

Eye iris: Contraction and miosis

Ciliary muscle: Contraction and accommodation of lens to near vision

Salivary/sweat/ lacrimal glands: ↑ Secretions

Bronchi: Constriction; ↑ secretions

Heart: Bradycardia, ↓ conduction velocity

GI tract: ↑ Tone, ↑ peristaltic activity, ↑ secretions; relaxation of sphincters

Urinary bladder: Contraction of detrusor muscle; relaxation of sphincter

Male reproductive tract: Erection

Uterus: Variable

Question 4

Nicotinic Effects of Acetylcholine

Answer 4

If large doses of acetylcholine are injected after administration of atropine, acetylcholine produces nicotinic effects: an initial increase in blood pressure due to stimulation of sympathetic ganglia and consequent vasoconstriction, and a secondary rise resulting from release of catecholamines from the adrenal medulla.

Question 5

Choline Esters

Answer 5

Choline esters are all quaternary ammonium compounds and are thus poorly absorbed and poorly distributed into the central nervous system.

They differ markedly in their susceptibility to hydrolysis by cholinesterase.

Acetylcholine is very rapidly hydrolyzed: A large IV bolus injection has a brief effect, typically 5–20 seconds, whereas IM and SC injections produce only local effects.

Methacholine, carbachol and bethanechol are more resistant to hydrolysis by cholinesterase and have longer durations of action.

Question 6

Acetylcholine

(Choline Ester)

Answer 6

Acetylcholine has virtually no systemic therapeutic applications because of its multiplicity of actions, and its rapid hydrolysis by both acetylcholinesterase, and plasma butyrylcholinesterase.

USES

Acetylcholine is used to obtain rapid miosis after delivery of the lens in cataract surgery, in penetrating keratoplasty, iridectomy and other anterior segment surgery where rapid miosis may be required.

Question 7

Bethanecol

(Choline Ester)

Answer 7

Not hydrolyzed by acetylcholinesterase. Inactivated through hydrolysis by other esterases. Little or no nicotinic actions. Strong muscarinic activity.

USES

Treatment of acute postoperative and postpartum non obstructive (functional) urinary retention and for neurogenic atony of the urinary bladder with retention.

ADVERSE (of any muscarinic agonist; same for all)

Causes the effects of generalized cholinergic stimulation: Sweating, salivation, flushing, low blood pressure, nausea, abdominal pain, diarrhoea, bronchospasm.

Question 8

Carbachol

(Choline Ester)

Answer 8

Both muscarinic and nicotinic agonist. Like bethanechol, carbachol is an ester of carbamic acid, and therefore a poor substrate for acetylcholinesterase. Hydrolyzed by other esterases at much slower rate.

USES

Intraocular use for obtaining miosis during surgery.

In addition, it reduces intraocular pressure after cataract surgery.

Question 9

Methacholine

(Choline Ester)

Answer 9

Hydrolyzed by acetylcholinesterase at considerably slower rate than acetylcholine. Almost totally resistant to hydrolysis by nonspecific cholinesterase or butyrylcholinesterase.

Predominantly muscarinic agonist. Slight nicotinic actions.

USES

Diagnosis of bronchial airway hyperreactivity in subjects who do not have clinically apparent asthma.

Question 10

Natural Alkaloids

Answer 10

Muscarine acts almost exclusively at muscarinic receptor sites.

Arecoline acts at muscarinic and nicotinic receptors.

Pilocarpine has mainly a muscarinic action.

Present clinical use of the natural alkaloids is largely restricted to pilocarpine as a sialagogue and miotic agent.

Question 11

Pilocarpine

(Natural Alkaloid)

Answer 11

Tertiary amine. Stable to hydrolysis by acetylcholinesterase. Partial muscarinic agonist.

USES Glaucoma

Second line agent for open angle glaucoma. (Pilocarpine was the most widely used anti-glaucoma drug before timolol was introduced).

Management of acute angle-closure glaucoma. Treatment includes several drugs: timolol, pilocarpine, apraclonidine, acetazolamide and an osmotic agent, such as oral glycerol and IV mannitol.

ADVERSE

Can enter brain and cause CNS disturbances. Stimulates sweating and salivation.

Question 12

Nicotine

Nicotinic Receptor Agonists

Answer 12

Ganglion Stimulant: Tertiary amine. Nicotine affects the neuromuscular junction in concentrations only slightly greater than those that affect ganglia.

