CHOLINERGIC DRUGS

PARASYMPATHOMIMETIC DRUGS

Mechanism of action
Ach is the neurotransmitter for the sympathetic and parasympathetic automatic ganglia, the
preganglionic fibres ending in the adrenal medulla and the postganglionic fibers of
parasympathetic. It is a quaternary ammonium ester that is rapidly hydrolised by
acetylcholinesterase and plasma cholinesterase. Ach released from the presynaptic membrane:
 binds to the cholinergic receptors resulting in activation of the cholinergic receptors;
 binds to acetylcholinesterase and inactivates Ach.

THE RECEPTORS

 the muscarinic receptors are stimulated by muscarine, an alkaloid existing in certain

poisonous mushrooms.
o there are several classes of muscarinic receptors: Ml (on gastric parietal cells),
M2 (on cardiac cells and smooth muscle), M3 (on exocrine glands and smooth
muscle), M4, M5;
o location:
 on autonomic effector organs: heart, brain, exocrine glands, smooth
muscles;
 on ganglia of peripheral nervous system.
 the nicotinic receptors are stimulated by nicotine.
o location: CNS, autonomic ganglia, adrenal medulla, neuromuscular junction.

Some of the effects of the parasympathetic nervous system stimulation are:

 pupillary constriction;
 increased secretion by digestive glands;
 increased smooth muscle activity along the GI tract;
 bronchoconstriction;
 reduced heart rate and negative inotropic effects.
Classification
 Direct acting (stimulating the nicotinic or muscarinic receptors)
o Choline esters:
ACETYLCHOLINE (all Ach receptors)
CARBACHOL (all muscarinic and some nicotinic receptors)
METHACOLINE (all muscarinic receptors)
BETHANECHOL (M3 receptors)
o Natural alkaloids:
PILOCARPINE
ARECOLINE
MUSCARINE
NICOTINE
 Indirect acting
o Reversible cholinesterase inhibitors
NEOSTIGMINE
PHYSOSTIGMINE
PYRIDOSTIGMINE
EDROPHONIUM
 DONEPEZIL
o Irreversible cholinesterase inhibitors (organophosphate compounds)
ECHOTHIOPHATE
ISOFLUROPHATE
MALATHION

DIRECT CHOLINERGIC AGONISTS

Mechanism of action
 they act directly upon the cholinergic receptors, stimulate them and produce
characteristic effects.

 ACETYLCHOLINE

Parmacodynamic actions
The muscarinic effects appear after small doses.
 cardiac effects:
o decrease of the cardiac output and the heart rate:
 decrease the contraction force of the atriums (negative inotropism);
 decrease of the firing rate at sinoatrial node.
o decrease in blood pressure.
 respiratory effects:
o bronchoconstriction;
o stimulation of bronchiolar secretion.
 digestive effects:
o stimulation of the GI smooth muscles;
o stimulation of the gastric secretion (gastric acid hypersecretion);
o stimulation of the intestinal secretion and motility;
 o stimulation of the gall bladder.
 urinary system effects:
o stimulation of the urinary bladder;
o increased tone of detrusor urine muscle.
 eye effects:
o miosis (constriction of pupille sphincter muscle);
o stimulation of cilliary muscle contraction (for near vision);
o decrease of the intraocular pressure (after local administration).
 CNS effects – stimulation.
 exocrine glands – hypersecretion.
The nicotinic effects appear only after large doses.

 CARBACHOL

Mechanism of action
 it has both nicotinic and muscarinic action;
 it is biotransformed by esterases at a much slower rate when compared to Ach;
 it has a strong action on GI system, urinary bladder, eye.

Indications
 glaucoma, applied localy (the clinical use is limited due to its high potency and long
duration of action);
 stimulation of postoperative atonic urinary bladder;
 stimulation of atonic intestinal smooth muscle.
Adverse effects
 gastric acid hypersecretion.
Preparations
Carbachol - Miostat opthalmic sol.

 METACHOLINE

Mechanism of action
 acts on the cardiovascular system.
Indications
 Raynaud syndrome;
 paroxystic tachycardia

 BETHANECOL

Mechanism of action
 it has a strong muscarinic action and no or little nicotinic action;
 acts on smooth muscle of bladder and GI tract (duration of action – aproximately one
hour).
Indications
 stimulation of atonic bladder;
 stimulation of atonic intestinal smooth muscle.
Adverse effects
 salivation, abdominal pain, diarrhea;
 sweating;
 low blood pressure.
  PILOCARPINE

Chemistry
 it is an alkaloid from leaves of Pilocarpine jaborandi.

Pharmacodynamic actions. Mechanism of action.

 it has muscarinic action;
 rapid miosis (contraction of the cilliary muscle);
 lowering of the intraocular pressure as a result of increased drainage of aqueous
humor, due to the extreme efficiency in opening the trabecular meshwork surrounding
Schlemm's canal; the vision is fixed at a certain distance and focussing becomes
impossible;
 stimulates secretions (sweat, saliva, tears).
Indications
 glaucoma (the effect lasts 4-6 hours);
 iritis, irido-capsulitis;
 lithiasis of the salivar glands;
 the intoxication with Atropine (administrated IV).
Adverse effects
 sweating;
 salivation;
 pain in the eyebrow region (at the beginning of the treatment);
 may appear tolerance at ocular effects.
Preparations
Pilocarpine - Dropil ophtalmic sol. 2%

INDIRECT CHOLINERGIC AGONISTS

Mechanism of action
Anticolinesterases form a complex with acetylcholinesterase and inhibit it's hydrolyzing
activity of Ach. Therefore, Ach accumulates in the synaptic gap and the Ach's effects are
prolonged and very strong.

