CHOLINERGIC DRUGS

CHOLINERGIC DRUGS

CHOLINERGIC AGONISTS

PARASYMPATHOMIMETICS

CHOLINOMIMETICS

Acetylcholine is a cholinergic neurotransmitter. It is synthesised by cholinergic nerves, released by cholinergic nerve impulse and acts by binding with cholinergic receptors. Acetylcholine is ester of acetic acid and Choline (Choline is member of Vitamin B complex group). Acetylcholine is metabolised by Acetyl cholinesterase to form Choline and Acetate by hydrolysis.

Acetylcholine is found in

1.      Parasympathetic and Sympathetic Ganglia

2.      Parasympathetic post ganglionic nerve fibres termination in effecter organs

3.      Preganglinic nerve fibres termination in Adrenal Medula

4.       

Cholinergic drugs produce effect similar to Acetylcholin effects on human body. Thus they are also called as cholinergic agonist, Cholinomimetic or Parasympathomimetic drugs.

Classification:

Cholinergic drugs are classified into following two classes:

1.      Direct Acting Parasympathomimetic Drugs

a.      Synthetic Choline Esters

                                                              i.      Acetylcholine

                                                            ii.      Carbachol

                                                          iii.      Bethacol

                                                          iv.      Methacol

b.      Cholinomimetic Natural Alkaloids

                                                              i.      Pilocarpine

                                                            ii.      Muscarine

c.       Miscellaneous

                                                              i.      Oxotremorine

2.      Indirect acting parasympathomimetic Drugs (Anticholinestearase or Cholinestearase Inhibitors)

a.      Reversible Anticholinestearase

                                                              i.      Neostigmine

                                                            ii.      Physostigmine

                                                          iii.      Pyridostigmine

                                                          iv.      Propoxur

                                                            v.      Carbofuran

b.      Irreversible Anticholinestearase (Organophasphorus Compounds)

                                                              i.       Ecothiphate

                                                            ii.      Insecticides

1.      Parathione

2.      Melathione

3.      Dimethoate

                                                          iii.      War Gas

1.      Samon

2.      Sarin

3.      Tabun

Direct Acting Parasympathomimetic Drugs:

They directly bind with cholinergic receptors to produce effect actions of acetylcholine. Some of them are used therapeutically.

Acetylcholine: Synthetic Acetylcholine is not used clinically due to following characteristics

a.       Poor Lipid Solubility

b.      Poor GIT Absorption

c.       Poor BBB penetration

d.      Quick Hydrolysis by Acetylcholine Estearase

e.       Short duration of Actions

f.       Multiple actions due to stimulation of both Muscarinic and Nicotinic Receptors

Pharmacological Actions:

A.    Muscarinic Effects: Action similar to action produced by and alkaloid muscarine obtained from certain Mushroom

1.      Eye: Miosis (Constriction of pupil) due to stimulation of iris circular muscles (sphincter Muscles). Lens fixation for near vision occurs due to iris ciliary muscle stimulation.

2.      Secretory Glands: Stimulation of smooth muscles of secretory glands increases their secretions. Ex. Salivary Gland, Glands in GIT, Gall Bladder, Lacrymal Gland, Broncheal Glands, Sweat Glands, Urinary Bladder, Ureter.

3.      CVS: Slowdown Heart Rate (Bradycardia) and decrease cardiac output

4.      Blood Vessels: Vasodilation to produce decrease in blood pressure (Hypotension)

B.     Nicotinic Effects: Action similar to action produced by an alkaloid nicotine obtained from Tobacco.

1.      Skeletal Muscle Contraction

2.      Parsympathetic and sypmrthetic autonomic ganglia stimulation

3.      CNS stimulation followed by depression  

Synthetic Choline Esters: Other synthetic esters of choline has following characteristics:

1.      More resistant to choline estearase hydrolysis

2.      Methylation of Acetylcholine reduces nicotinic receptors stimulation effects

3.      Esters of carbamic acid are choline estearase resistant

Bethanechol: Methylation of acetylcholine produces Bethanechol. It is resistant to acetylcholine esterase due to methylation. It has no nicotinic action and strong muscarinic actions.

