Autonomic ns pharmacology A35 Autonomic Nervous System Pharmacology



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Autonomic NS Pharmacology A35 ()

Autonomic Nervous System Pharmacology

Cholinergic Agonists 1

Direct acting cholinergic agonists 2

Anticholinesterases (s. indirect acting cholinergic agonists) 4

Reversible 4

Irreversible 5

Cholinergic Antagonists (s. anticholinergics) 7

Antimuscarinic agents 7

Ganglionic blockers 10

Adrenergic agonists (s. sympathomimetics) 11

Direct-acting adrenergic agonists 12

Catecholamines 12

α1-Agonists 15

β2-Agonists 16

Central α2-agonists 17

Indirect-acting adrenergic agonists 17

Mixed action (direct & indirect) adrenergic agonists 22



Adrenergic antagonists (s. adrenoblockers, sympatholytics) 23

β-Adrenergic blockers 23

α1-Adrenergic blockers 25

α1,2 -Adrenergic blockers 26

α1 and β1,2 -Adrenergic blockers 26

other antiadrenergics 27



Drugs that produce therapeutic effect by mimicking / altering functions of autonomic nervous system are called autonomic drugs.

Cholinergic Agonists



General effects of cholinergic stimulation / intoxication:

Muscarinic effects:

  1. Salivation & sweating & lacrimation

  2. Miosis, accommodation spasm (blurred vision)

  3. Flushing, BP↓, bradycardia

  4. Bronchospasm & bronchorrhea, rhinorrhea

  5. Abdominal pain, nausea, vomiting, diarrhea, fecal incontinence

  6. Urinary urgency & incontinence

N.B. atropine is antidote!

Nicotinic effects:

  1. Skeletal muscle fasciculations → paralysis (due to prolonged nicotinic action) (breathing difficulty, etc).

  2. Pallor, tachycardia, BP↑

CNS effects (if agent can enter CNS) – mimics alcohol intoxication:

  1. Agitation, headache, drowsiness, confusion, ataxia, delirium

  2. Convulsions

  3. Coma

Direct acting cholinergic agonists

- directly bind to cholinoreceptors.

In general, little specificity to N or M receptors – limited clinical usefulness!

Acetylcholineno therapeutic application:


  1. very shortly acting (rapid inactivation by acetylcholinesterase)

  2. quaternary ammonium compound – cannot penetrate membranes (active only i/v)

  3. multiplicity of actions

  • Acch i/v → cardiodepression, vasodilation (→ brief BP↓) → sympathetic ganglia & adrenomedullary stimulation → BP↑.

  • may be used as myotic in cataract surgery.

Bethanechol (synthetic ester of choline – resist hydrolysis by acetylcholinesterase, but slowly hydrolysed by other esterases)

  • muscarinic agent - strongly binds to M receptors, almost no nicotinic activity:

  1. intestinal motility & tone↑

  2. expulsion of urine

  • duration of action ≈ 1 hour.

  • clinical application:

  1. stimulation of atonic urinary bladder (i.e. nonobstructive retention - postpartum, post operation, etc).

  2. esophageal reflux disease

Carbachol (synthetic ester of choline – resist hydrolysis by acetylcholinesterase, but slowly hydrolysed by other esterases)

  • has both – muscarinic and nicotinic (ganglionic) – actions.

  • duration of action ≈ 1 hour.

  • clinical applicationeye drops to produce miosis and decrease intraocular pressure.

Pilocarpine (natural alkaloid, tertiary amine, stable to hydrolysis by acetylcholinesterase)

  • preferentially binds to M receptors (muscarinic agent).

  • far less potent than other agents.

  • clinical application:

    1. eye drops to produce miosis, emergency (!) lowering intraocular pressure (drug extremely effectively opens Schlemm canal; effect lasts up to 24 hours)

    2. burnos skalavimas sukelti seilių išsiskyrimą.

Methacholine

  • pure muscarinic agent.

