ANS neuropharmacology Flashcards
Main mechanisms by which drugs act on the nervous system
Mimicking the neurotransmitter action (Agonist at the receptor level), Blocking the neurotransmitter action (antagonist at the receptor level), or change normal action of transmitter indirectly (ie. Change synthesis, storage, releaseor block inactivation)
Which drugs are most selective
drugs that act post synaptically are most selective and thus have highest clinical utility
- List the steps in the synthesis, storage acetylcholine, and drugs that affect these processes.
Synthesis/storage: Choline taken up by cell (rate limiting step, blocked by hemicholinium) >choline acetyl transferase catalyzes > Ach stored in vesicles by transporter (inhibited by vesamicol)
- List the steps in the release of acetylcholine, and drugs that affect these processes.
Spontaeous release occurs continuously (leakage via choline carrier). Stimulation-evoked quantal release depends on action potential and on influx of Ca++ (Blocked by botulinum toxin, Increased by black widow spider toxin). Release also decreased by NE interaction with a2 adrenergic heteroreceptor on pressynaptic terminal
- List the steps in the inactivation of acetylcholine, and drugs that affect these processes.
Hydrolysis of Ach by acetylcholinesterase inactivates Ach. (Cholinesterase inhibitor drugs act as indirect agonists, by blocking breakdown of Ach). Redistribution not important. Butyrylcholinesterase is a pseudo cholinesterase that hydrolyzes longer chain esters
- For cholinergic receptors: a. List the locations of and the differences between nicotinic and muscarinic cholinergic receptors
nicotinic: ligand gated ion channels. Muscarinic: G protein coupled receptors
- For cholinergic receptors: b. Describe the signal transduction mechanisms activated by stimulation of nicotinic versus muscarinic cholinergic receptors
Nicotinic: Alterations in ionic permeability (increased Na+ - Ca++ ion conductance). Muscarinic: Alterations in enzyme activity • Gq activates phospholipase C [M1: neuronal (CNS and ENS) / GI glands, M3: exocrine glands / smooth muscle] • Gi inhibits adenylyl cyclase [M2, M4: heart, lungs, CNS])
What general effect do cholinergic agonists have?
Agonists: Produce the same effect as ACh at muscarinic receptors on parasympathetic end organs. Direct agonists activat muscarinic receptor, while indirect agonists inhibit cholinesterase activation
What general effect do cholinergic antagonists have?
Block effects of ACh at cholinergic receptors at various anatomic locations, including parasympathetic end organs (antimuscarinic or anticholinergic agents), at the NMJ (neuromuscular blockers) or at autonomic ganglia (ganglionic blockers)
What general effect do adrenergic agonists have?
Produce the same effect as NE and Epi at α- and β-adrenergic receptors on sympathetic end organs. Direct agonists activate adrenergic receptors, indirect agonists increase NE release
What general effect do adrenergic antagonists have?
Block effects of NE and Epi at α- and β-adrenergic receptors on sympathetic end organs.
What general effect do sympatholytic agents have?
Interference with adrenergic function in the presynaptic neuron via block of synthesis, storage or release
List direct acting muscarinic receptor agonists
Bethanechol (choline ester): synthetic analog of Ach with selectivity for muscarinic receptor and resistant to ACHE. Pilocarpine (parasympathomimetic alkaloid): selectivity for muscarinic and not a substrate for ACHE
Pharmacokinetics of direct acting muscarinic agonists
Bethanechol: low lipid solubility (poor absorption/distribution into CNS), increased duration of action. Pilocarpine: lipid soluble (well absorbed), excreted by kidneys (is a weak base, so excretion increases with acidic urine)
List 3 categories of indirect cholinergic agonists, inlcuding examples and the nature of the inhibitors interaction with ACHE
- Reversible, short acting (Edrophonium-donepezil): binds to anionic site, forming reversible ionic bond. 2. Reversible, intermediate to long acting (Neostigmine-Physostigmine): Forms carbamyl-serine-enzyme bond at anionic site that is hydrolyzed slowly. 3. Irreversible, very long acting (Isofluorphate-nerve gas): Does not bind anionic site, covalently transfers phosphate group to serine and phosphorylated enzyme does not undergo hydrolysis.
Acetylcholinesterase inhibitors action
By blocking cholinesterase, ACH accumulates in the synapse and exerts increased effects at both muscarinic and nicotinic receptrs
Anticholinesterase inhibitors pharmacokinetics- absorption
Physostigmine: Well absorbed; distributed to CNS Quaternary carbamates (e.g., neostigmine): Absorption from conjunctiva, skin, lungs is poor; neglible penetration into CNS. Organophosphates: Well absorbed from skin, lung, gut, and conjunctiva; very lipid-soluble,nreach CNS; malathion rapidly metabolized to inactive products in mammals (not parathion)Physostigmine: Well absorbed; distributed to CNS Quaternary carbamates (e.g., neostigmine): Absorption from conjunctiva, skin, lungs is poor; neglible penetration into CNS. Organophosphates: Well absorbed from skin, lung, gut, and conjunctiva; very lipid-soluble,nreach CNS; malathion rapidly metabolized to inactive products in mammals (not parathion)
List the categories of anticholinergic drugs and examples
1.antimuscarinic: M1 selective (pirenzepine) or nonselective (atropine). 2. Antinicotinic: ganglion blockers (hexamethonium) or neuromuscular blockers (tubocurarine). 3. Cholinesterase regenerators: oximes (pralidoxime)
Antimuscarinic agents MOA
Reversible, competitive inhibitors of muscarinic receptors. Has greatest clinical utility (often just called anticholinergic agents). May have partially selective effects: M1 (CNS, gastric parietal, sympathetic postganglionic cells), M2 (cardiac cells) or M3 (smooth muscle organs/glands)
Name specific muscarinic antagonists and how they are classified
Atropine and Scopolamine are alkaloids (tertiary amines) with high affinity and specificity for muscarinic receptors. Examples of semisynthetic agents include propantheline (a quaternary ammonium with greater effect on GI activity), oxybutynin and Tolderodine (a tertiary amine which exert actions on CNS)
Pharmacokinetics of antimuscarinic agents -absorption and elimination
Tertiary amines are well absorbed by GI and conjuctiva, distribute rapidly in CNS, and are eliminated by hepatic metabolism and renal excretion. Quaternary compounds have poor oral absorption, excreted unchange in urine
Structure of catecholamines
dopamine, norepinephrine, epinephrine have a phenylethylamine nucleus and catechol hydroxyl. Catecholamines plus indoleamine 5-hydroxytryptamine (serotonin) are known as monoamines or “biogenic” amines.
Synthesis of norepinephrine and inhibitors
Tyrosine > dihydroxyphenylalanine (DOPA- by tyrosine hydroxylase)(rate limiting- inhibited by metyrosine) > dopamine (by L-aromatic amino acid decarboxylase) (inhibited by α-methyl dopa and carbidopa) > taken up by vesicle then converted to NE by dopamine B hydroxylase > converted to epinephrine by phenylethanolamine N methyl transferase (adrenal gland and some CNSneurons)
Storage/release of Norepinephrine
VMAT pump transports NE, dopamine or epi into vesicle in adrenergic nerve endings and adrenal medulla. This protects from degradation by monoamine oxidases. Catecholamines are released when nerve stimulation causes Ca influx (blocked by bretylium)
