Drugs which mimic the action of stimulation of cholinergic receptors.
Also called cholinomimetic or cholinergic drugs.
Classification—
According to the mode of action—
Directly acting—acts exactly like acetyl choline
Indirectly acting (Anti-cholinesterase)—acts by inhibiting the enzyme acetyl-cholinesterase.
Directly acting—
Alkaloid {Muscarine, Nicotine, Pilocarpine} & Esters {Acetyle-choline, Methacholine, Bethanecol, Carbacol}
Indirectly acting—(Anti-cholinesterase)
Reversible {Physostigmine, Neostigmine, Pyridostigmine} & Irreversible {Organo-phosphorous compound-OPC}
Indirectly acting cholinergic drugs are further classified according to chemical structure—
a. Simple alcohol—Edrophonium.
b. Carbamic acid esters of alcohol—Neostigmine, Physostigmine, Pyridostigmine.
c. Organo-phosphates—Parathione, Malathione, Soman (nerve gas), Ecothiophate.
According to the receptor on which they act—
1. Selectively muscarinic—Muscarine, Bethanecol, Pilocarpine, Oxotremorine, methacholine.
2. Selectively nicotinic—Nicotine, Lobeline, DMPP.
3. Non-selective—Ach (major action on M-receptor), Carbacol (major action on N-receptor)
*** Pilocarpine is given in glaucoma to ↓ the intra-ocular pressure. It is given as eye-drop and if it passes into the circulation it can cause ↓ HR.
*** Muscarine = mushroom, when muscarinic receptors are stimulated the sign symptoms are same like eating mushrooms.
***when nicotinic receptors are stimulated the sign symptoms are like taking nicotine.
Synthesis of Acetyl-choline—Acetyl co-A + choline→ Acetyl-choline (by conjugation)
{Acetyl co-A is secreted from nerve body}
Storage of Acetyl-choline—stored in the vesicles along with Ca++, ATP, other proteins, phospholipids etc.
Release of Acetyle-choline—when the parasympathetic system is stimulated due to any reason that develops action potential that travels down to the nerve terminals. If the action potential is strong enough then it causes opening of the calcium channel and calcium enters into the nerve terminal and fusion occurs—them release of acetyl-choline.
Fate of Acetyl-choline—80% is reuptaken by the same nerve terminal.
within milliseconds (flash of time)—major portion of the Ach is degraded by cholinesterase. (true cholinesterase is found in the nerve terminals and pseudo-cholinesterases are found in the liver, skin, brain, GIT and also in plasma in soluble form)
*** pseudo-cholinesterases are Suxamethonium, Butyrylcholine, Procaine, Benzoycholine.
*** if Ach is given IV then it is degraded by the pseudo-cholinesterase. Also all synthetic drugs are destroyed by pseudo-cholinesterase.
Acetyl-choline has no clinical utility—
§ It undergoes rapid hydrolysis (by the pseudo-cholinesterases)
§ It is wide spread, diffuse, non selective pharmacological effect
§ If given orally then rapidly hydrolyzed by the gastric enzymes
*** it is used for the experimental purpose as it is the prototype.
Classification of the cholinergic receptors—
Pharmacological effect of acetyl-choline / cholinomimetic drugs—
Muscarinic action—
On Eye—binds and acts on the muscarinic receptors in the radial, circular and pupillary muscle of the eye. Produces pupillary constriction (myosis) and reduction of the intra-ocular pressure by improving the aqueous humor drainage (opening the angle of Schlem). Can be used in glaucoma.
On CVS—↓ HR, ↓ force of contraction, ↓ A-V conduction. (can be used in shock), ↓ CO
On blood vessels—Ach binding with the muscarinic receptor of the endothelium releases EDRF (endothelium derived releasing factor) that comes back to the smooth muscle and the muscle relaxes. (indirect method)
On Respiratory system—acetyl-choline acting on the smooth muscle of the bronchi causes bronchoconstriction, acting on the glands it also ↑ secretion.
On GIT—acting on the smooth muscle it increases the contraction thus increases the peristalsis. Acting on the glands it causes increase in secretion.
On Genito-urinary system—causes contraction of the visceral smooth muscles. Relaxation of the sphincters of the urinary bladder.
