Autonomic Nervous System Neuropharmacology Flashcards Preview

Nervous System: Unit I > Autonomic Nervous System Neuropharmacology > Flashcards

Flashcards in Autonomic Nervous System Neuropharmacology Deck (27)
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1
Q

Common mechanisms of drug action @ ANS (3)

A
  • Mimicking the neurotransmitter action (generally at the receptor level): Agonists
  • Blocking the neurotransmitter action (generally at the receptor level): Antagonists
  • Changing the normal action of the neurotransmitter (indirect action) by altering:
    • Synthesis of the neurotransmitter (increase or decrease)
    • Storage and release of the neurotransmitter (increase or decrease)
    • Inactivation of the neurotransmitter following release (block of inactivation)
2
Q

Effectiveness of drugs w/presynaptic vs. post-synaptic actions

A
  • post-synaptic actions (@ specific receptors) >> presynaptic actions b/c of greater selectivitiy
  • presynaptic = alter synthesis, storage, or release
    • less usefull b/c affect all synapses regardless of postsynaptic receptor subtybe
  • agonists & antagonists = most clinically usefull drugs
3
Q

Mechanism of ACh synthesis & storage (+drugs that impact these processes)

A
  1. Choline is taken up by an active transport system dependent on Na+ and blocked by hemicholinium (rate-limiting step)
  2. Catalyzed by choline acetyl transferase [ChAT] (marker for cholinergic neurons)
  3. ACh is stored within vesicles by a second transporter that is inhibited by vesamicol
4
Q

Mechanism of ACh release (+drugs that impact these processes)

A
  1. Spontaneous release occurs continuously (leakage via choline carrier)
  2. Stimulation-evoked quantal release depends on action potential and on influx of Ca++
    1. Blocked by botulinum toxin
    2. Increased by black widow spider toxin
  3. Presynaptic receptors; e.g. NE @ α2-adrenergic heteroreceptor ==> decreased ACh release
5
Q

Mechanism of inactivation of ACh (+ drugs that impact this process)

A
  • hydrolysis catalyzed by acetylcholinesterase (AChE)
    • ACh ==> choline + acetate
  • AChE localized @ synpase + located on postsynaptic membrane
  • Cholinesterase inhibitors ==> indirect agonists
  • Mechanism of AChE?
6
Q

Classes of cholinergic receptors (types & families)

A
  • Nicotinic = ligand-gated ion channels
  • Muscarinic = G-protein coupled receptors
7
Q

Consequences of ACh stimulation of cholinergic receptors

A
  • Nicotinic: alterations of ionic permeability
    • increased Na+- Ca2+ ion conductance
  • Muscarinic: alterations in enzyme activity
    • Gq ==> increased phospholipase C
      • M1: neuronal (CNS and ENS)/GI glands
      • M3: exocrine glands / smooth muscle
    • Gi ==> decreased adenylyl cyclase [M2, M4: heart, lungs, CNS])
8
Q

Choline esters mechanism & examples

A
  • direct-acting muscarinic agonists
  • acteylcholine: not used
  • bethanechol: synthetic analog of acetylcholine
      • methyl group to choline ==> increased selectivity for muscarinic
    • replace acetyl w/carbamyl group ==> increased resistance to AChE
9
Q

Classes of direct-acting muscarinic receptor agonists

A
  • choline esters
  • parasympathomimetic alkaloids
10
Q

Choline esters pharmacokinetics

A
  • low lipid solubility
  • poor oral absorbtion
  • poor distribution to CNS
11
Q

Parasympathomimetic alkaloids mechanism + examples + pharmacokinetics

A
  • MOA: Direct-acting muscarinic agonists
  • e.g. Pilocarpine
  • PK:
    • lipid soluble ==> well absorbed; distributes to CNS
    • not susceptible to AChE
    • renal excretion
12
Q

Nicotine MOA + effects

A
  • MOA: Direct-acting nicotinic neuronal (ganglionic) receptor agonist
  • Causes stimulation at low doses (i.e. cigarette smoking) as _agonist _
    • CV: Increases in BP, HR, vasoconstriction via EPI released from adrenal gland activating SNS
  • Increased GI motility  via ganglionic stimulation (ACh) of PNS end organs
  • CNS: Euphoria, arousal, relaxation, increased attention / learning
13
Q

