Acetylcholine is the prototype of the group parasympathomimetics. It is NOT USED AS A DRUG
Acetylcholine is rapidly hydrolyzed, if effects are to be observed, very high IV doses are to be administered, while IM and subcutaneous injections produce only local effect.
Pharmacokinetics
Acetylcholine & other choline esters have a permanently charged quaternary ammonium group in their structure, thus are polar compounds and are poor lipid soluble, resulting in decreased absorption, especially by oral route.
They are rapidly hydrolyzed. Acetylcholine is hydrolyzed more rapidly and produces effects only for 5-20 seconds. Methacholine has beta methyl group, so is more resistant to hydrolysis. It has longer duration of action. Carbachol is more resistant, so has further longer action. All are hydrolyzed in the GIT.
The tertiary natural cholinomimetic alkaloids (pilocarpine, nicotine, lobeline) are well absorbed from most sites of administration. They are lipid soluble thus cross into CNS and bring about stimulant effects on brain. Muscarine, a quaternary amine is less completely absorbed from the GIT and is toxic too.
Nicotine is easily absorbed from skin, lungs, GIT. Among naturally acting, muscarine has quaternary structure and are less absorbed from GIT, when ingested has potential toxic effects involving CNS (exception).
Most of the drugs are excreted by kidney. Acidification promotes their elimination.
| True cholinesterase or Acetyl cholinesterase | Pseudocholine esterase or Butyryl cholinesterase |
| Rapidly acting | Slow acting |
| Synthesized by neurons and muscles | Synthesized by liver |
| Found in RBCs, synaptic cleft, nerve endings | Found in plasma, mammary glands, lymph, glial cells, satellite cells, pre and post synaptic terminals. |
| 2 portions; active/esteratic site and anionic site |
Pharmacological Actions/ Organ system effects:
a. Muscarinic Actions
b. Nicotinic Actions
Eye (M3):
- Miosis (constriction of pupil).
- Spasm of accommodation (ciliary muscles)
These two effects are effective in glaucoma, an increase in intra-ocular due to resistance to flow of aqueous humor which has to be drained by canal of Schema.
3. Decrease in intraocular pressure.
4. Conjunctiva hyperemia (dilatation of vessels)
5. Lacrimation due to stimulation of lacrimal glands
CVS (Heart & Blood Vessels)
a. Heart (M2)
Acetylcholine has depressant effect similar to activation of vagus nerve. It decreases total peripheral resistance and blood flow. In small doses decrease in total peripheral resistance causes reflex increase in heart rate. In high IV doses decrease total peripheral resistance occurs along with hypotension, decreased intraventricular conduction.
Mechanism:
- Negative ionotropic
- Negative chronotropic
- Decrease in AV conduction
- Little effects on ventricles because cholinergic receptors are more in atria than ventricles.
Acetylcholine has direct effect on SA node (negative ionotropic and negative chronotropic)
b. Blood Vessels (M3)
Acetylcholine has relaxant effect on the smooth muscles in blood vessels through nitric oxide. Endothelial derived relaxant factor (EDRF) is released which causes activation of guanylcyclase activity leading to increased cGMP, producing hyper polarization and smooth muscle relaxation along with vasodilatation.
Pilocarpine has different action. Instead of hypotension, it causes hypertension. Initial hypotension is followed by hypertension. M1 postganglionic receptors are activated through sympathetic ganglion system, K+ channels are closed (instead of opening), causing post-synaptic potentials. Hence hypertension is seen.
M5 receptors in brain release NO which produces vasodilatation.
If endothelium is damaged, acetylcholine directly acts on smooth muscles increasing intracellular calcium (IP3, DAG) producing vasoconstriction.
Respiratory system (M3)
Activation of tracheo-bronchial tree occurs leading to bronchoconstriction and bronchospasm. Excessive bronchial secretion also takes place. Chronic obstructive pulmonary disease may occur.
Gastro intestinal tract
Stimulation of gastric salivary secretions occur which are excessively produced. The sphincters are relaxed and increase in peristaltic movements occur, which may cause diarrhea, by
- release of calcium from channels
- depolarization produced through nicotinic receptors
Urinary bladder
Contraction of detrusor muscles and relaxation of sphincters and trigone occurs, which promotes voiding.
Exocrine glands
Acetylcholine causes stimulation of sweat, lacrimal, nasolacrimal and GIT secretions thus profused sweating, excessive salivation and increased lacrimation occurs.
Its effects on adrenal medulla cause increase in catechol secretion while exocrine portion of pancreas has increased secretions as well.