On CNS—inhibitory or excitatory neurotransmitter
Nicotinic action—
On autonomic ganglion—
o On CVS—sympathomimetic effects, ↑ BP
o GIT—parasympathomimetic effect, ↑ motility
o Urinary bladder—parasympathomimetic effect, voiding of urine
o CNS—Parkinsonism
On skeletal neuromuscular junction—when acetyl-choline acts on the nicotinic receptor of the skeletal muscles, it causes contraction (Fasciculation and Twitching). Ex—Neostigmine.
On adrenal medulla—stimulation of the chromaffin cells→ secretion of adrenaline (80%) and noradrenaline (20%)→ vasoconstriction → ↑ BP
Anticholinesterase—Reversible (Neostigmine, Physostigmine) and Irreversible.
§ Quaternary carbamates are poorly absorbed from the skin, conjunctiva, lungs. (neostigmine)
§ Physostigmine is well absorbed from all sites and can be used topically in the eye.
§ Physostigmine is distributed to the CNS and more toxic than polar quaternary carbamates.
§ OPC are well absorbed from the skin, lung, gut thus making them dangerous to human and highly effective as insecticides.
Pharmacological action—
On N-M junction—anti-cholinesterase drugs by inhibiting the acetyl cholinesterase enzyme prolongs and intensifies the action of Ach at skeletal muscle junction. This results in ↑ strength of muscle contraction.
On Eye—it can reduce the intra-ocular pressure by causing contraction of the ciliary body and facilitates the outflow of the aqueous humor.
On GIT and GUT—peristaltic activity is increased by increased contraction of the smooth muscle, it occurs due to depolarization of the smooth muscle. In clinical disorder of depressed muscular activity, without obstruction anti-cholinesterase may be used.
On CNS—in low doses it can cause alertness but at high doses it can cause convulsion.
Difference between neostigmine and physostigmine—
PHYSOSTIGMINE
NEOSTIGMINE
Natural source
Synthetic source
Tertiary amine
Quaternary amine
High lipid solubility
Low lipid solubility
More CNS toxic
Less CNS toxic
Doesn’t have a direct action on skeletal muscle junction (on nicotinic receptor)
Has also direct action on skeletal muscle junction
Mechanism of action of Physostigmine—
Active Acetyl-cholinesterase
↓ ← Physostigmine (stage-I)
Carbamylated enzyme
↓ (stage-II)
Inactivation of the cholinesterase
↓
Inhibition of the hydrolysis of the acetyl choline
↓
Accumulation of increased concentration of acetyl choline
↓
Prolonged action of acetyl-choline
Indications—
1. Glaucoma—Pilocarpine, Physostigmine (↓ the intraocular pressure)
2. Myasthenia gravis (profound muscular weakness)—Neostigmine.
3. Bladder problem (unable to pass urine)—Alkaloids (contracts the smooth muscle)
4. Tachycardia.
OPC—all are insecticides, they are highly lipid soluble and can easily penetrate any organic barrier. It can enter the body from the GIT, Respiratory tract, Skin, Conjunctiva and Mucus membrane.
OPC poisoning—exaggerated function of Ach, they destroy all cholinesterase.
Sign symptom of OPC poisoning—
1. ↓ HR, severe Bradycardia.
2. Severe bronchoconstriction with excessive bronchial secretion causing severe dyspnoea and frothing from the mouth, nostrils. Death is mainly due to respiratory failure.
3. Excessive salivation from the mouth.
4. Excessive sweating and there will be depolarizing block leading to neuromuscular block, causing paralysis.
5. There is CNS involvement, may cause excitement.
6. Myosis.
7. Severe headache due to intense pupillary and ciliary muscle contraction.
Management of OPC poisoning—
Supportive treatment—
1. Decontamination to prevent further absorption
2. Start oxygen after clearing the airway
3. Open IV line and start infusion to maintain fluid and electrolyte balance as well as emergency IV administration.
Specific treatment—
1. Very large and usually repeated doses of Atropine should be given.
0.6mg / ample Atropine in every 2-4 min until the sign symptom of OPC poisoning disappear. {when mouth becomes dry, HR becomes almost normal}. Them the atropine is given every 2-4 hrs accordingly.
2. Pralidoxine
3. Diazepam may be used for relieving the CNS from excitement.
*** a cholinesterase inhibitor may be used to reverse the effects in case of Atropine poisoning.
Also called cholinomimetic or cholinergic drugs.
