ANTICHOLINERGIC DRUGS

Presented by:Dr. Vishalkr. Kandhway

ANTICHOLINERGIC DRUGS

Anti cholinergic drugsAre those which antagonise the effect of neurotransmitter Acetylcholine (ACh) on autonomic effectors & in the CNS exerted through “Muscarinic receptors”. Though nicotinic antagonists also block certain actions of Ach, they are referred to as “Ganglion blockers” & “Neuromuscular blockers”

• Muscarinic receptor site-• Heart• Salivary glands• Smooth muscles of GIT• Genitourinary tract • Urinary bladder

• Nicotinic acetyl choline receptor site-– Nerve endings of neuromuscular junction.

• Acetylcholine is also the neurotransmitter at postganglionic nicotinic receptors located at the NMJ (Neuromuscular junction) & autonomic ganglia.

• Effects of anticholinergic drugs at nicotinic cholinergic receptors is little / nil as compared at muscarinic receptors.

• Anticholinergic drugs are considered – selectively antimuscarinic.

Naturally Occurring (Tertiary Amine)

Atropine Scopolamine(Alkaloids of belladonna plants

Synthetic compound(Glycopyrrolate)

(Quaternery Ammoniums Derivatives)

• More potent than parent compounds

• Lack CNS activity because of poor penetration in brain

Classification• Natural alkaloid – Atropine,

Scopolamine(hyoscine)

• Semi-synthetic derivative – Homatropine, Atropine mithonitrate, Ipratropium bromide.

• Synthetic compound – a) Mydriatics : Cyclopentolate, tropicamide

b)Anti-seceretory -

Quarternary : Glycopyrolate, Propantheline, Isopropamide.

Tertiary amines : Pirenzepine, Dicyclomine c)Vasicoselective : Oxybutynin, flavoxate.

d)Anti-parkinsonian : Benzhexol, biperiden.

Mechanism of action• Anticholinergic are the class of drugs that

block the neurotransmitter acetylcholine in CNS and PNS.

• Anticholinergic drugs combine reversibly with muscarinic cholinergic receptors thus preventing access of neurotransmitter acetylcholine in these sites.

Muscarinic Receptor Subtypes

M1 M2 M3 M4 M5

Location • CNS• Stomach

• Heart• CNS• Airway

Smooth Muscle

• CNS• Salivary

glands• Airway

smooth muscle

• Vascular endothelial cells

• CNS• Heart

• CNS

Clinical Effects • HydrogenIon Secretion

• Bradycardia • Salivation • Bronchodilati

on • Vasodilation

? ?

Clinically selective drugs available

Yes No No No No

Atropine

• Atropine sulphate is a tertiary amine & the naturally occuring levorotatory form is active.

• Administered IV/IM in a range of 0.01-0.02 mg/kg upto adult dose of 0.4-0.6 mg.

• Larger IV doses upto 2 mg may be required to completely block the cardiac vagal nerves in treating severe bradycardia.

Pharmacological Actions• CNS : -Atropine has CNS stimulant action. However

these effects are not appriciable at low doses. -Atropine stimulates many medullary centres –

vagal, respiratory, vasomotor. - It depresses vestibular exitation and has anti-

motion sickness property. - It supresses tremor & rigidity of parkinsonism. - High doses cause cortical exitation, restlessness,

disorientation, hallucination & delirium followed by respiratory depression & coma.

• CVS : - Most prominent effect is to cause tachycardia

due to blockade of M2 receptors at SA node.

• Eye : - Topical instillation of atropine causes

mydriasis, abolition of light reflex and cycloplegia resulting in photophobia & blurring of near vision.

• Smooth muscles : - All visceral smooth muscles that receive

parasympathetic motor innervation are relaxed by atropine due to M3 blockade.

- Tone & amplitude of contractions of stomach & intestine are reduced, the passage of chyme is slowed – constipation may occur & spasm may be relieved.

- Atropine causes bronchodilatation & reduces airway resistance especially in COPD & Asthma patients.

- Atropine has relaxant action on ureter & urinary bladder.

• Glands : - Atropine markedly decreases sweat, salivary,

tracheobronchial & lacrimal secretions by M3 blockade.

- Skin & eyes become dry, talking & swallowing may be difficult.

• Body temperature : - Rise in body temperature occur at high doses due to

both inhibition of sweating as well as stimulation of temperature regulating centre in the hypothalamus.

- Children are highly succeptible to Atropine fever.• Local anaesthetic : Atropine has mild anesthetic

action on the cornea.