NICOTINE: ACTIONS

The action of nicotine is the same on both parasympathetic and sympathetic ganglia. In low doses nicotine causes ganglionic stimulation by depolarization. The initial response to nicotine therefore resembles simultaneous discharge of both the parasympathetic and the sympathetic nervous systems.

In the cardiovascular system, the effects of nicotine are mainly sympathomimetic: Nicotine produces an increase in heart rate and blood pressure due to catecholamine release from adrenergic nerve terminals and from the adrenal medulla.

In the GI and urinary tracts the effects are largely parasympathomimetic: nausea, vomiting, diarrhea, and voiding of urine are commonly observed. Nicotine also causes an initial stimulation of salivary and bronchial secretions.

At high doses nicotine causes ganglionic blockade as a consequence of prolonged depolarization. Nicotine also causes neuromuscular blockade.

USES
Nicotine is used for smoking cessation therapy.

Question 13

Acute Nicotine Poisoning

Answer 13

Symptoms of acute, severe nicotine poisoning include: nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweat, mental confusion and weakness. The blood pressure falls, the pulse is weak, rapid and irregular. Collapse may be followed by terminal convulsions. Death may occur from paralysis of respiratory muscles and/or central respiratory failure.

Nicotine is highly liposoluble. Absorption is fast via oral mucosa, lungs, GI mucosa and skin. Crosses placental membrane and is secreted in milk.

Question 14

Anticholinesterases

(Indirect-Acting Cholinergic Agonists)

Answer 14

1. Simple alcohols bearing a quaternary ammonium group: Edrophonium (only member of this group)

2. Carbamates: Neostigmine, physostigmine and pyridostigmine.

3. Organophosphates: Echothiophate, parathion, malathion, etc.

Question 15

Edrophonium

Answer 15

Simple alcohol bearing a quaternary ammonium group: Binds reversibly to the active site of the enzyme, thus preventing access of acetylcholine. The enzyme-inhibitor complex does not involve a covalent bond and is short-lived (2 - 10 minutes). Anticholinesterase.

USES

Diagnosis of myasthenia gravis. Because of its brief duration of action, it is not recommended for maintenance therapy in myasthenia gravis.

Used to reverse the neuromuscular block produced by non-depolarizing muscular blockers.

Question 16

Carbamates

Anticholinesterase

Physostigmine, Neostigmine, and Pyridostigmine

Answer 16

Carbamates form a covalent bond with the enzyme. The carbamate-cholinesterase bond spontaneously hydrolyzes within 30 minutes - 6 hours. Clinical recovery occurs in several hours; only rarely in more than 24 hours.

Question 17

Physostigmine

Answer 17

PHYSOSTIGMINE: Tertiary amine. Can enter and stimulate the CNS. Anticholinesterase; Carbamate

USES

Treatment of overdoses of anticholinergic drugs. The tertiary amine structure of physostigmine allows it to penetrate the blood-brain barrier and exert central cholinergic effects as well. NOTE: Physostigmine should not be given to a patient with suspected TCA overdose because it can aggravate depression of cardiac conduction.

ADVERSE EFFECTS

Its effects on CNS may lead to convulsions when high doses are used.

Bradycardia may occur.

Inhibition of acetylcholinesterases at the NMJ causes accumulation of acetylcholine and results in paralysis of skeletal muscle.

These effects are rarely seen with therapeutic doses.

Question 18

Neostigmine

Answer 18

NEOSTIGMINE: Quaternary ammonium; doesn’t enter CNS. Anticholinesterase; Carbamate

USES

Reversal of effects of non-depolarizing neuromuscular blockers after surgery. Most commonly used drug for this indication.

Used for symptomatic treatment of myasthenia gravis. Pyridostigmine is most commonly used.

Prevention and treatment of postoperative distention and urinary retention.

ADVERSE EFFECTS

Salivation, flushing, low blood pressure, nausea, abdominal pain, diarrhea, bronchospasm.

Question 19

Pyridostigmine

Answer 19

PYRIDOSTIGMINE: Anticholinesterase; Carbamate; Quaternary ammonium.

USES

Indicated for treatment of myasthenia gravis. Most commonly used anticholinesterase for this indication.