Classification—
According to the mode of action—
Directly acting—acts exactly like acetyl choline
Indirectly acting (Anti-cholinesterase)—acts by inhibiting the enzyme acetyl-cholinesterase.
Directly acting—
Alkaloid {Muscarine, Nicotine, Pilocarpine} & Esters {Acetyle-choline, Methacholine, Bethanecol, Carbacol}
Indirectly acting—(Anti-cholinesterase)
Reversible {Physostigmine, Neostigmine, Pyridostigmine} & Irreversible {Organo-phosphorous compound-OPC}
Indirectly acting cholinergic drugs are further classified according to chemical structure—
a. Simple alcohol—Edrophonium.
b. Carbamic acid esters of alcohol—Neostigmine, Physostigmine, Pyridostigmine.
c. Organo-phosphates—Parathione, Malathione, Soman (nerve gas), Ecothiophate.
According to the receptor on which they act—
1. Selectively muscarinic—Muscarine, Bethanecol, Pilocarpine, Oxotremorine, methacholine.
2. Selectively nicotinic—Nicotine, Lobeline, DMPP.
3. Non-selective—Ach (major action on M-receptor), Carbacol (major action on N-receptor)
*** Pilocarpine is given in glaucoma to ↓ the intra-ocular pressure. It is given as eye-drop and if it passes into the circulation it can cause ↓ HR.
*** Muscarine = mushroom, when muscarinic receptors are stimulated the sign symptoms are same like eating mushrooms.
***when nicotinic receptors are stimulated the sign symptoms are like taking nicotine.
Synthesis of Acetyl-choline—Acetyl co-A + choline→ Acetyl-choline (by conjugation)
{Acetyl co-A is secreted from nerve body}
Storage of Acetyl-choline—stored in the vesicles along with Ca++, ATP, other proteins, phospholipids etc.
Release of Acetyle-choline—when the parasympathetic system is stimulated due to any reason that develops action potential that travels down to the nerve terminals. If the action potential is strong enough then it causes opening of the calcium channel and calcium enters into the nerve terminal and fusion occurs—them release of acetyl-choline.
Fate of Acetyl-choline—80% is reuptaken by the same nerve terminal.
within milliseconds (flash of time)—major portion of the Ach is degraded by cholinesterase. (true cholinesterase is found in the nerve terminals and pseudo-cholinesterases are found in the liver, skin, brain, GIT and also in plasma in soluble form)
*** pseudo-cholinesterases are Suxamethonium, Butyrylcholine, Procaine, Benzoycholine.
*** if Ach is given IV then it is degraded by the pseudo-cholinesterase. Also all synthetic drugs are destroyed by pseudo-cholinesterase.
Acetyl-choline has no clinical utility—
§ It undergoes rapid hydrolysis (by the pseudo-cholinesterases)
§ It is wide spread, diffuse, non selective pharmacological effect
§ If given orally then rapidly hydrolyzed by the gastric enzymes
*** it is used for the experimental purpose as it is the prototype.
Classification of the cholinergic receptors—
Pharmacological effect of acetyl-choline / cholinomimetic drugs—
Muscarinic action—
On Eye—binds and acts on the muscarinic receptors in the radial, circular and pupillary muscle of the eye. Produces pupillary constriction (myosis) and reduction of the intra-ocular pressure by improving the aqueous humor drainage (opening the angle of Schlem). Can be used in glaucoma.
On CVS—↓ HR, ↓ force of contraction, ↓ A-V conduction. (can be used in shock), ↓ CO
On blood vessels—Ach binding with the muscarinic receptor of the endothelium releases EDRF (endothelium derived releasing factor) that comes back to the smooth muscle and the muscle relaxes. (indirect method)
On Respiratory system—acetyl-choline acting on the smooth muscle of the bronchi causes bronchoconstriction, acting on the glands it also ↑ secretion.
On GIT—acting on the smooth muscle it increases the contraction thus increases the peristalsis. Acting on the glands it causes increase in secretion.
On Genito-urinary system—causes contraction of the visceral smooth muscles. Relaxation of the sphincters of the urinary bladder.
