Autonomic Pharmacology

Autonomic Pharmacology

• The autonomic nervous system (ANS) consists of the parasympathetic and sympathetic systems

Parasympathetic System

• Known as the "rest and digest" system

Sympathetic System

• Known as the "fight or flight" system

Adrenergic System

• Adrenergics target the sympathetic nervous system (SNS)

Adrenergic Receptors

• α1 receptors cause vasoconstriction, bladder sphincter contraction, pupil dilation (mydriasis), and are involved in glycogenolysis
• α2 receptors reduce intraocular pressure (IOP) and salivary gland activity
• β1 receptors increase heart rate and aqueous humor production
• β2 receptors cause bronchodilation, increased mucociliary clearance, glycogenolysis (short-term), insulin release (long-term), and uterus relaxation
• β3 receptors relax the bladder detrusor muscle and increase lipolysis

Direct Adrenergic Agents

Non-Selective Adrenergic Agents

• Adrenaline is used for cardiac arrest and anaphylactic shock
• Norepinephrine is used for severe hypotension, increasing blood pressure without significantly raising heart rate

Weird Selective Adrenergic Agents

• Dopamine is used for cardiac arrest and hypotension, and also increases diuresis

Adverse Effects of Adrenergic Agents

• Hypertension
• Necrosis due to excessive vasoconstriction at the injection site
• Tachycardia
• Reflex bradycardia
• Ventricular arrhythmias

α Selective Adrenergic Agents

• Oxymetazoline is used for nasal congestion
• Phenylephrine is used for hypotension and nasal congestion
• Brimonidine is used for open-angle glaucoma and is neuroprotective

β Selective Adrenergic Agents

• Isoprenaline is used for asthma and cardiac arrest
• Dobutamine is used for congestive heart failure
• Salbutamol/Terbutaline are used for asthma and premature labor
• Mirabegron is used for overactive bladder

Indirect Adrenergic Effects

• Neurotransmitters are stored in vesicles, released into the synaptic cleft, taken back up by transporters into the presynaptic neuron, and broken down by MAO

Moclobemide

• A MAOA inhibitor used as an antidepressant
• Prevents the breakdown of norepinephrine, increasing its levels in the synaptic cleft and exerting CNS effects

Tricyclic Antidepressants

• Block the reuptake of norepinephrine into the presynaptic neuron
• This prolongs its presence in the synaptic cleft and exerts CNS effects

Pseudoephedrine

• Used as a nasal decongestant
• Taken into the presynaptic neuron and displaces norepinephrine from vesicles
• This allows norepinephrine to exit the vesicle into the synaptic cleft, increasing its levels

Direct Antiadrenergic Agents

α Selective Antiadrenergic Agents

• Phenoxybenzamine is used in the treatment of pheochromocytoma
• This is a tumor that releases excessive amounts of norepinephrine and adrenaline, causing complications like hypertension
• Phenoxybenzamine binds to α adrenoceptors to produce a temporary blockade
• "axosin"s like prazosin are used for hypertension and urinary symptoms of benign prostatic hyperplasia

β Selective Antiadrenergic Agents

• Propranolol is used for hypertension, angina, arrhythmias, myocardial infarction, and excessive catecholamine action in hyperthyroidism
• Sotalol is used for arrhythmias
• Timolol is used for glaucoma
• Bisoprolol is used for hypertension, angina, and myocardial infarction
• Betaxolol is used for glaucoma

Indirect Antiadrenergic Agents

• Dexmedetomidine is a sedative
• It binds to α2 adrenoceptors in the presynaptic neuron, decreasing norepinephrine release into the synaptic cleft
• This leads to a reduction in vasoconstriction and increased CNS effects like sedation

Methyldopa

• Used for hypertension
• Inhibits tyrosine hydroxylase, leading to the formation of false transmitter methylnoradrenaline instead of norepinephrine
• This reduces vasoconstriction and increases effects such as sedation
• Can cause adverse effects like hemolytic anemia and hepatotoxicity

Cholinergics

• Cholinergics target the parasympathetic nervous system (PNS)

Cholinergic Receptors

• M1 receptors are located in the stomach and CNS
• M2 receptors are located in the heart and CNS
• M3 receptors are located in the lungs, glands, GI tract, and CNS, causing contractions and secretions
• Note: M3 receptors include eccrine sweat glands, which are controlled by the SNS
• M4 and M5 receptors are located in the CNS
• Nm (N1) receptors are located in skeletal muscle
• Nn (N2) receptors are located in the ganglion and CNS

Direct Cholinergic Agents

Non-Selective Cholinergic Agents

• Acetylcholine has no clinical uses as it is broken down by acetylcholinesterase

m Selective Cholinergic Agents

• Pilocarpine is used for glaucoma and dry mouth (xerostomia)
• Bethanechol is used for gastric atony and urinary retention

n Selective Cholinergic Agents

• Nicotine is used to aid smoking cessation
• Varenicline is also used to aid smoking cessation, but may cause psychiatric symptoms

Indirect Cholinergic Drugs

• Act on nicotinic receptors in the postganglionic neuron in the PNS

Physostigmine

• Used for atropine poisoning
• Crosses the blood-brain barrier (BBB) and has both CNS and peripheral effects

Neostigmine

• Used for myasthenia gravis and reversal of non-depolarizing neuromuscular blockade
• Does not cross the BBB and is selective for peripheral effects

Donepezil

• Used for Alzheimer’s disease
• Crosses the BBB readily and is selective for CNS effects

Sarin

• Causes poisoning
• It is an organophosphate and a suicide inhibitor of acetylcholinesterase (AChE)
• Can be treated with pralidoxime, which binds with higher affinity to phosphate in organophosphate and regenerates cholinesterase
• Does not work after "aging" occurs (further chemical changes that make inhibition irreversible)