Autonomic Nervous System Neuropharmacology [4]

Question 1

Describe the general mechanisms by which most drugs alter activity in the autonomic nervous system

Answer 1

1. Mimicking the neurotransmitter action (generally at the receptor level): Agonist
2. Blocking the neurotransmitter action (generally at the receptor level): Antagonist
3. Changing the normal action of the neurotransmitter (indirect action) by altering neurotransmitter synthesis, storage or inactivation.

Question 2

Compare and contrast the

modes of drug action with respect to selectivity of action and clinical utility

Answer 2

Greatest selectivity: drugs that act POST-synaptically at a specific receptor subtype as either agonist or antagonist (most clinically useful)

Least selectivity: dugs that act PRE-synaptically by altering synthesis, storage or release of neurotransmitters. Less clinically useful because it affects all synapses for that particular neurotransmitter

Question 3

List the steps in the synthesis, storage, release and inactivation of acetylcholine

Answer 3

Acetyl-CoA + Choline ←→ ACh + CoA

• Forward reaction catalysed by choline acetyle transferase (CAT)
• Backward reaction catalysed by acetyl-cholinesterase (AChE)

ACh is then transported into vesicles by the acetylcholine transporter. Following Ca2+ release, ACh vesicles fuse with the presynaptic membrane and exocytose their contents into the synaptic cleft.

Question 4

For cholinergic receptors:

List the locations of and the differences between nicotinic and muscarinic cholinergic receptors

Answer 4

Nicotinic: found in autonomic nervous system ganglia (SNS and PNS preganglionic neurotransmission). Muscle-type nicotinic cholinergic receptors are found in the NMJ.

Muscarinic: postsynaptic terminal of postganglionic parasympathetic synapses. Also on sweat glands (SNS).

Question 5

For cholinergic receptors:
Describe the signal transduction mechanisms activated by stimulation of nicotinic versus muscarinic cholinergic receptors

Answer 5

Nicotinic: nicotinic cholinergic receptors are either ligand gated ion channels or ionotropic receptors.

Muscarinic: GPCRs or metabotropic receptors.

Question 6

For cholinergic receptors:

State the significance of presynaptic versus postsynaptic cholinergic receptors

Answer 6

• Presynaptic: presynaptic cholingergic receptors are responsible for passing along messages sent by the CNS to the PNS. Therefore, presynaptic cholingergic receptors are generally ligand gatedion channels or ionotropic receptors capable of propogating the action potential postsynaptically.
• Postsynaptic: postsynaptic cholinergic receptors (muscarinic receptors) are responsible for effecting a response from an end organ target. Therefore, postsynaptic cholinergic receptors are generally GPCRs or metabotropic receptors, capable of effecting function responses in the end organ.

Question 7

What are the muscarinic cholinerigic AGONIST drugs and their basic mechanism?

Answer 7

Acetylcholine, Bethanechol, Pilocarpine

• Produce effects similar to physiological simtulation of the PNS: ↑salivation, miosis & accommodation, ↑urinary and GI tract motility. Overdose→SLUDGE (Rx→atropine)
• Additional peripheral effects like Vasodilation and decrease peripheral resistance due to activation of non-innervated MRs on endothelial cells of arterioles and veins and release of NO. Increase sweating due to sympathetic cholinergic response.

Question 8

For acetylcholinesterase inhibitors (indirect agonists):
List the 3 categories of inhibitors and describe the relation between the nature of the inhibitor interaction with AChE and its duration of action-clinical utility

Answer 8

1. Reversible, short-acting [Edrophonium]: Binds only to the anionic site of the enzyme and no covalent bond is formed at the serine site. The ionic bond is readily reversible.
2. Reversible, intermediate-to-long acting [Neostigmine - Physostigmine]: Binds to anionic site and covalently transfers a carbamyl group [NH2-COO], rather than acetyl group, to serine site. The carbamyl-serine-enzyme is hydrolyzed slowly (minutes) to yield the free, active
   AChE enzyme.
3. Irreversible, very long acting [Isofluorophate - Nerve Gas]: Does not bind to anionic site, but covalently transfers a phosphate group to serine site. The phosphorylated enzyme does not undergo spontaneous hydrolysis, essentially irreversibly inactivating the enzyme.

Question 9

For acetylcholinesterase inhibitors (indirect agonists):

Describe their pharmacologic actions and why they affect both muscarinic and nicotinic cholinergic transmission.

Answer 9

• Inhibition of AChE hydrolysis of ACh to choline and acetate greatly potentiates/prolonges ACh action.
• AChE inhibitors affect both muscarininc and nicotinic cholinergic transmission because ACh is active at both MRs and nAChRs.

Question 10

For adrenergic agonist drugs:

Distinguish the different mechanisms of actions for direct-acting and indirect acting agonists

Answer 10

• Direct acting: bind to postsynaptic adrenergic subtypes at SNS and CNS sites.
• Indirect acting: enhance release of the NTM.
• Mixed-acting: both direct-acting and indirect-acting.