Organ	Actions	Results
Eye	Iris Circular Muscle Contraction	Miosis,
	Iris ciliary Muscle Contraction	Spasm of Accommodation, Fixation for Near Vision
Salivary Glands	Contraction	Salivation
Sweat Glands	Contraction	Diaphoresis
GIT	Increase in peristaltic Movements	Nausea, Vomiting Diarrhoea
Urinary Bladder	Contraction	Urinary Urgency, Micturition
Respiratory System	Contraction	Bronchospasm. Air way Bleckage to Lungs, Asthmatic Attack
Blood Vessel	Vasodialtion	Decrease in Blood Pressure, Flushing
CVS	Relaxation	Low Cardiac output, Bradycardia

Adverse Effects: Miosis, Spasm of Accommodation, Eye Fixation for near vision, Salivation, Diaphoresis, Nausea, Vomiting, Diarrhoea, Bronchospasm, Hypotension, Flushing, Bradycardia.

Carbachol: Pharmacological Action similar to Bethanicol. Carbachol is used as eye drop to constrict pupil and decrease intra ocular pressure in Glaucoma. It shows nicotinic action thus it is not used clinically for any purpose.

Natural Choline Estres:

Pilocarpine: It is natural alkaloid and less potent drug. It has only muscarinic effects and no nicotinic effect.

Pharmacological Actions: It stimulates muscarine receptors present in exocrine glands but it is not used clinically for this purpose.It has very little effect on smooth muscles and CVS. It is readily absorbed from eye conjunctiva to produce miosis and spasm of accommodation (vision fixed for particular distance).But it is not used clinically.

Therapeutic Uses: It is drug of choice to decrease intraocular pressure in both type of Glaucoma. It is used only in emergency condition due to short duration of action and side effects spasm of accommodation.  Choline estearase inhibitors are better choice than Pilocarpine for regular use due to longer duration of action.

Indirect Acting Parasympathomimetic Drugs (Anticholine estearase Drugs): They inhibits acetyl choline estearase competitively prevent hydrolysis of endogenous acetyl choline. These drugs increase muscarinic, Nicotinic, Neuromuscular Junction and CNS effects of acetyl choline. They increasesduration of action of endogenous acetylcholine and its concentration.

1.      Reversible anticholine estearase drug s

2.      Irreversible anticholine estearase drugs

Reversible Anticholine estearase Drugs: They are ester of carbamic acid. They have structural similarity with acetylcholine. They form reversible complex with acetylcholine esterase. Thus acetylcholine esterase will not be available to hydrolyse acetylcholine. Acetylcholine esterase hydrolyse drug slowly.  Lipid soluble reversible anticholinestearase drugs can cross blood brain barrier. Thus they show very little effect on neuromuscular junction. They produce muscarinic, ganglionic and CNS effect. Water soluble reversible anticholinestearase cannot easily cross BBB. Thus they show little effect in CNS. They show their effects on skeletal muscle and ganglia.

Ex.

1.      Tertiary Amine

a.       Physostigmine (Lipid Soluble)

2.     Quaternary ammonium Compound

a.       Neostigmine                 

b.      Pyridostigmine             Water

c.       Edrophonium                Soluble

d.      Demecarium

3.      N-Methyl Carbamate Esters  

a.       Propoxur (Baygon)

b.      Carbofuran

Physostigmine: It is lipid soluble tertiary amine alkaloid obtained from plant calabar beans (Physostigmine venenosum). It is well absorbed from GIT and cojuctiva. It can cross BBB. It form reversible complex with acetylcholinestearase enzyme. Thus it potentiate cholinergic effects. It also stimulates nicotinic receptors but this action is very low and have no clinical importance.

Therapeutic Uses:

1.      Ophthalmic: It produces miosis, spasm of accommodation and decrease intraocular pressure. It is used as ocular hypotensive agent to decrease intraocular pressure in Glaucoma. However pilocarpine is more effective than physostigmine to treat glaucoma.

2.      Micturition: It stimulates post operative atonic urinary bladder to produce mcturition in non obstructive urinary retention.

3.      It is also used to stimulates atonic GIT.

4.      It is used to treat overdose of Atropine (Anticholinergic) Phenothiazine and Tricyclic Antidepressant (TCA)

Adverse Effects: Convulsion and Bradycardia. Accumulation of Ach at neuromuscar Junction to produce paralysis. But this effect Does not appear at therapeutic dose.

Neostigmine: It is polar synthetic quaternary ammonium compound poorly absorbed fro GIT and conjunctiva. It does not cross BBB and produce nicotinic effects with very low muscarinic effects of Ach.

Therapeutic Dose:

1.       It is mainly used for symptomatic treatment of Mysthenia Gravis, an auto immune disease. (Antibodies bind with Ach receptors at neuromuscular Junction. Neostigmine hydrolyse these antibodies and Ach receptor will be available for endogenous Ach)

2.      It is used as antidote in tubocurarine and other neuromuscular blocking agents poisoning

3.      It is used to stimulate atonic urinary bladder and GIT.

Adverse Effects:  Nausea, Vomiting, Diarrhoea, Abdominal pain, Salivation, Flushing, Hypotension and Bronchospasm.