Question 20

Organophosphates

Echothiophate, parathion, malathion: Anticholinesterases

Answer 20

Organophosphates phosphorylate the active site of the enzyme. The covalent phosphorous-enzyme bond is extremely stable. The phosphorylated enzyme complex may undergo a process called ageing which further strengthens the phosphorous-enzyme bond. If given before ageing has occurred, strong nucleophiles like PRALIDOXIME are able to split the phosphorous-enzyme bond and can be used as cholinesterase regenerator drugs for organophosphate insecticide poisoning. Once ageing has occurred, the enzyme-inhibitor complex is more difficult to split.

NOTE: All of the organophosphates, except echothiophate, are fully distributed to all parts of the body, including the CNS. Poisoning with these agents therefore includes an important component of CNS toxicity.

Question 21

Echothiophate

Answer 21

Organophosphate: Anticholinesterase

Used for chronic open-angle glaucoma, subacute or chronic angle-closure glaucoma after iridectomy or where surgery is refused or contraindicated.

Question 22

Malathion and Parathion

Answer 22

THIOPHOSPHATE INSECTICIDES:

Activated in the body by conversion to oxygen analogs.

Malathion is rapidly metabolized to inactive products in birds and mammals, but not in insects. It is considered safe enough for sale to the general public.

Parathion is not detoxified effectively in vertebrates; thus it is considered more dangerous than malathion to humans and livestock and is not available for general public use.

Question 23

Tabun, Sarin, and Soman

Answer 23

ORGANOPHOSPHATE NERVE AGENTS: Anticholinesterases

Among the most potent synthetic toxic agents known.

Question 24

Organ System Effects of Anticholinesterases

Answer 24

CNS: In low concentrations, the liposoluble cholinesterase inhibitors cause diffuse activation of the EEG and a subjective alerting response. In higher concentrations they cause generalized convulsions, which may be followed by coma and respiratory arrest.

EYE, RESPIRATORY TRACT, GI TRACT & URINARY TRACT: The effects of cholinesterase inhibitors on these systems, all of which are well innervated by the parasympathetic system, are qualitatively similar to the effects of the direct-acting cholinomimetics.

CARDIOVASCULAR SYSTEM: The cholinesterase inhibitors can increase activation in both sympathetic and parasympathetic ganglia supplying the heart and at the acetylcholine receptors on neuroeffector cells (cardiac and vascular smooth muscles) that receive cholinergic innervation.

In the heart, the effects on the parasympathetic limb predominate. Negative chronotropic, dromotropic, and inotropic effects are evoked, and cardiac output falls. The fall in cardiac output is due to bradycardia, decreased atrial contractility and reduction in ventricular contractility. The latter effect occurs as a result of prejunctional inhibition of norepinephrine release and inhibition of postjunctional sympathetic effects.

Cholinesterase inhibitors have less marked effects on vascular smooth muscle and on blood pressure than direct-acting muscarinic agonists. This is because indirect-acting drugs can modify the tone of only those vessels innervated by cholinergic nerves1 and because the net effect on vascular tone may reflect activation of both parasympathetic and sympathetic systems. Since few vascular beds receive cholinergic innervation, the cholinergic effect at vascular smooth muscle is minimal. Activation of sympathetic ganglia would tend to increase vascular resistance.

Large (toxic) doses of these drugs cause more marked bradycardia (occasionally tachycardia) and hypotension.

THE NEUROMUSCULAR JUNCTION: Low (therapeutic) concentrations moderately prolong and intensify actions of physiologically released acetylcholine. This results in increased strength of contraction, especially in muscles weakened by curare-like neuromuscular blocking agents, or by myasthenia gravis. At higher concentrations, the accumulation of acetylcholine may result in fibrillation of muscle fibers.

Some quaternary carbamate cholinesterase inhibitors, e.g. neostigmine, have an additional direct nicotinic effect at the neuromuscular junction. This may contribute to the effectiveness of these agents in the therapy of myasthenia gravis.

Question 25

Donepezil, Rivastigmine, Galantamine Use in Alzheimer's Disease

Answer 25

Patients with Alzheimer disease have reduced cerebral production of choline acetyl transferase, which leads to a decrease in acetylcholine synthesis and impaired cortical cholinergic function. The mainstay of therapy for patients with Alzheimer disease is the use of **centrally acting cholinesterase inhibitors** to attempt to compensate for the depletion of acetylcholine in the cerebral cortex and hippocampus. **Donepezil, rivastigmine, and galantamine** are orally active inhibitors of acetylcholinesterase approved for the treatment of Alzheimer's disease.