  • clinical application:

    1. vasodilator in peripheral vascular disease

    2. inducing hyperemia (locally by iontophoresis) in arthritis

    3. inducing bronchospasm during PFTs - bronchial asthma diagnosis

Cevimeline (Evoxac) - indicated for treatment of dry mouth in Sjögren’s syndrome.

Anticholinesterases (s. indirect acting cholinergic agonists)

- prolong lifetime of acetylcholine (→ stimulation of N & M cholinoreceptors).

Reversible



  • act as substrate for acetylcholinesterase, and form relatively stable enzyme-substrate intermediate.

Physostigmine (tertiary amine, alkaloid)

  • duration of action 2-4 hours.

  • well absorbed from GI tract; can enter (and stimulate) CNS.

  • indications:

    1. intestinal / bladder atony

    2. producing miosis and lowering intraocular pressure (pilocarpine is more effective!)

    3. overdosage of anticholinergics (e.g. atropine, phenothiazines, tricyclic antidepressants).

  • precautions, contraindications – see below (anticholinergic poisoning).

Neostigmine (synthetic quaternary amine)

  • duration of action 2-4 hours.

  • more polar molecule – not well absorbed orally, does not enter CNS.

  • effects on skeletal muscles (greater than that of physostigmine; because of additional direct nicotinic stimulation) – indications:

  1. curare antidote

  2. myasthenia gravis treatment

Pyridostigmine

  • neostigmine; duration of action 3-6 hours (more suitable in chronic treatment of myasthenia gravis).

Edrophonium (Tensilon®)

  • neostigmine; duration of action 10-20 min (used in diagnosis of myasthenia gravis, or as curare antidote).

Newer centrally acting agents (tacrine, donepezil, galanthamine, rivastigmine) – used in treatment of Alzheimer disease (žr. S11 p.)

Irreversible



- covalently bind to acetylcholinesterase & pseudocholinesterase.

  • enzyme molecule is inactivated (activity restoration requires synthesis of new enzyme molecules); “aging” – inactivated enzyme molecule slowly releases alkyl group and so becomes permanently inactivated (impossible to reactivate).


cholinergic poisonings


organophosphates

  • extremely toxic synthetic agents:

  1. military nerve agents (convulsions, breathing muscle paralysis); newer military agents “age” in minutes ÷ seconds.

  2. insecticides (e.g. parathion, chlorpyrifos, diazinon, malathion, trichlorofon)

  • readily absorbed (even through intact skin).

  • some are lipid soluble (accumulate).

  • clinical features – general cholinergic effects (muscarinic + nicotinic + CNS);

    • toxicity manifests when > 50% acetylcholinesterase is inactivated.

    • garlic-like / petroleum-like odor in patient’s breath.

    • 1-3 weeks after initial exposure, organophosphate-induced delayed polyneuropathy (OPIDP) may develop - distal dying back axonopathy - cramping muscle pain in legs, paresthesias, motor weakness (e.g. foot drop, weakness of intrinsic hand muscles, absent ankle jerk, weakness of hip and knee flexors).

  • confirmatory diagnosis:

  1. erythrocyte (true) cholinesterase – gold standard (reflects enzyme activity in neural tissues) – below 70% of normal.

  2. plasma (pseudo) cholinesterase – levels affected by many other conditions.

  3. urine screen for metabolites.

  • treatment:

  1. ABC Do not use morphine, aminophylline!

  2. benzodiazepines for seizures

  3. decontamination (avoid self-contamination - wear protective clothing, masks, gloves!) – gastric lavage with charcoal, skin flushing with water and soap.

  4. antidotes:

atropine in high doses (1-2 mg IM q1h) can reverse many muscarinic and CNS effects.

        • tachycardia is not contraindication.

        • end point for atropine administration is drying of bronchial secretions.

Acetylcholinesterase reactivationpralidoxime (PAM) 1 g IV:

        • effective only if given before “aging” (but late presentation does not preclude administration).

        • acts at nicotinic receptors; cannot reverse CNS effects (drug molecule has charged group).



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