Anticholinergic drugs

in general

Anticholinergic drugs (also called cholinergic blockers) are drugs that oppose the
physiological action of the neurotransmitter acetylcholine

first type

second type

Cholinoceptor blockers

Are antagonists or inverse agonists that bind to muscarinic or nicotinic receptors and prevent the effects of ACh and other cholinergic agonists

Cholinesterase regenerators

Pralidoxime (2-PAM)

has two types

Antimuscarinic agents

antinicotinic

Muscarinic receptors

Five subtypes (M1 to M5 )
ligand binding pocket are conserved among all muscarinic receptor subtypes.

difficulty in identifying
subtype-selective

nonselective

also called parasympatholytic agents, are substances that reduce
the activity of the parasympathetic nervous system.

Because of the wide distribution of parasympathetic nerves, these drugs affect
many organs and structures of the body

including the eyes, the respiratory and
gastrointestinal tracts, the heart and the bladder

types

  1. Atropine

It is an alkaloid that is found in the plant Atropa belladonna
and many other plants.

Mechanism of Action

a nonselective, reversible and competitive antagonist that binds with high affinity to of all five known (M1 to M5) muscarinic receptors

s lipid-soluble and readily crosses membrane barriers
… so gets well distributed into the CNS, the eye, and other organs

an effective antidote used in the treatment of organophosphate anticholinesterase poisoning, overdose by a muscarinic agonist

Side effects

Dry mouth, urinary retention, blurred vision,
tachycardia and constipation

  1. Scopolamine

Most commonly used for preventing motion sickness and nausea

an adjunct for treating poisoning by organophosphate
anticholinesterases

because

more readily cross the blood brain barrier

has a greater action on the CNS

has a longer duration of action

Side effects

has a limited use clinclly due to

Blocking short-term memory

Sedation

Euphoria and is susceptible to abuse

  1. Tropicamide

It is a short acting antimuscarinic drug commonly applied as eye drops (ophthalmic
solution) prior to retinal exams

It produces mydriasis (dilation of the pupil) for 6h by inhibiting the contraction of the
iris sphincter muscles

  1. Darifenacin and oxybutynin

These synthetic atropine-like drugs are used to treat overactive bladder

  1. Pirenzepine

Is an M1 selective antagonist, is used in the treatment of peptic ulcers, as it
reduces gastric acid secretion and reduces muscle spasm

has another divided

to

Natural alkaloids

Tertiary amines

Quaternary amines

Absorption

Distribution

Metabolism and Excretion

Contraindications

Natural alkaloids and most tertiary antimuscarinic drugs are well absorbed

only 10–30% of a quaternary antimuscarinic drug is absorbed after oral administration and decreased lipid solubility

Atropine and tertiary agents are widely distributed rapidly and fullydistributed into the CNS

quaternary agents are poorly taken up by the brain and therefore
have no CNS effects at low doses

Atropine

metabolism in the liver and partially unchanged in
the urine (~50%)

elimination from the blood

rapid phase is 2 hours

slow phase is ~13 hours

The drug’s effect declines rapidly in all organs … and the duration of action at normal
doses is 4-8 h except in the eye (where the effect lasts for days)

Some people with glaucoma, gastrointestinal disease or urinary retention should avoid using anticholinergic drugs

• Narrow Angle Glaucoma

Even moderate doses of drugs given systemically can
induce acute glaucoma. When this occurs, it is considered a medical emergency

Urinary or GI tract Obstruction

Antimuscarinic drugs may reduce the contractility of bladder smooth muscle resulting in acute urinary retention. Also, reduction of GI motility may worsen symptoms in patients with intestinal obstruction

Neuromuscular blockers

Ganglionic blockers

useful during surgery to provide complete muscle relaxation at lower anesthetic doses, allowing for more rapid recovery from anesthesia and reducing postoperative respiratory depression

has two types

Nondepolarizing

Depolarizing

Mechanism of action

competitively block ACh transmission at the nicotinic receptors … By doing so, they prevent depolarization at the muscle cell membrane and inhibit muscular contraction

Pharmacokinetics

(IV or intramuscular) since they are not effective orally

do not enter cells or cross the blood–brain barrier

Drugs that are eliminated in the bile have shorter durations of action than those eliminated by the kidney

Succinylcholine

Mechanism of action

However, unlike ACh (quickly destroyed by AChE), Succinylcholine is more resistant to degradation by AChE  remains attached for a longer time and provides constant stimulation of the receptor

But, because tension cannot be maintained in skeletal muscle without periodic repolarization, continuous depolarization causes a resistance to depolarization (Phase II) and results in muscle relaxation and paralysis

This agonist binds to the nicotinic receptor and, like ACh, causes the opening of the sodium channel and depolarizes the junction (Phase I)

Pharmacokinetics

Succinylcholine is injected intravenously. Its duration of action is longer than that of ACh (5–30 s), but it’s also brief (few min) which results from redistribution and rapid hydrolysis by plasma pseudocholinesterase … Therefore, drug effects rapidly disappear upon discontinuation

Side effects

  1. Respiratory paralysis
  1. Autonomic effects
  1. Hyperkalemia

Drug interactions

Inhaled anesthetics

Aminoglycoside antibiotics

especially isoflurane, strongly potentiate and prolong the neuromuscular blockade. A rare interaction of succinylcholine with inhaled anesthetics can result in malignant hyperthermia. A very early sign of this potentially life-threatening condition is contraction of the jaw muscles (trismus)

(e.g. gentamicin) and antiarrhythmic drugs may
potentiate and prolong the relaxant action of neuromuscular blockers

Hexamethonium

These agents competitively block the entire autonomic outflow at the nicotinic receptor

their lack of selectivity confers a broad range of undesirable effects and
limits their clinical use

is the prototype cholinesterase regenerator

Mechanism of Action

It can reactivate the AChE that is inhibited by an organophosphate agent

The oxime group (=NOH) in pralidoxime has a high affinity for the phosphate group
of organophosphates

Because of this high affinity, pralidoxime binds to organophosphates and hydrolyzes the bond between the organophosphate agent and the cholinesterase

so

if aging has not occurred … The enzyme is thus regenerated

2-PAM is not as effective against the chemically different “carbamate” type anticholinesterase agents (such as neostigmine and pyridostigmine) because carbamates do not have a phosphate group

Atropine
Scopolamine

Tropicamide
Oxybutynin and Benztropine

Ipratropium Tiotropium

examples

Cisatracurium

Rocuronium

Pancuronium