Question 26

Pralidoxime

Answer 26

REACTIVATOR OF ACETYLCHOLINESTERASE Pralidoxime is a synthetic compound that can **reactivate inhibited acetylcholinesterase.** If given before ageing has occurred, pralidoxime is able to split the phosphate-enzyme bond and can be used as **cholinesterase regenerator** drug for organophosphate insecticide poisoning. Because of its positive charge, it doesn’t enter the CNS and is ineffective in reversing the central effects of organophosphate poisoning. Pralidoxime is not generally used for carbamate intoxication, because the cholinesterase inhibition is spontaneously reversible and short-lived. **However, if the exact agent is not identified and the patient has significant toxicity, pralidoxime should be given empirically.**

Question 27

Muscarinic Receptor Antagonists Tertiary Amines v. Quaternary ammoniums What are Belladona Alkaloids?

Answer 27

Block muscarinic receptors. They don’t block nicotinic receptors: little or no action at NMJ or autonomic ganglia. **Atropine is the prototype.** Atropine and its naturally occurring congeners are **tertiary amines.** **The tertiary amines** **are often used for their effects on the eye or the CNS.** Many antihistaminic, antipsychotic, and antidepressant drugs have similar structures and predictably significant antimuscarinic effects. **Quaternary ammonium antimuscarinics** have been developed to produce more peripheral effects with **reduced CNS effects.** **Belladona Alkaloids: Atropine and Scopolamine** The belladonna drugs are widely distributed in nature, especially in the Solanaceae plants. Atropa belladonna, the deadly nightshade, yields mainly the alkaloid atropine. Atropine is also found in Datura Stramonium, known as Jamestown or jimsonweed, stinkweed, thorn-apple and devil’s apple. The alkaloid scopolamine is found chiefly in the shrub Hyoscyamus niger (henbane) and Scopolia carniolica.

Question 28

Atropine Effects on the Eye, GI, Urinary, Cardiovascular, and secretory systems, plus Atropine Flush

Answer 28

Binds competitively to muscarinic receptors, preventing acetylcholine from binding. Tertiary amine. Both central and peripheral muscarinic blocker. ## Footnote * *ACTIONS** * *Eye:** mydriasis; unresponsiveness to light. Cycloplegia. In patients with glaucoma intraocular pressure may rise dangerously. **GI:** can be used as antispasmodic. Gastric motility is reduced, but HCl production is not affected: not effective in promoting healing of peptic ulcer. **Urinary System:** Decreases hypermotility of urinary bladder. **Cardiovascular:** **The atria of the heart are richly innervated by parasympathetic nerve fibers, and the SA node is therefore sensitive to muscarinic receptor blockade.** The effect of moderate to high therapeutic doses is a **blockade of atrial M2 receptors and tachycardia.** **NOTE:** Lower doses of atropine often result in initial **bradycardia** before the effects of atrial M2 receptor blockade become manifest. This effect is due to blockade of **presynaptic muscarinic M2 receptors** on vagal postganglionic fibers that normally inhibit acetylcholine release in the sinus node. **At toxic doses**, and in some individuals at normal doses, antimuscarinic agents cause cutaneous vasodilation, especially in the upper portion of the body. This is called **‘atropine flush’**. The mechanism is unknown. **Secretions:** salivary, sweat and lachrymal glands are blocked. Inhibition of sweat glands may cause high body temperature.

Question 29

Atropine Uses and Adverse Effects

Answer 29

**USES** Atropine is indicated when excessive muscarinic effects are life threatening or are producing symptoms severe enough to call for muscarinic blockade. Examples are: As an **antisialogogue**, prior to surgery, when reduction of secretions of the respiratory tract are needed. **To increase heart rate or decrease AV-block** when bradycardia or AV-block are hemodynamically significant and thought to be due to excess vagal tone. As an antidote for **overdose of cholinergic drugs.** As an antidote for the "rapid” type of mushroom poisoning due to the presence of the alkaloid muscarine, in certain species of fungus such as **Amanita muscaria.** **To alleviate the muscarinic side effects of anticholinesterase drugs** (e.g. neostigmine) used for reversal of neuromuscular blockade **PHARMACOKINETICS** Readily absorbed, partially metabolized by liver, eliminated primarily in urine. Half-life 4 hours. **ADVERSE EFFECTS** Dry mouth, blurred vision, sandy eyes, tachycardia, constipation. Effects on CNS: restlessness, confusion, hallucinations, delirium, which may progress to depression, collapse of the circulatory and respiratory systems and death. In older individuals, the use of atropine to induce mydriasis and cycloplegia is considered too risky since it may exacerbate an attack of glaucoma in someone with a latent condition.