On CNS—inhibitory or excitatory neurotransmitter
Nicotinic action—
On autonomic ganglion—
o On CVS—sympathomimetic effects, ↑ BP
o GIT—parasympathomimetic effect, ↑ motility
o Urinary bladder—parasympathomimetic effect, voiding of urine
o CNS—Parkinsonism
On skeletal neuromuscular junction—when acetyl-choline acts on the nicotinic receptor of the skeletal muscles, it causes contraction (Fasciculation and Twitching). Ex—Neostigmine.
On adrenal medulla—stimulation of the chromaffin cells→ secretion of adrenaline (80%) and noradrenaline (20%)→ vasoconstriction → ↑ BP
Anticholinesterase—Reversible (Neostigmine, Physostigmine) and Irreversible.
§ Quaternary carbamates are poorly absorbed from the skin, conjunctiva, lungs. (neostigmine)
§ Physostigmine is well absorbed from all sites and can be used topically in the eye.
§ Physostigmine is distributed to the CNS and more toxic than polar quaternary carbamates.
§ OPC are well absorbed from the skin, lung, gut thus making them dangerous to human and highly effective as insecticides.
Pharmacological action—
On N-M junction—anti-cholinesterase drugs by inhibiting the acetyl cholinesterase enzyme prolongs and intensifies the action of Ach at skeletal muscle junction. This results in ↑ strength of muscle contraction.
On Eye—it can reduce the intra-ocular pressure by causing contraction of the ciliary body and facilitates the outflow of the aqueous humor.
On GIT and GUT—peristaltic activity is increased by increased contraction of the smooth muscle, it occurs due to depolarization of the smooth muscle. In clinical disorder of depressed muscular activity, without obstruction anti-cholinesterase may be used.
On CNS—in low doses it can cause alertness but at high doses it can cause convulsion.
Difference between neostigmine and physostigmine—
PHYSOSTIGMINE
NEOSTIGMINE
Natural source
Synthetic source
Tertiary amine
Quaternary amine
High lipid solubility
Low lipid solubility
More CNS toxic
Less CNS toxic
Doesn’t have a direct action on skeletal muscle junction (on nicotinic receptor)
Has also direct action on skeletal muscle junction
Mechanism of action of Physostigmine—
Active Acetyl-cholinesterase
↓ ← Physostigmine (stage-I)
Carbamylated enzyme
↓ (stage-II)
Inactivation of the cholinesterase
↓
Inhibition of the hydrolysis of the acetyl choline
↓
Accumulation of increased concentration of acetyl choline
↓
Prolonged action of acetyl-choline
Indications—
1. Glaucoma—Pilocarpine, Physostigmine (↓ the intraocular pressure)
2. Myasthenia gravis (profound muscular weakness)—Neostigmine.
3. Bladder problem (unable to pass urine)—Alkaloids (contracts the smooth muscle)
4. Tachycardia.
OPC—all are insecticides, they are highly lipid soluble and can easily penetrate any organic barrier. It can enter the body from the GIT, Respiratory tract, Skin, Conjunctiva and Mucus membrane.
OPC poisoning—exaggerated function of Ach, they destroy all cholinesterase.
Sign symptom of OPC poisoning—
1. ↓ HR, severe Bradycardia.
2. Severe bronchoconstriction with excessive bronchial secretion causing severe dyspnoea and frothing from the mouth, nostrils. Death is mainly due to respiratory failure.
3. Excessive salivation from the mouth.
4. Excessive sweating and there will be depolarizing block leading to neuromuscular block, causing paralysis.
5. There is CNS involvement, may cause excitement.
6. Myosis.
7. Severe headache due to intense pupillary and ciliary muscle contraction.
Management of OPC poisoning—
Supportive treatment—
1. Decontamination to prevent further absorption
2. Start oxygen after clearing the airway
3. Open IV line and start infusion to maintain fluid and electrolyte balance as well as emergency IV administration.
Specific treatment—
1. Very large and usually repeated doses of Atropine should be given.
0.6mg / ample Atropine in every 2-4 min until the sign symptom of OPC poisoning disappear. {when mouth becomes dry, HR becomes almost normal}. Them the atropine is given every 2-4 hrs accordingly.
2. Pralidoxine
3. Diazepam may be used for relieving the CNS from excitement.
*** a cholinesterase inhibitor may be used to reverse the effects in case of Atropine poisoning.
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