Overview- Indirect cholinergic agonism (AchE inhibition)

- Muscarinic antagonism (emphasis on drugs and organ effects)

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

Indirect cholinergic agonistsInhibitors 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 parasympatheticUSESApprox DurationALCOHOLS

Edrophonium Myasthenia gravis5 15 minutesarrythmias

CARBAMATES

NeostigmineMyasthenia gravis0.5 2hPyridostigmineMyasthenia gravis3 6hPhysostigmineGlaucoma0.5 2hDemecarium Glaucoma4 6h

Organophosphates

EchotiophateGlaucoma100 h (> 4 days)

Treatment of organophosphate poisoning1 - 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 antagonismAttropa belladona

Muscarinic AntagonistsATROPINESCOPOLAMINE

Muscarinic AntagonistsATROPINESCOPOLAMINEAttropa 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 actionCompetitively 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/sourcesAtropa belladona - used in the renaissanceDeadly 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 reviewAntidotesORGAN DRUGAPPLICATIONCNS Benztropine Treat Parkinsons disease Scopolamine Prevent/Reduce motion sickness

Eye Atropine Pupil dilation

Bronchi IpatropiumBronchodilate in Asthma, COPD

GI MethscopolamineReduce motility/crampsGU OxybutininTreat transient cystitisPostoperative bladder spasms

Toxicity of muscarinic antagonistsDRY 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/depolarizingCompetitivePhysically blocks Ach bindingINHIBITOR

Examples of competitive/depolarizing drugsCompetitiveTubocurarineMivacuriumDepolarizingAchEButyrylcholinesteraseSensitive sitesSuccinylcholine

Clinical usesAdjuvant 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/DurationAGENT CLASS PROPERTY ONSET DURATION Succinylcholine Dicholine ester Depolarization 1 min 5 8 min

Tubocurarine Alkaloid Competitive 5 min 80 120 min

Atracurium BenzylisoquinolineCompetitive 3 min 30 60 min

Mivacurium Benzylisoquinoline Competitive 3 min 12 18 min

Pancuronium Ammonio SteroidCompetitive 5 min 120 180 min

Vecuronium Ammonio SteroidCompetitive 3 min 60 90 min

Hydrolysis by esterasesLiver clearance/renal eliminationBoth

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

SummaryXTetrodoxinBatrachotoxinXHemicholiniumBotulinum toxinXCurare alkaloidsSnake venom XAchHydrolysisAchE inhibitorsXDantroleneAchpilocarpineMuscarineBethanecholNeostigmine**Edrophonium**

X** IndirectAtropineScopolamineTubocurarineMivacurium

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