Question 30

Scopolamine

Answer 30

Another belladonna alkaloid; produces peripheral effects similar to atropine. Greater actions on CNS and longer duration of action. **ACTIONS** **One of the most effective anti-motion sickness drugs available.** Can be administered through the transdermal route. **Unusual effect:** **blocks short-term memory.** In contrast to atropine, it produces **sedation;** at higher doses can produce excitement. **USES** For mydriasis and cycloplegia in diagnostic procedures. For some pre- and postoperative states when a mydriatic and cycloplegic is needed in treatment of iridocyclitis. For prevention of nausea and vomiting associated with motion sickness.

Question 31

Ipratropium and Tiotropium

Answer 31

SYNTHETIC & SEMISYNTHETIC DRUGS **QUATERNARY AMMONIUM MUSCARINIC ANTAGONISTS** Ipratropium and tiotropium are used as inhalational drugs in the treatment of chronic obstructive pulmonary disease (COPD). They are also used as inhalational drugs in asthma.

Question 32

Homatropine, Cyclopentolate and Tropicamide

Answer 32

**TERTIARY AMINE MUSCARINIC ANTAGONISTS** Particularly useful in ophthalmology. They produce mydriasis with cycloplegia. These agents are preferred to atropine because of their shorter duration of action.

Question 33

Benztropine and Trihexyphenidyl

Answer 33

Tertiary-amine muscarinic antagonists gain access to the CNS and are therefore the anticholinergic drugs used to treat **parkinsonism and the extrapyramidal effects of antipsychotic drugs.** Specific agents used primarily for these conditions include **benztropine and trihexyphenidyl.**

Question 34

Glycopyrrolate and Tolterodine

Answer 34

**Glycopyrrolate:** Quaternary ammonium compound. Used orally to inhibit GI motility. Also used parenterally to prevent bradycardia during surgical procedures. **Tolterodine:** Tertiary amine used for overactive bladder.

Question 35

Contraindications of Antimuscarinic Agents

Answer 35

Antimuscarinic drugs are contraindicated in patients with **angle-closure glaucoma.** Antimuscarinics should be used with caution in patients with **prostatic hypertrophy:** antimuscarinics decrease detrusor contraction and increase the risk of urinary retention; this risk may be even greater in patients with increased urethral resistance. Antimuscarinics should also be used with caution in the **elderly.** Depending on the dose, antimuscarinic agents may cause bradycardia and sedation at low-to-medium levels of muscarinic blockade, and tachycardia and CNS hyperexcitation with delirium, hallucinations, and seizures at higher levels of blockade. Other adverse effects may include blurred vision (cycloplegia and mydriasis), dry mouth, ileus, urinary retention, flushing and fever, agitation, and tachycardia.

Question 36

Adverse Effects of Anticholinergic Agents in Geriatric and Cognitively Impaired Patients

Answer 36

**Anticholinergic adverse effects are potentially hazardous to elderly patients, especially those with cognitive impairment.** Many common drugs possess some anticholinergic activity, and the elderly (and especially the cognitively impaired elderly) are very sensitive to cholinergic blockade (due to central cholinergic hypofunction and dysfunction in ageing and dementia, respectively). Adverse effects caused by anticholinergic drugs in the elderly may include acute encephalopathy (delirium, confusional state), falls, urinary retention, constipation, and exacerbation and decompensation of underlying cognitive, functional, and behavioral deficits (particularly in patients with dementia).

Question 37

Nicotinic Receptor Antagonists

Answer 37

**Ganglion Blockers** **Neuromuscular Blockers:** Block cholinergic transmission between motor nerve endings and the nicotinic receptors on the neuromuscular end-plate of skeletal muscle. Structural analogs of acetylcholine. Two classes: competitive antagonists (nondepolarizing) and agonists (depolarizing). ***Used during surgery to produce complete muscle relaxation.*** **Inhibitors of Acetylcholine Synthesis** **Inhibitors of Acetylcholine Release** **Inhibitors of Acetylcholine Storage**