Indirect-acting cholinergic drugs MOA + categories

A
  • = cholinesterase inhibitors ==> prevent ACh breakdown ==> increased ACh/effects @ cholinergic receptors
  • categories:
    • reversible interaction w/AChE, short-acting (Edrophonium)
    • reversible interaction, intermediate/long-acting (Neostigmine; Physostigmine)
    • irreversible, very long acting (Isofluorophate; Nerve Gase)
14
Q

Edrophonium MOA

A
  • indirect cholinergic = cholinesterase inhibitor
  • reversible interaction w/AChE: ionic bond that is readily broken
15
Q

Neostigmine/Physostigmine MOA

A
  • indirect cholinergic = cholinesterase inhibitor
  • reversible interaction w/AChE:
    • covalent transfer of carbamyl
    • carbamyl-serine-enzyme hydrolyzed slowly (minutes)
16
Q

Isofluorophate/Nerve Gas MOA

A
  • indirect cholinergic = cholinesterase inhibitor
  • irreversible interaction w/AChE:
    • covalent transfer of phosphate group
    • phosphorylated enzyme does not undergo spontaneous hydrolysis
    • irreversible inactivation
17
Q

Categories of anticholinergic agents

A
  • antinicotinic agents (not commonly used)
  • antimuscarinic = greatest clinical utility
    • non-selective vs. selective
      • M1 = CNS, gastric parietal, sympathetic postganglionic cells
      • M2 = cardiac
      • M3 = smooth muscle
18
Q

Classes of antimuscarinic agents (based on structure) + examples

A
  • alkaloids
    • atropine
    • scopolamine
  • semisynthetic/synthetic agents
    • tertiary amines: benztropine
    • quaternary ammonium: propantheline
19
Q

Catecholamine neurotransmitters + examples

A
  • adrenergic neurotransmitters
  • dopamine, norepinephrine, epinephrine
20
Q

Targets in storage, release, and reuptake of NE for drugs

A
  • Release of NE <== bretylium inhibits
  • Reuptake by NET (NE transporter) <== cocaine, tricyclic antidepressants inhibit ==> increased action
    • <== amphetamines, pseudoephedrine inhibit indirectly
21
Q

NE interaction w/postsynaptic receptros (a1, a2, b1, b2)

A
  • a1 ==> activates phospholipase C ==> increased intracell Ca2+
  • a2 ==> inhibits adenylyl cyclase ==> decreased cAMP ==> decreased intracell Ca2+
  • b1 & b2 ==> stimulates adenylyl cyclase ==> increased cAMP ==> increased intracell Ca2+
22
Q

Primary MOAs for Adrenergic agonists

A
  • direct = binds directly to receptor
  • indirect = effects the processing of NT
    • releasers ==> increased storage and release
    • reuptake-i ==> prevent NT reuptake from synapse
23
Q

General pharmacokinetics of Adrenergic Agonists

A
  • not effective orally
  • do not enter brain well
  • short durations of action
24
Q

Primary MOAs for Adrenergic Antagonists

A
  • sympatholytic = interferes w/fxn @ presynaptic neuron
    • lack of specificity of action limits clinical utility
  • receptor blockers = varying specificity, but can target specific receptors/groups of receptors
    • much greater clinical utility
25
Q

Sympatholytic agents

A
  • most inhibit enzymes of catecholamine synthetic enzymes e.g.
  • metyrosine ==l tyrosine hydroxylase (rate-limiting step)
    • ==l means “inhibits”
  • a-methyldopa ==l L-aromatic amino acid decarboxylase (l-AAD)
  • cabidopa ==l L-aromatic amino acid decarboxylase (l-AAD)
    • used in parkinson’s
  • disulfiram ==l dopamine b-hydroxylase
26
Q

a-adrenergic receptor antagonist types + examples

A
  • non-selective:
    • phentolamine
    • phenoxybenzamine
  • selective (block a1 only):
    • prazosin
27
Q

b-adreneric receptor antagonists types + examples

A
  • differences in relative affinities for b1 (heart) and b2 (lung/blood vessels)
  • Nonselective: propranolol
  • b1 selective (heart): metoprolol, atenolol
    • selectivity seen only at lower doses