ANS Pharmacology - French Flashcards
Agonists -
Antagonists -
Other -
Where to the most clinically useful drugs act?
Agonists - mimic the neurotransmitter action at the receptor
Antagonists - block the neurotransmitter action at the receptor
Changing the normal action of the neurotransmitter (decrease synthesis, increase/decrease release, block inactivation)
The most clinically useful drugs act POST SYNAPTICALLY at the receptor as agonist or antagonist.
- List the players involved in the synthesis, storage, release and inactivation of acetylcholine, and drugs that affect these processes (synthesis, storage, release, degradation).
Synthesis - choline uptake (rate limiting, Na dependent) blocked by hemicholine. CAT (Choline Acetyltransferase) produces AcH
Storage - put into vesicles by VAT, blocked by vesamicol.
Release - Ca influx triggers release. blocked by Botulinum toxin, increased by black widow toxin
Ach degradation by cholinesterase. Blocked by pyridostigmine, neostigmine, edrophonium.
- For cholinergic receptors:
a) list the locations of and the differences between nicotinic and muscarinic cholinergic receptors;
b) describe the signal transduction mechanisms activated by stimulation of nicotinic versus muscarinic cholinergic receptors
c) state the significance of presynaptic versus postsynaptic cholinergic receptors.
a)
b) Nicotinic = ionotropic (ligand-gated ion channels) Muscarinic = G protein-coupled
c)
Name 3 muscarinic cholinergic agonists. Which are absorbed into the CNS?
Bethanechol, methacholine (choline esters) - Basically these drugs are resistant to degradation by acetylcholinesterase due to the addition of an acetyl/carbamyl group which vastly increases the duration. Do not distribute well to CNS.
Pilocarpine (alkaloid) - is a naturally occurring alkaloid that is lipid soluble and distributes into the CNS. Specific for muscarinic receptors. No info on clinical usage given.
- For acetylcholinesterase inhibitors (indirect agonists):
a) name 3 drugs and their categories/mode of action
b) why are both Muscarinic and Nicotinic receptors affected by these drugs?
a) Short (ionic) - Edrophonium
Intermediate (covalent) - Carbamates (Neostigmine, Phyostigmine)
Long (phosphorylation) - Organophosphates (Isofluorophate [nerve gas])
b) Notes don’t say this, but I’m assuming you just increase Ach levels in the synapse, and both nicotinic and muscarinic receptors are present.
- Describe adrenergic neurotransmission (neurotransmitter synthesis, storage, release, inactivation, interaction with receptors, and signal transduction mechanisms) that represent targets for adrenergic and antiadrenergic drug action.
Synthesis: Tyrosine converted to DOPA by tyrosine hydroxylase (rate limiting step - inhibited by metyrosine). DOPA converted to dopamine (inhibited by carbidopa, used in parkinsons treatment)
Storage: dopamine uptake by VMAT and conversion to NE by DβH. In the adrenal medulla, NE –> Epinephrine. Vesicles protect from MAO (monoamine oxidase).
Inactivation: reuptake into presynaptic terminal by NET (norepinephrine transporter). Cocaine, tricyclic antidepressants target (block) NET. Amphetamines and pseudoephedrine reverse the NET transporter.
- For adrenergic antagonist drugs: a) compare the modes of action of sympatholytic agents vs receptor blocking agents with respect to selectivity of action and overall clinical utility, and b) describe how an agonist of α2 adrenergic receptors can have antagonistic effects on the SNS.
a) sympatholytic agents are nonselective (all adrenergic synapses are affected) which greatly limits their clinical utility. Receptor antagonists can be targeted much more specifically (eg beta-blockers, etc) b) Stimulation of presynaptic α2 receptors –> decreases NE release from sympathetic neurons (agonist creating an antagonistic effect)
Cholinergic Agonists: also known as ____ or _____.
aka parasympathomimetics or cholinomimetics
**These can be direct acting (on the postsynaptic receptor) or indirect (eg acetylcholinesterase inhibitors)
Cholinergic Antagonists also known as:
- At parasympathetic end organs known as ____ or ____
- At the neuromuscular junction (NMJ) known as ____
- At the autonomic ganglia known as _____
At the parasympathetic end organs known as antimuscarinic agents or parasympatholytics (Greatest clinical utility - thus antimuscarinic often used synonymously with anticholinergic)
At the neuromuscular junction (NMJ) known as neuromuscular blockers
At the autonomic ganglia known as ganglionic blockers (not clinically available anymore)
Adrenergic Agonists: are also known as ____ or _____.
sympathomimetics or adrenomimetics
NE binds α1 receptors–>
Gq protein activates PLC –>formation of IP3 (releases intracellular Ca++) and DAG (activates PKC)
NE binds α2 receptors–>
Gi protein inhibits AC –> decrease cAMP levels or opens K+ channels (hyperpolarization) - couples to Go to decrease Ca++ movement through L- and N- type channels
NE binds β1 and β2 receptors–>
Gs protein that stimulates adenylyl cyclase –> increased cAMP synthesis. cAMP is the second messenger that activates protein kinase A catalytic activity. Stimulation of β1 adrenoreceptors also increases Ca++ movement through L-type Ca++ channels.
What does “catechol” mean (as in “catecholamines”)?
Presence of 3,4 -OH group on the phenyl ring.
ie Ephinephrine, norepinephrine, and dopamine all have 3,4 -OH groups, so are termed “catecholamines”
Ephedrine, amphetamine do not
Describe the pharmacokinetics of the adrenergic agonists. What factors influence CNS absorption? What factors influence liver metabolism (first pass)? What affects oral effectiveness?
Non-catecholes have INcreases oral effectiveness (due to avoidance of 1st pass liver metabolism) and INcreases CNS uptake due to hydrophobic nature (ephedrine, amphetamine)
A methyl group on the alpha carbon protects from degradation by MAO (ephedrine, amphetamine).
**Ephedrine and amphetamine meet ALL these criteria! This separates them from NE, E on oral solubility, metabolism, and CNS uptake.
What are 3 enzymes in catecholamine synthesis that can be blocked by adrenergic antagonists? What drugs block each of these enzymes, and what conditions might each be used to treat?
Metyrosine - inhibits tyrosine hydroxylase (pheochromocytoma)
α-methyldopa (antihypertensive), carbidopa (parkinsons adjunct) - inhibit L-DOPA decarboxylase
Disulfiram - inhibit dopamine β-hydroxylase
Tryosine–(TH)–>L Dopa–(dopa decarb.)–>Dopamine–(DBH)–>NE
