Autonomic Nervous System Neuropharmacology

Question 1

Common mechanisms of drug action @ ANS (3)

Answer 1

• 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)

Question 2

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

Answer 2

• 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

Question 3

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

Answer 3

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

Question 4

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

Answer 4

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

Question 5

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

Answer 5

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

Question 6

Classes of cholinergic receptors (types & families)

Answer 6

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

Question 7

Consequences of ACh stimulation of cholinergic receptors

Answer 7

• 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])

Question 8

Choline esters mechanism & examples

Answer 8

• 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

Question 9

Classes of direct-acting muscarinic receptor agonists

Answer 9

• choline esters
• parasympathomimetic alkaloids

Question 10

Choline esters pharmacokinetics

Answer 10

• low lipid solubility
• poor oral absorbtion
• poor distribution to CNS

Question 11

Parasympathomimetic alkaloids mechanism + examples + pharmacokinetics

Answer 11

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

Question 12

Nicotine MOA + effects

Answer 12

• 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

Question 13

Indirect-acting cholinergic drugs MOA + categories

Answer 13

• = 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)

Question 14

Edrophonium MOA

Answer 14

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

Question 15

Neostigmine/Physostigmine MOA

Answer 15

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

Question 16

Isofluorophate/Nerve Gas MOA

Answer 16

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

Question 17

Categories of anticholinergic agents

Answer 17

• 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

Question 18

Classes of antimuscarinic agents (based on structure) + examples

Answer 18

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

Question 19

Catecholamine neurotransmitters + examples

Answer 19

• adrenergic neurotransmitters
• dopamine, norepinephrine, epinephrine

Question 20

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

Answer 20

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

Question 21

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

Answer 21

• 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⁺

Question 22

Primary MOAs for Adrenergic agonists

Answer 22

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

Question 23

General pharmacokinetics of Adrenergic Agonists

Answer 23

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

Question 24

Primary MOAs for Adrenergic Antagonists

Answer 24

• 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

Question 25

Sympatholytic agents

Answer 25

• 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

Question 26

a-adrenergic receptor antagonist types + examples

Answer 26

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

Question 27

b-adreneric receptor antagonists types + examples

Answer 27

• 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