Drugs That Affect Neurotransmission

• Drugs that affect the cholinergic system
• Direct agonists
• ACh – stimulates both nicotinic and muscarinic receptors
• Carbachol – stimulates both nicotinic and muscarinic receptors, miotic
• Bethanechol and Methacholine – stimulate muscarinic receptors, evacuate bladder
• Arecholine – stimulates both nicotinic and muscarinic receptors, alkaloid
• Pilocarpine – stimulates muscarinic receptors, miotic
• Indirect agonists (inhibit AChE)
• Physostigmine – glaucoma
• Neostigmine – myasthenia gravis
• Pyridostigmine (Mestinon) – MG
• Parathion, Mlalthion – pesticides
• Edrophonium (Tensilon) – tests for MG (competaive inhibitor)
• Muscarinic antagonists
• Atropine
• Scopolamine
• Trihexylphenidyl (Artane) – Parkinsons
• Benztropine (Cogentin) – Parkinsons
• Neuromuscular blockade (NMJ nicotinic antagonists)
• Depolarizing – succinylcholine
• Non-depolarizing – curare, vecuronium
• Drugs that affect the adrenergic system
• Norepinepherine (NE)
• Excitatory neurotransmitter
• Found at the postsynaptic sympathetic synapse and throughout the brain
• Made from phenylalanine
• Rate-limiting step is conversion of tyrosine to DOPA by tyrosine hydroxylase
• NE receptors
• a1 – constriction (vasoconstriction, radial muscle of the iris)
• a2 – presynaptic inhibition  (decreases sympathetic outflow form the CNS)
• b1 – increase heart rate, inotrope
• b2 – muscle relaxation (bronchioles, skeletal muscle)
• Catecholamines (agonists)
• Epinephrine – a1>b2, used for anaphylaxis
• Norepinephrine – a>b1>>b2, used to increase SVR
• Isoproterenol – b agonist
• Dobutamine – b1 agonist, increase HR, contractility
• Dopamine – D>b>a
• Non-catecholamine agonists
• Phenylepherine – a1, increases SVR (reflex bradycardia)
• Metaproterenol – b2 agonist, bronchiodilation
• Indirect NE agonist
• Amphetamine – releases NE from presynaptic terminals
• Cocaine – prevents reuptake
• a2 agoinists (decrease sympathetic outflow, decrease BP)
• Clonidine, Guanabenz, Aldomet
• a antagonists
• Phenoxybenzamine – irreversible, noncompetitive
• Phentolamine – reversible, competitive
• Non-specific NE antagonists
• Guanethidine – decreases NE release
• Bretylium – decreases NE release
• Reserpine – depletes presynaptic vesibles
• Specific NE receptor subtype antagonists
• Anti-a1 – Prozasin, Terazosin
• Anti-b – Propranolol, nadolol, timolol, pindolol
• Anti-b1 – Metoprolol, Atenolol, Esmolol
• Anti-a,b – Labetolol
• GABAergic System
• GABA-
• Inhibitory action by increasing Cl^- permeability
• Receptor has 5 subunits (a₂b₂ and g or d), blocked by picrotoxin (causes seizures)
• GABA receptors
• GABA-A receptor
• a binds GABA, benzodiazepines, and barbitautes (agonists)
• b binds GABA
• GABA-B receptor
• a binds GABA and baclofen (agonists)
• Glycine
• Cl^- channel, binds to strychnine (causes rigidity); Renshaw cells of spinal cord
• Glutamatergic System
• Most common excitatory neurotransmitter in the CNS
• Receptors
• All are ion channels with 4 transmembrane domains
• NMDA – associated with cell death
• Voltage – and ligand-gated
• Depolarization removed Mg⁺⁺ blockade, allowing further activation to open the channel when glutamate is present
• Permits Na⁺ and Ca⁺⁺ movement
• Requires glycine co-activation
• AMPA/quisqualate, kainite receptors permeable to monovalent cations
• Metabotropic receptors linked to second messenger systems
• Dopaminergic System
• Many different subtypes of receptors
• D1 – activates adenylate cyclase (cAMP) through a G-protein
• D2 – inhibits adenylate cyclase through a G-protein, inhibits IP₃ turnover