Question 38

Ganglion Blockers

Answer 38

Ganglion-blockers block the action of acetylcholine at the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia. Some members of this group also block the ion channel that is gated by the nicotinic cholinoceptor. **By prolonged depolarization: Nicotine**, a ganglion stimulant, can block ganglia after initial stimulation, by this mechanism. **By antagonism of nicotinic receptors: Mecamylamine, trimethaphan, and hexamethonium** act in this way. **USES OF GANGLION BLOCKERS** Ganglion blockers such as **hexamethonium, mecamylamine and trimethaphan** were extensively used to treat hypertension in the past. However, due to their numerous undesirable adverse effects ganglion blockers have been replaced by superior antihypertensive agents. **PHARMACOLOGICAL PROPERTIES OF GANGLION BLOCKERS** The effects of ganglion blockers can be predicted by a knowledge of **which division of the autonomic nervous system exercises dominant control of various organs.** THE FOLLOWING TABLE GIVES EXAMPLES: **Arterioles;** ***Sympathetic* (adrenergic):** Vasodilation; increased peripheral blood flow; hypotension **Veins;** ***Sympathetic* (adrenergic):** Dilation; peripheral pooling of blood; decreased venous return; decreased cardiac output **Sweat glands; *Sympathetic* (cholinergic):** Anhydrosis Eveyrthing else has ***predominant parasympathetic* control:** **Heart, Iris, Ciliary muscle, GI tract, Urinary bladder, and Salivary glands**

Question 39

Tubocurarine | (the prototype)

Answer 39

**MECHANISM OF ACTION** They bind to nicotinic receptor and prevent acetylcholine binding; in this way they prevent depolarization of muscle cell membrane and inhibit muscular contraction. During anesthesia, the IV administration of a nondepolarizing blocker first causes motor weakness; ultimately, skeletal muscles become totally flaccid and inexcitable to stimulation. Their action can be overcome by increasing concentration of acetylcholine in synaptic cleft, for example with cholinesterase inhibitors such as *neostigmine or edrophonium*. **USES** Adjuvant drugs in anaesthesia during surgery to relax skeletal muscle. **PHARMACOKINETICS** Given IV. Oral absorption is minimal. Penetrate membranes very poorly. Don’t cross blood-brain barrier. * *ADVERSE** * *Autonomic effects:** some agents are moderate blockers of muscarinic receptors. **Histamine release:** tubocurarine may cause histamine release.

Question 40

Succinylcholine

Answer 40

**DEPOLARIZING BLOCKERS** **MECHANISM OF ACTION** Succinylcholine binds to the nicotinic receptor and acts like acetylcholine to cause depolarization of the end plate. This in turn spreads and depolarizes adjacent membranes, causing generalized disorganized contraction of muscle motor units. Succinylcholine is not metabolized effectively at the synapse, therefore the membrane remains depolarized and unresponsive to additional impulses. A flaccid paralysis results. **PHARMACOKINETICS** Given IV by continuous infusion. Rapidly hydrolysed by plasma cholinesterase. Extremely brief duration of action (5-10 min) and rapid onset (1-1.5 min). **USES** Useful when rapid endotracheal intubation is needed. Also used during ECT. **ADVERSE** **Malignant hyperthermia:** autosomal dominant disorder of skeletal muscle. Caused by stimulus-elicited excessive release of Ca2+ from the SR. One of the main causes of death due to anesthesia. **Most of the incidents arise from the combination of succinylcholine and an halogenated anesthetic.** Treated with ***DANTROLENE***, which blocks release of calcium from SR, reducing heat production and relaxing muscle tone.

Question 41

Hemicholinium-3

Answer 41

**INHIBITORS OF ACETYLCHOLINE SYNTHESIS** Hemicholinium-3 blocks the high-affinity transporter for choline, and thus prevents the uptake of choline required for ACh synthesis. Only used as a research tool.

Question 42

Vesamicol

Answer 42

**INHIBITORS OF ACETYLCHOLINE STORAGE** Vesamicol blocks the ACh-H+ antiporter that is used to transport ACh into vesicles, thereby preventing the storage of ACh. Only used as a research tool.

Question 43

Botulinum Toxin

Answer 43

**INHIBITORS OF ACETYLCHOLINE RELEASE** Protein produced by the anaerobic bacillus Clostridium botulinum. Botulinum toxin, a potent neurotoxin, prevents synaptic vesicle fusion with the axon terminal membrane, **thus inhibiting acetylcholine release.** Injected locally into muscles, it is used in the treatment of several diseases associated with increased muscle tone, such as **torticollis, achalasia, strabismus, blepharospasm, and other focal dystonias.** Botulinum toxin is also approved for cosmetic treatment of facial wrinkles, and is being increasingly used to treat various headache and pain syndromes.