Edrophonium: Similar as Neostigmine. But it is more rapidly absorbed, short duration of action (about 10 minutes) and more specific nicotinic action on skeletal muscles

It is used to diagnose Mysthenia Gravis due to more specific action on neuromuscular junction and short duration of action. It is administered intra venously to produce increase in muscular strength. Excess ose may provoke cholinergic crisis. Atropine is antidote for this effect.

Pyridostigmine: Similar as Neostigmine. It is less potent, slow onset of action and long duration of action.  (3-6 hrs) It is used in symptomatic treatment of Mysthenia Gravis.

Irreversible Anticholine esterase (Organo Phosphorus Compounds):

                                                            1.            Clinically Usefull

a.       Ecothiphate

b.      DFP (Diisopropyl fluorophosphate)

                                                            2.            Insecticides

a.       Parathione

b.      Melathione

c.       Dimethoate

                                                            3.            War Gas

1.      Samon

2.      Sarin

3.      Tabun

Organophosphorus Compounds are highly lipid soluble, non polar, volatile compound except Ecothiophate. They are rapidly absorbed from intact skin, mucus membrane like conjunctiva, lungs and GIT. They easily cross BBB. They form irreversible complex with Acetyl Choline esterase and irreversibly block action of Acetyl Choline esterase. This complex is highly stable and hydrolyses at very slow rate. Body synthesise new acetyl Choline esterase molecule to fulfil deficiency of Acetyl Choline Esterase. This synthesis process takes several weeks. Thus they are not used clinically. They are used as pesticide, insecticide or war gas. Parathione is used as garden insecticide. Malathione is used to control fruit flies and mosquitoes.

Echothiophate is water soluble, stable and potent drug. It is not used systemicallydue to its toxicity. Topically it is used to treat glaucoma. Single dose effect remains effective for 2-3 weeks. Organophosphorous compounds have toxic importance. They are used as insecticide in agriculture but they are not harmful for birds and mammals. Birds and mammals (except human) easily metabolise organophasphorous compounds. Due to this property organophosphorous compounds have replaced all chlorinated compounds like DDT as agriculture insecticide and pesticide.

Organophosphorous compounds poisoning is very common due to their wide used in agriculture. They may produce poisoning effects in following manners that may be life threatening.

1.      Occupational: Spray of insecticide without precautions

2.   Accidental: Insecticides sprayed agricultural product consumption without proper washing

3.      Suicidal: Intentional consumption for self destruction.

Symptoms: Following symptoms occur in organophosphorous compound poisoning:

1.      Muscle: Twitching, depolarisation blockage and paralysis

2.  Exocrine Gland secretions: Increased secretion causes salivation, Sweating, increased bronchial secretions, bronchospasm, edema, diarrhoea.

3.      Eyes: Miosis, spasm of accommodation,

4.   CNS: Excitation, Convulsion followed by depression, unconsciousness and respiratory failure.

Treatment: It is life threatening poisoning. Treatment should be carried out immediately inn following manners:

1.      Decontamination: Organophosphorous compounds are lipid soluble and highly volatile in nature. Thus they are rapidly absorbed from contaminated cloth through skin and respiratory tract. Thus following precautions must be taken immediately:

a.      Removal of contaminated cloth and their proper washing by using detergent

b.   Through washing of nail, hair, hands body etc with large amount of water and soap.

c.  Oral administration of 50 to 100 gram activated charcoal with 300 to 1000 ml drinking water and sorbitol for gastric lavage.

d.      Sodium sulphate and magnesium sulphate oral administration as purgative.

e.      Attendant should take proper precautions to avoid contamination like use of mask and gloves.

2.      Artificial Respiration: Respiratory air way must remain clean. Artificial respiration is used to counter respiratory depression.

3.      Atropine: Atropine sulphate injection acts as antagonist to acetyl Choline. But it only counter muscarinic effects of Acetyl Choline.It is ineffective against nicotinic action of Acetyl Choline. Thus atropine controls sweating, salivation, lacrimatiom, air way resistance, bronchial spasm, miosis etc.

4.      Pralidoxime: It reactivates acetyl Choline esterase enzyme. That metabolise Acetyl Choline. It produces relief from both muscarinic and nicotinic effects (muscle twitching, muscular weakness and respiratory depression) of Acetyl Choline. 

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