Anti-cholinergic and anti emetics.

Pharmacology and anesthetic implications.

Anticholinergic DrugsThese drugs competitively antagonize the effects of the neurotransmitter acetylcholine at cholinergic post ganglionic sites designated as muscarinic receptors.

Classification:

Natural alkaloids Atropine, Hyoscine(Scopolamine).

Semisynthetic derivatives Homatropine,Atropine methonitrate, Hyoscinebutylbromide, Ipratropium bromide, Tiotropium bromide.

Synthetic compounds

(a) Mydriatics: Cyclopentolate, Tropicamide

(b) Antisecretory-antispasmodics :

(i) Quaternary compounds: Propantheline,Oxyphenonium, Clidiniurn,

Pipenzolate,methylbromide, Isopropamide,Glycopyrrolate.

(ii) Tertiary amines: Dicyclomine, Valethama,Pirenzepine.

(c) Vasicoselective: Oxybutynin, Flavoxate,Tolterodine.

(d) Antiparkinsonian: Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden

Structure

Muscarinic Receptors

Effects on various organ systems:

CVS:

Causes tachycardia. Low doses can cause paradoxical bradycardia. <0.4mg Large doses can cause atropine flush

Respiratory:

Inhibits secretions from the respiratory tract. Decreases airway resistance and increases anatomical dead space.

CNS:

Cerebral stimulation may present as excitation,restlessness, or hallucinations. Cerebral depression,including sedation and amnesia, are prominent after scopolamine

Contd..

Gastrointestinal:

Salivary secretions are markedly reduced by anticholinergic drugs.

Gastric secretions are also decreased, but larger doses are necessary. Decreased intestinal motility and peristalsis prolong gastric emptying time.

Lower esophageal sphincter pressure is reduced.

Genitourinary:

Ophthalmic:

Thermoregulation:

Comparative Effects:

Pharmacokinetics:

IM/IV administration.

Atropine onset of action 1min. Duration 30-60min.

Glycopyrrolate has a slower onset of action 2-3min but a

longer duration of action.

Atropine and Scopolamine are highly lipid soluble and

cross the blood brain barrier.(tertiary amines)

They also cross the placenta but fetal heart rate is not

significantly altered.

Clinical Uses:

1.Pre-op medication: Atropine 0.01-0.02mg/kg IV

2.Sedation: Scopolamine 0.3-0.5mg IM

3.Anti-sialagouge effect: Scopolamine0.3-

0.5mg IM>Glycopyrrolate 0.005-0.01mg/kg>Atropine

0.01-0.02mg/kg IV

4.Treatment of bradycardia: Vagolytic dose Atropine

3mg.

5.Combination with anticholinesterase drugs

Other uses:

Bronchodialtation: Ipratropium bromide

Biliary and smooth muscle relaxation:

Mydriasis and cycloplegia:

Antagonism of gastric hydrogen ion secretion

Prevention of motion induced nausea

Parkinsons disease

Central Anticholinergic

Syndrome

Atropine more than scopolamine

Symptoms: Restlessness and hallucinations to

somnolence and unconsciousness.

MOA: Blockade of muscarinic receptors and competitive

inhibition of effects of acetylcholine in the CNS.

Treatment: PHYSOSTIGMINE 15-60mcg/kg IV. Repeat

every 1-2hrs.

Overdose:

Hot as a hare: (increased body temperature- ATROPINE

FEVER)

Blind as a bat :Mydriasis

Dry as bone-:Dry mouth, dry eyes, decreased sweat

Red as beet: Flushed face

Mad as a hatter: Delirium

Anti-emetics

Mechanism of vomiting

Nausea: Defined as a feeling of unease or discomfort in the stomach with an urge to vomit.

Vomiting: forceful expulsion of gastric contents through nose or mouth.

PCRF Parvicellular: Reticular Formation

NTS: Nucleus tractus Solitarius

SP: Substance P

Classification:

Anticholinergics

Hyocine: short duration of action produces sedation and

anticholinergic side effects.

