Autonomic System Drugs

Nicotinic Agents

Nicotinic receptors are present both at the autonomic ganglia and at the neuromuscular junction.
– The NMJ blockers (muscle relaxants) are either non-depolarizing which directly block the receptor or depolarising, which give persistent stimulation to prevent stimulation of contraction by ACh.

Ganglion Blockers

e.g. Trimethaphan + Mecamylamine

These are competitive antagonists at both the sympathetic and parasympathetic ganglia

– They are rarely used except to lower blood pressure in hypertensive emergency 

Depolarising blockers

e.g. Succinylcholine/Suxamethonium

This is the only depolarising muscle relaxant used today which has a very short duration of action

– It is used in surgery to induce brief paralysis in short surgeries and also to aide intubation 

Side effects
  • Bradycardia + Increased ocular pressure
  • Hyperkalaemia –> due to loss of tissue potassium during depolarization
  • Malignant hyperthermia –> rapid increase in muscle metabolism (seen with gas anaesthetics)
  • Suxamethonium apnoea – this occurs in people who are slow to breakdown the drug. It leads to prolonged inhibition of the NMJ
  • Patients wake up from anaesthesia but their respiratory muscles are paralysed
  • It is a potential emergency as they cannot breathe, so they must be re-intubated.

Non-Depolarising Blockers

e.g. Atracurium + Mivacurium + Vecuronium (suffix = -ium)

They are used in surgery and electroconvulsive therapy to give muscle relaxation

Side effects
  • Histamine release –> hypotension + increased heart rate + bronchospasm

Muscarinic Agonists

Methacholine – Methyl-acetylcholine which gives it selectivity to muscarinic receptors

Bethanecol – This is used to stimulate detrusor muscle activity to prevent urine retention

Pilocarpine – Used to treat open-angle glaucoma as contracts ciliary muscle to improve drainage of aqueous humour, lowering ocular pressure

Cevimeline – Used to treat Sjogren syndrome, as it increases salivation.

Side effects
  • Vomiting
  • Salivation
  • Sweating
  • Bronchoconstriction
  • Low BP
Contraindications
  • Asthma
  • Heart disease
  • Parkinson’s
  • Peptic Ulcer (increase acid secretion)

Muscarinic Antagonists

Atropine – This is used to treat bradycardia in myocardial infarction and to block side effects of cholinergic excess (e.g. overdose of AChE inhibitor)

Scopolamine (hyoscine) – Prevents motion sickness by blocking muscarinic receptors in vestibulum and also used as an anti-spasmodic in the gut (Buscopan)

Ipratropium/Tiotropium – Used in inhalers to produce bronchodilation

Darifenacin – M3 selective antagonist used to relax detrusor muscle to treat stress incontinence

Tropicamide – used in the eye to produce mydriasis (dilation) before ophthalmic exam

Side effects
  • Mydriasis
  • Dry eyes
  • Tachycardia
  • Urine retention
  • High temperature
Contraindications
  • Glaucoma
  • Peptic ulcer
  • GI/urinary tract obstruction (e.g. BPH)

Phosphodiesterase inhibitors

These are indirect parasympathomimetic agents which prolong the action of ACh at the synaptic cleft. They are split into short, medium and long acting.

Short-acting inhibitors

e.g. Edrophonium + Donepezil + Galantamine

These bind non-covalently to inhibit the enzyme, but they have a very short half-life.
– Donepezil is used in Alzheimer’s disease
– Edrophonium is used to diagnose myasthenia gravis –> a positive result is if the patient feels improvement in muscular function after injection 

Medium-acting inhibitors

e.g. Rivastigmine + Neostigmine (suffix = -stigmine)

These transfer a carbamoyl group to AChE which takes longer to hydrolase, prolonging action
– They are used to treat Alzheimer’s disease and myasthenia gravis 

Long-acting inhibitors

e.g. Ecothiopate + Isoflurophate

These are organophosphates that irreversibly inhibit AChE, leading to a very long duration of action 

Side effects
  • Excessive salivation
  • Pupil constriction
  • Urination
  • Respiratory failure

– To reverse the side effects, give Pralidoxime which removes the phosphate group reactivating AChE

ADRENERGIC DRUGS

Sympathomimetics

The direct agonists are split into alpha and beta-agonists which are subdivided into receptor subtypes

i) Direct agonists

Non-selective Alpha agonist – Methoxamine –> Used for Nasal decongestion

A1-agonists – Phenylephrine + Oxymetazoline –> Used for Nasal decongestants

A2-agonists – Clonidine –>  Anti-hypertensive

B1-agonists – Dobutamine –>  Used in acute heart failure

B2-agonists – Salbutamol + Salmeterol –> Used in asthma treatment

B3-agonist – Mirabegron –> Relaxes detrusor in bladder to increase capacity in overactive bladder 

ii) Indirect agonists

Amphetamines

e.g. Amphetamine + Modafinil

These are transported into nerve terminals and exchanged with NA in the vesicle.
– This NA then leaks out of the nerve terminal leading to indirect stimulation.
– Used to treat ADHD and narcolepsy, but also has the effect of reducing appetite 

Adrenergic Antagonists

These can be divided into alpha and beta receptor antagonists. The beta-blockers are used in the cardiovascular system (anti-dysrhythmics + anti-hypertensive) and eye to reduce intraocular pressure.

Non-specific alpha blockers

e.g. Phentolamine + Phenoxybenzamine

These drugs reduce peripheral resistance and blood pressure. They are used to treat pheochromocytoma before surgery as this can lead to massive catecholamine release into the blood.
– Not used to treat hypertension as they lower blood pressure so much they cause a reflex tachycardia

Side effects
  • Postural hypotension
  • Tachycardia
Contraindications
  • Asthma (due to bronchoconstriction)
  • Depression
  • Heart failure

Alpha-1 inhibitors

e.g. Prazosin + Terazosin (suffix= -azosin)

These are specific to the a1 receptor so cause vasodilation decreasing peripheral resistance and BP
– Used to treat hypertension + urinary obstruction due to prostatic hypertrophy
Tamsulosin and Silodosin are preferred for urinary obstruction as they are selective for a1A receptors

Side effects
  • Postural hypotension but no reflex tachycardia

Disulfiram

This inhibits the conversion of dopamine to noradrenaline

– It is used to treat alcoholism as it inhibits alcohol dehydrogenase, which means that any effects of a hangover are felt as soon as you drink alcohol.

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