 NEOSTIGMINE

Chemistry
 it is a quaternary amonium compound.
Pharmacodynamic actions
 muscarinic effects – stimulates the motility of the digestive tract and of the urinary
bladder;
 nicotinic effects – stimulates the contractility of the skeletal muscles (at small doses).

Pharmacokinetics
 Absorption: it is not well absorbed orally;
 Distribution: it does not penetrate the biological membranes and does not enter the
CNS;
 Biotransformation and elimination: it is destroyed by plasma esterases and is excreted
in the urine.
Indications
  myasthenia gravis;
 intestinal or bladder atony;
 antidote for tubocurarine and other competitive neuromuscular blocking agents;
 glaucoma.
Adverse effects
 nausea, vomit, salivation, abdominal pain, diarrhea;
 sweating.
Contraindications
 pregnancy;
 bronchial asthma;
 Parkinson’s disease.
Preparations
Neostigmine – Miostin vials

 PHYSOSTIGMINE

Pharmacodynamic actions
 muscarinic effects – miosis and decreased intraocular pressure (the effects last for 24
-48 h);
 nicotinic effects – contraction of scheletal muscles.
Indications
 glaucoma;
 treatment of overdoses of drugs with antichiolinergic actions (Atropine,
phenothiazines, tryciclic antidepressants).
Adverse effects
 local irritation after a long lasting administration.

 PYRIDOSTIGMINE

Pharmacodynamic actions
 the action is similar with Physostigmine, but more intensive and prolonged.
Indications
 postoperative intestinal atony;
 myastenia gravis.

 EDROPHONIUM

Mechanism of action
 acts mainly on scheletal muscle (short duration of action).
Indications
 diagnosis of myastenia gravis;
 antidote for tubocurarine.

 ECOTHIOPHAT

Mechanism of action
  irreversible anticolinesterases are able to form a covalent bind with a serine “–OH” at
the active site of acetylcholinesterase; the enzyme is permanently inactivated and the
restoration of acetylcholinesterase activity requires the synthesis of new enzyme
molecules; following covalent modification of acetylcholinesterase, the
phosphorylated enzyme slowly releases one of its isopropyl groups; the loss of an
alkyl group is called aging and makes it impossible for chemical reactivators such as
pralidoxime to break the bond between the remaining drug and the enzyme.
Indications
 glaucoma (topically), resulting an intensive lowering in intraocular pressure which
lasts for 1 – 2 weeks.
Adverse effects
 specific cataract after long treatment with high doses.

CHOLINERGIC ANTAGONISTS

Classification
 natural
ATROPINE
SCOPOLAMINE
 synthetic
PIRENZEPINE HOMATROPINE
PROPANTELINE TRIHEXYPHENIDYL
TROPICAMIDE BUTILSCOPOLAMINE
Mechanism of action
 they block the muscarinic synapses of the parasympathetic nerves; the effects of
parasympathetic inervation are thus interrupted.

 ATROPINE

Chemistry
 Atropine is a belladona alkaloid.
Mechanism of action
 it has a high affinity for muscarinic receptors where it binds competitively, preventing
Ach from binding to that site.
Pharmacodynamic actions
 cardiac effects:
o small doses – bradycardia and low blood pressure;
o usual doses – tachycardia.
 digestive effects:
o xerostomia;
o inhibition of the gastric acid secretion;
o antispasmodic on the gall bladder.
 urinary system effects:
o reduces the hypermotility state of the urinary bladder.
 respiratory effects:
o decreased bronchiolar secretion;
o bronchodilation, inhibit the bronchospasm.
  eye effects:
o mydriasis;
o unresponsiveness to light;
o cyclopegia (inability to focus for near vision);
o high intraocular pressure;
o diminished tears secretion.
 CNS effects:
o at high doses it stimulates the CNS (confusion, hallucination, delirium,
collapse of the circulatory and respiratory systems, death);
o favorable effect in Parkinson’s disease.
Pharmacokinetics
 Absorption: it is rapidly absorbed after oral or parenteral administration;
 Distribution: well diffused in tissues and organs;
 Biotransformation and elimination: partially metabolized by the liver, eliminated
primarily in the urine.
Indications
 preanesthetic agent, because it reduces the secretion in the upper and lower respiratory
tract;
 antidote in the intoxication with anticolinesterases (Pilocarpine and organophosphate
compounds);
 MI (it treats sinus node bradycardia or a high grade AV block);
 in ophtalmology: because of the mydriatic and cyclopegic effect which permits the
measurement of the refractive errors without interference by the accomodative
capacity of the eye.
Adverse effects
 xerostomia (dry mouth);
 blurred vision;
 "sandy eyes";
 urinary retention;
 restlessness, confusion, hallucination, delirium, convulsions, coma.
Preparations
Atropine - Atropine sulfate vials

 SCOPOLAMINE

Chemistry
 Scopolamine is a belladona alkaloid.
Pharmacodynamic actions
 the effects are similar to those of Atropine but with a short duration of action and two
times higher than the effects of Atropine;
 acts mainly on exocrine glands and eye;
 produces sedation but at higher doses can instead produce excitement.
Indications
 preanesthetic agent (in association with Morphine);
 motion sickness;
 Parkinson’s disease.

 PIRENZEPINE

Mechanism of action
  diminishes the excitosecretory vagal influences and decreases the basal gastric
secretion, thus having antispastic and antisecretory effects;
 blocks the Ml muscarinic receptors;
 it has the same efficiency with Cimetidine in the treatment of the gastric ulcer.
Indications
 active gastric and duodenal ulcer;
 reflux esophagitis;
 Zollinger-Ellison syndrome.

 PROPANTELINE

Indications
 gastric ulcer;
 hyperacid gastritis