• Sensitivity of different organs & tissues to atropine varies & can be graded as –

• Saliva, sweat, bronchial secretion > eye, bronchial muscle, heart > smooth muscle of intestine, bladder > gastric glands & smooth muscles.

Uses• As anti-secretory : - Pre-anesthetic medication : reduces excessive

salivation & respiratory secretions. - Peptic ulcer : decreses gastric secretions & provide

symptomatic relief in peptic ulcer now been superseded by H2 blockers.

• As anti-spasmodic : - If there is no mechanical obstruction intestinal & renal

colic, abdominal cramps symptomatic relief is affordable.

- Gastritis, gastric hypermortility. - To relive urinary frequency & urgency.

• Can be given in patients of Bronchial Asthma • As mydiatric & cycloplegic.• As cardiac vagolytic• For central actions in Parkinsonism as an

adjuvant to levodopa.• To antagonise muscarinic effects of anti-

Cholinesterase i.e OP Poisoning with dose 2mg IV with repeated doses and early mushroom poisoning.

Side effects

• Belladona poisoning due to drug overdose.• Dry mouth, difficutly in swallowing and talking.• Dry ,flushed and hot skin.• Fever difficulty in micturition , decreased bowel

sounds.• Dilated pupil, photophobia, blurring of near vision.• Excitement, ataxia, delirium, hallucination.• Convulsion and coma may occur in severe poisoning.

• Treatment : Physostigmine 15- 60 micro gram / kg IV every

1- 2 hourly. • Contraindications : - Narrow angle glaucoma - BPH - Hyperthyroidism - CAD

Glycopyrolate• Glycopyrolate is a synthetic product that differs from atropine in

being a quaternary amine.• The pre-medication dose is 0.005 – 0.01 mg/kg upto 0.2-0.3 mg

in adults.• Clinical consideration :• Because of its quaternary structure, glycopyrolate can’t cross

BBB & is almost devoid of CNS & Opthalmic activity.• Potent inhibition of salivary gland & respiratory tract secretions

is the primary rationale for using glycopyrolate as pre-medication.

• Heart rate increases after IV administration.• It has longer duration of action than atropine sulphate i.e 2-4

hrs.

Scopolamine• Scopolamine is a naturally occuring tertiary amine.• It’s dose is 0.3-0.5 micro gram I/M.• Clinical Consideration :• Lipid soluble.• Easy penetrate BBB.• More potent antisialagogue than Atropine & causes greater

CNS effects • Clinical doses results in restlessness, drowsiness, amnesia,

dizziness & delirium.• It has the added virtue of preventing motion sickness.• The lipid solubility allows trans-dermal absorption & has

been used to prevent post-operative nausea & vomiting• Best avoided in patients with closed angle glaucoma.

DifferencesAtropine Glycopyrrolate

1. Lipid solubility - Lipid soluble - Poorly soluble (Quaternary ammonium compound)

2. Blood brain barrier crossing

- Good - Minimum ability of crossing BBB

3. Metabolization - 50% from liver -

4. Excretion - 18% unchanged - 80% unchanged

5. Treatment - bradycardia at low dose - 0.2 – 0.4 mg IV -Dose for intra operative bradycardia 1.2 mg -Max dose for bradycardia 3 mgHiccups (Occurring after

laryngeal mask placement) - 0.5 mg IV

Intra operative bradycardia

6. Heart rate Increases Increases

Differences

Atropine Glycopyrrolate

7. Effect on smooth muscles

Decreases tone of smooth muscles of biliary tract & ureter

8. Antisialagauge effect

- Less then scopolamine More

9. T½ - 2.3 hrs Prolonged in uremic patients 1.25 hrs

Comparative effects of anticholinergic drugs Sedation Antisialagogue Increase Heart

RateRelax smooth

MusclesAtropine + + +++ ++

Scopolamine +++ +++ + +

Glycopyrrolate 0 ++ ++ ++

Mydriasis cycloplegia

Prevent Motion induced Nausea

Decrease Gastric

Hydrogen Ion secretion

Alter Fetal Heart Rates

Atropine + + + 0

Scopolamine +++ +++ + ?

Glycopyrrolate 0 0 + 0

Central Anticholinergic Syndrome • Anticholinergic drugs like scopolamine, atropine can enter

central nervous system (CNS) and produce some unusual symptoms which are characterized in a syndrome which is known as central anticholinergic syndrome. Symptoms are -– Restlessness– Hallucination to somnolence – Unconsciousness

Glycopyrrolate does not easily cross BBB & not likely cause CACS.

• References :- Stoelting’s Pharmacology & Physiology. Morgan & Mikhail’s Clinical Anesthesiology. KD Tripathi Essentials of Medical Pharmacology.

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