Central Nervous System
Both muscarinic and nicotinic receptors are stimulated. More muscarinic receptors are found in the brain, still nicotinic effects are more prominent. Alkaloid nicotine has more potent CNS effects because is lipid soluble, can cross BBB and has toxic potential. It is obtained from plant source. 40 mg nicotine or one drop of pure nicotine is found in two cigarettes and has toxic effects on CNS. But most of it gets burned in smoke. If alkaloid is ingested in high amounts, vomiting and expulsion occurs. If ingested by small children, toxicity occurs leading to tremors and fatigue. Increased doses cause convulsions, respiratory distress or even coma. Carcinoma might result as well.
Peripheral nervous system
Sympathetic limb effects are more pronounced in CVS, in rest of the systems parasympathetic, effects are more pronounced e.g. respiratory, eye, GIT, urinary and exocrine systems.
N.M Junction
NM receptors are more activated. Agonists combine with nicotinic receptors having specific structure (4 subunits 2 alpha and 2 beta). Acetylcholine combines with 2 alpha subunits hence conformational change takes place, opening sodium channels (nicotinic receptors), due to which depolarization takes place. As depolarization is due to agonist, it occurs as long as the agonist binds the receptors. If binding is for prolonged duration, muscle fasciculations might result.
Reproductive System
Erection and congestion occurs.
Adverse Effects
CNS
- Tremors
- Convulsions
- Coma
- Ataxia
- Confusion
Eye
- Miosis
- Hyperthermia
- Blurring of vision
- Excessive lacrimation
Respiratory System
- Increased bronchial secretions
- Bronchoconstiction/Bronchospasm
- Respiratory center excitation
- Asthma
- Chronic Obstructive pulmonary disease
- Respiratory distress
CVS
- Hypotension
- Cutaneous vasodilatation
- Bradycardia
GIT
- Nausea
- Emesis
- Abdominal cramps
- Diarrhoea
- Peptic Ulcer disease
- Excessive salivation
Urinary System
Excessive urination
Carbachol:
Carbachol is the ester of carbamic acid, having both muscarinic and nicotinic actions.
Muscarinic actions are prominent on eye, GIT & urinary bladder
Duration of action is more than 30 minutes (longer than acetylcholine)
Mechanism of Action
Carbamoyl group combines with the active site of pseudo cholinesterase, hydrolysis occurs and carbamoylated enzyme is produced, while free choline is regenerated. Then hydration occurs.
Therapeutic uses:
Glaucoma
Carbachol is not the first line agent because better drug therapies are available like beta blockers, PG analogs, etc. Nicotinic effects are more prominent. It has longer duration of action and receptor non-selectivity.
Adverse Effects
No adverse effects at therapeutic doses because it is a quaternary ammonium compound and lacks systemic penetration.
Methacholine:
Methacholine has methyl group in its structure. It is more resistant to hydrolysis by choline esterase. It has both muscarinic and nicotinic actions (very mild nicotinic actions )
Muscarinic actions are prominent on CVS (M2).
Duration of action is 15-20 minutes. Longer duration of action as compared to acetylcholine
Therapeutic uses:
1. Given subcutaneously for the relief of paroxysmal atrial tachycardia
Previously, it was said to be effective in paroxysmal atrial tachycardia, now better drugs are available like adenosine, Calcium channel blockers, esmolol, etc.
2. Diagnosis of belladonna poisoning
3. Diagnosis of bronchial hyperactivity
4. Glaucoma.
Bethanechol:
Structure related to Acetylcholine, acetate is replaced by carbamate & choline is methylated, thus it is carbomyl beta methyl choline.
It has no nicotinic actions
Muscarinic actions are prominent on eye, GIT & urinary bladder
Prolonged duration of action because is more resistant to hydrolysis.
Duration of action is one hour.
Therapeutic uses:
1. Post operative gastric distension
2. Paralytic ileus
3. Bladder atonia
4. Megacolon
It is given subcutaneously in 5 mg dose. Neostigmine is also given for these conditions (15 mg oral, 0.5-1 mg subcutaneously)
Mechanism of action is like carbamates.
Toxicity includes bronchospasm, it does not enter CNS.
Muscarine and Pilocarpine:
Muscarine
Quaternary amine (Amanita muscaria)
Poorly soluble, less complete absorption from the GIT
Very toxic & can even enter the brain
Treatment of overdosage: Atropine, 1-2 mg parenterally
Pilocarpine
Tertiary amine (plant source; Pilocarpus jaborandi leaves)
Has muscarinic actions
Therapeutic uses:
- Glaucoma
- To reduce the effect of mydriatics
- To break adhesions
- Sjogren’s syndrome (Cevimeline)
Not used for systemic diseases because increased tracheo-bronchial secretions lead to pulmonary edema. It is highly lipid soluble usually given topically.
Nicotine and Lobeline:
Alkaloids liquid in nature, obtained from plant source.
Actions are mainly on nicotinic receptors (CNS, PNS, NMJ)
Effects:
CNS, have important effects on brainstem and cortex.
PNS – autonomic ganglia.
NMJ, immediate depolarization of the end plate – increase in permeability to sodium and potassium ions.