Overview - Indirect cholinergic agonism (AchE inhibition) - Muscarinic antagonism (emphasis on drugs...

Overview

• - Indirect cholinergic agonism (AchE inhibition)

• - Muscarinic antagonism (emphasis on drugs and organ effects)

• - Nicotine-Ach receptor (emphasis on drugs and therapeutics)

Indirect cholinergic agonists

Inhibitors of acetylcholinesterase

-Increase acetylcholine concentration and lifetime by inhibiting degradation

-Act by binding to AchE active site causing reversible(non covalent) or long lasting (covalent modification)

Mechanisms of indirect agonism

- Quaternary alcohols (ephodronium) – reversible binding (limit acetylcholine access)

Non covalent – enzyme-inhibitor complex lifetime (2 - 10 minutes)

- Carbamate esters – neostigmine, physostigmine – reaction with AchE active site

Covalent carbamoylation – enzyme-inhibitor complex lifetime (0.5 - 6h)

- Organophosphates – Parathion, Sarin, Soman - phophorylates AchE active site

Covalent phosphorylation – very stable enzyme-inhibitor complex, days (especially after aging)

AchE Inhibitors (quaternary alcohols and carbamates)

Organophosphates

Aging

Organ effects/therapeutic uses

• - Effects are due to acetylcholine accumulation and are both sympathetic and parasympathetic

USES Approx DurationALCOHOLS

Edrophonium Myasthenia gravis 5 – 15 minutesarrythmias

CARBAMATES

Neostigmine Myasthenia gravis 0.5 – 2hPyridostigmine Myasthenia gravis 3 – 6hPhysostigmine Glaucoma 0.5 – 2hDemecarium Glaucoma 4 – 6h

Organophosphates

Echotiophate Glaucoma 100 h (> 4 days)

Treatment of organophosphate poisoning

• 1 - maintenance of vital signs (respiration particularly important)

• 2 - Decontamination (to avoid further absorption)

• 3 - Atropine parenterally (to minimize muscarinic effects) as required

• 4 - Rescue of AchE activity with Hydroxylamines (Pralidoxime, Diacetylmonoxime)

Muscarinic antagonism

Attropa belladona

Muscarinic Antagonists

ATROPINE

SCOPOLAMINE

Muscarinic Antagonists

ATROPINE

SCOPOLAMINE Attropa belladona

- Atropine and Scopolamine are belladona alkaloids (competitive inhibitors)

-Drugs differ in their CNS effects, scopolamine permeates the blood-brain barrier

-At therapeutic doses atropine has negligible effects upon the CNS, scopolamine even at low doses has prominent CNS effects.

Mechanism of drug action

- Competitively block muscarinic receptors

- Salivary, bronchial, and sweat glands aremost sensitive to atropine

- Smooth muscle and heart are intermediatein responsiveness

- In the eye, causes pupil dilation and difficulty for far vision accomodation

- Relaxation of the GI, slows peristalsis

History/sources

• Atropa belladona - used in the renaissance• Deadly nightshade - used in the middle ages to produce prolonged

poisoning

Jimson plant leaves burned in India to treat Asthma (1800) purification of atropine (1831)

Effect of muscarinic inhibitor in the eyePupil dilation vs accomodation

Effect of muscarinic inhibition in the heart and salivary glands

- Increases the heart rate after a transient bradychardia at the low dose- Diminishes gland excretory function

Graphic summary of atropine effects

Organ effect – drug reviewAntidotes

• ORGAN DRUG APPLICATIONCNS Benztropine Treat Parkinson’s disease

Scopolamine Prevent/Reduce motion sickness

Eye Atropine Pupil dilation

Bronchi Ipatropium Bronchodilate in Asthma, COPD

GI Methscopolamine Reduce motility/cramps

GU Oxybutinin Treat transient cystitisPostoperative bladder spasms

Toxicity of muscarinic antagonists

• “DRY AS BONE, RED AS A BEET, MAD AS HATTER.”

• Dry is a consequence of decreased sweating, salivation and lacrimation

• Red is a result of reflex peripheral (cutaneous) vasodilation to dissipate heat (hyperthermia)

• Mad is a result of the CNS effects of muscarinic inhibition which can lead to sedation, amnesia (hypersensitivity), or hallucination

Nicotinic – Acetylcholine Receptor

polarizedRelaxation

depolarizedcontraction

Signaling through Ach-nicotinic receptor(competitive and depolarizing blockers)

Competitive/depolarizing

CompetitivePhysically blocks Ach binding

INHIBITOR

DepolarizingBinds and locks the receptoropen

Examples of competitive/depolarizing drugs

Competitive

Tubocurarine Mivacurium

Depolarizing

AchEButyrylcholinesteraseSensitive sites

Succinylcholine

Clinical uses

• Adjuvant use in surgical anesthesia (muscular relaxation)

• Advantage – much lighter levels of anesthesia required

• Other uses: muscular relaxation for orthopedics (correction of dislocation/alignment of fractures)

• (short duration) – facilitate intubation, laryngoscopy, bronchoscopy, esophagoscopy

• Control of muscular spasms, strabism, hemifacial spasms, oromandibular and cervical dystonia, spasms of the lower esophageal sphincter

• Cosmetic – Bottox (Botulinum toxin A)

• Paralytic action on skeletal muscle

Agents/Features/Duration

• AGENT CLASS PROPERTY ONSET DURATION Succinylcholine Dicholine ester Depolarization 1 min 5 – 8 min

Tubocurarine Alkaloid Competitive 5 min 80 – 120 min

Atracurium Benzylisoquinoline Competitive 3 min 30 – 60 min

Mivacurium Benzylisoquinoline Competitive 3 min 12 – 18 min

Pancuronium Ammonio Steroid Competitive 5 min 120 – 180 min

Vecuronium Ammonio Steroid Competitive 3 min 60 – 90 min

Hydrolysis by esterases Liver clearance/renal elimination Both

Precautions/Toxicity

• - Prolonged apnea, cardiovascular collapse

Sequence of paralysis : Eye muscles, Jaw, Larynx, limbs and trunk, intercostal muscles and the dyaphragm

- Generally caused by diminished esterase activity, renal malfunction, liver insufficiency, poor circulatory function.

- Special caution in patients with electrolyte imbalance (K+)

- Antidote : Neostigmine/Ephodronium to increase Ach, and atropine to block Ach muscarinic stimulation.

- Malignant hyperthermia – results from a discharge of Ca2+, exacerbated muscular action – tachycardia, hyperthermia, acidosis and rigidity (mutations of RYR1, central core disease) treated with Dantrolene, preservation of respiration

Summary

X

TetrodoxinBatrachotoxin

XHemicholiniumBotulinum toxin

XCurare alkaloidsSnake venom α

XAch

HydrolysisAchE inhibitors

XDantrolene

AchpilocarpineMuscarineBethanecholNeostigmine**Edrophonium**

X

** Indirect

AtropineScopolamineTubocurarineMivacurium

Movie

http://www.youtube.com/watch?v=yd46Hs7pTowNicotine in the brain