Blocks conduction of cholinergic impulses from vestibular

apparatus to vomiting center.

Transdermal patch containing 1.5mg effective for 72hrs.

Dicyclomine: prophylaxis of motion sickness and morning

sickness.

H1 Anti-Histaminics

Anti emetic effect is due to sedative and anticholinergic properties.

Effective for morning sickness and post-op vomiting.

Dimenhydrinate, diphenhydramine, cyclizine and meclizine.

Cyclizine and Meclizine have less sedative effect. Cyclizine has shortest duration of action 8hrs.Meclizine has longest duration of action 24hrs.

S/E: sedation and dryness of mouth.

Butyrophenones

Droperidol: 0.625-1.25mg at the end of procedure.

Blocks dopamine D2 receptors in CTZ.

S/E: QT prolongation at high doses. (5-15mg)BLACK BOX WARING Use carefully in patients with Parkinsons and EPS. Can cause dysphoria and akathesia in patients.

Prochlorperazine: multiple receptors- histaminergic, dopaminergic, muscarinic.

S/E: Anti cholinergic effects and extra-pyramidal symptoms

Metoclopramide

MOA: peripherally as a cholinomimetic and centrally as dopamine

receptor antagonist.

Increases the LES tone, speeds gastric emptying and lowers gastric fluid

volume. Anti-emetic effect by blocking dopamine receptors in CTZ.

Pharmacokinetics: rapidly absorbed after oral administration. Peak

plasma conc in 40-120mins. Elimination t1/2 2-4hrs. Readily crosses blood

brain barrier.

Excreted in urine, dose reduction in patients with renal

dysfunction.

Drug interaction:

Anticholinergics block the GI effects of metoclopramide.Decreases the absorbtion of orally adminsitered cimetidine. Phenothiazines used along with it can increase chances of EPS

S/E: Rapid IV injection can cause abdominal cramping.

Hypertensive crisis in patient with phaeochromocytoma

Sedation nervousness and akathesia. Extrapyramidal

symptoms.

DOSE- 0.25mg/kg oral, IM, IV. 10-20mg.

5-HT3 Receptor Antagonists

The 5-HT3 receptor mediates

vomiting and is located

peripherally(abdominal vagal

afferents) and centrally CTZ of

the area postrema and the

NTS.

PHARMACOKINETICS:

Readily absorbed after oral

administration. Readily crosses

blood brain barrier.

Ondansetron metabolized by

Cyt P-450.

Liver failure impairs clearence

several fold.

Uses and side effects

Generally administered at the end of surgery.

Dose: 12.5mg dolasetron 1mg granisetron 4mg

ondansetron

S/E: headache, diarrhea, cardiac dysrhythmia,

conduction disturbance

Prolongation of QTc interval (dolasetron)

Elimination t1/2 Dose

Ondanserton 3-4hrs 4mg

Tropisetron 7hrs 2mg, 5mg

Granisetron 9hrs 1mg

Palonosetron 40hrs 0.075mg

Dexamethasone

Exerts anti-emetic effects through central inhibition of NTS

but not on area postrema.

Dose- 4mg

Given at the time of induction due to slow onset of

action.

No significant long lasting side effects.

Neurokinin-1 receptor antagnist

Substance P is a regulatory peptide that acts at NK-1

receptors found in vagal afferents in the gastrointestinal

tract.

NK-1 antagonists inhibit substance P at central and

peripheral receptors.

Aprepitant DOSE- 40mg (currently approved by the FDA)

Superior for the prevention of vomiting but not for prevention of nausea.

References

Millers 7th edition

Clinical Anesthesiology- Morgan 5th edition

Stoeltings handbook of pharmacology and physiology in

anesthetic practice. 4th edition

Clinical Anesthesia Barash 7th edition

Essentials of Medical Pharmacology by KD Tripathi

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