Question 11

For adrenergic agonist drugs:
Describe the relationship of drug structure to pharmacokinetics with regards to absorption, distribution, and duration of action

Answer 11

Oral absorption effectiveness increases with: Drugs that are non-catechols (i.e, no 3,4-hydroxyl [OH] groups on the phenyl ring) and Drugs that possess a methyl group on the α-carbon of the phenylethylamine (protects them degradation by monoamine oxidase (MAO) in the liver)

Distribution: The ability to enter the CNS is increased with drugs that have no hydroxyl groups on the phenyl ring since this increases the drug’s lipophilicity (e.g., ephedrine, amphetamine)

Duration of action: The half-life is increased by the same factors that protect drug from COMT or MAO metabolism

Question 12

For adrenergic antagonist drugs:
Compare the modes of action of sympatholytic agents vs receptor blocking agents with respect to selectivity of action and overall clinical utility

Answer 12

Sympatholytic agents: Interference with adrenergic function in the presynaptic neuron. Lack of specificity of action (all adrenergic synapses affected) greatly limits their clinical utility.

Receptor blocking agents: Block of responses to sympathetic nervous system stimulation by combining with adrenergic receptors at postganglionic sympathetic neuroeffector sites without eliciting a response. α and β adrenergic receptors (plus subtypes) exhibit sensitivity to specific pharmacologic antagonists, thus much greater clinical utility

Question 13

For adrenergic antagonist drugs:

Describe how an agonist of α2 adrenergic receptors can have antagonistic effects on the SNS

Answer 13

Counter intuitively, reduces sympathetic nervous system activity.

Preferentially stimulates peripheral α2 (presynaptic) receptors and thus reduces norepinephrine release from sympathetic neurons

Question 14

How does Botulinus Toxin affect ACh?

Answer 14

Inhibits ACh release at excitatory NMJs by cleaving synaptobrevin (required for vesicle fusion with the membrane). Causes flaccid paralysis. Used clinically in disorders of cholinergic hyperactivity.

Question 15

How does Tetanus toxin affect ACh?

Answer 15

Inhibits ACh release at inhibitory NMJs by cleaving synaptobrevin (required for vesicle fusion with the membrane). Causes tetany.

Question 16

How does black widow spider venom affect ACh?

Answer 16

Stimulates ACh release by favoring excessive vesicle clumping and “explosive release”

Question 17

What drugs act as Acetylcholinesterase inhibitors and what are there affects relevant to ACh?

Answer 17

Lead to prolongation of ACh activity in the synapse and at the ACh receptor.
•Physostigmine
•Donepezil
•Neostigmine
•Edrophonium
•Organophosphates

Question 18

What are muscarinic cholinergic antagonist drugs? What is their general mechanism?

Answer 18

Atropine, Scopolamine, Tropicamide

•Inhibit the action of ACh at MRs. Single competitive inhibitors.

Question 19

For the muscarinic antagonist drug Atropine, what is the mechanism of action and side effects?

Answer 19

tertiary amine that readily crosses the BBB. Used in emergency treatment of mushroom poisoning, AChE inhinitor toxicity, severe bradycardia, asthmatic attack when patient unresponsive to beta-AR agonists, Parkinson’s Disease and side effects (extrapyramidal) of antipsychotic agents.

Question 20

For the muscarinic antagonist Scopolamine, what is the mechanism of action and the side effects?

Answer 20

tertiary amine that readily crosses the BBB. Compared to atropine, produces MORE CNS depression and vestibular system suppression; used as a preanesthetic medication and to prevent motion sickness.

Question 21

For the muscarinic antagonist Tropicamide, what is the mechanism of action and the side effects?

Answer 21

tertiary amine that readily crosses the BBB. Used in ophthalmology to produce mydriasis and cycloplegia (paralysis of accommodation) for eye exams. Duration of action approx 6 hours.

Question 22

For the muscarinic agonist Acetylcholine, what is the mechanism of action and the side effects?

Answer 22

Does what Acetylecholine does!

Very short half life→not good pharmaceutically.

Question 23

For the muscarinic agonist Bethanechol, what is the mechanism of action and the side effects?

Answer 23

Quaternary amino acholine ester that does not pass the BBB and is resistant to metabolism by AChE.

Side effects: Urinary retention (postop and postpartum); paralytic ileus (non-obstructive)

Question 24

For the muscarinic agonist Pilocarpine, what is the mechanism of action and the side effects?

Answer 24

Tertiary amino alkyloid that crosses BBB

Side effects: Induction of miosis for cataract surgery; glaucoma; diagnose xerostemia (deficient salivation).

Question 25

Describe the neurotransmitter synthesis that represent targets for adrenergic and anti-adrenergic drug action

Answer 25

• Tyrosine→L-Dopa; tyrosine hydroxylase
• L-Dopa→DA; Dopa decarboxylase
• DA→NE; Dopamine beta-hydroxylase
• NE→E; phenylethanolamine-N-methyltransferase

Drug targets:
•alpha-methyl tyrosine is a tyrosine hydroxylase inhibitor.
•Alpha-methyldopa is a tyrosine hydroxylase inhibitor

Question 26

Describe the neurotransmitter storage that represent targets for adrenergic and anti-adrenergic drug action

Answer 26

Vesicular monoamine transporter (VMAT) transports DA in vesicles (where it is converted to NE).

Drug targets:
•Resperine inhibits VMAT and depletes DA and NA stores

Question 27

Describe the neurotransmitter inactivation that represent targets for adrenergic and anti-adrenergic drug action

Answer 27

Action is terminated primarily by reuptake into neuron via membrane transporter (DA: DAT; NE: NET). Degradation follows uptake into the neuron or by liver (catecholamines that escape into circulation) via monoamine oxidase (MAO A: NE, Serotonin, tyramine; MAO B: DA) or catechol-O-methyl transferase (COMT).

Drug targets:
•Phenelzine is an irreversible inhibitor of MAO A and B
•Selegiline is an irreversible inhibitor of MAO B

Question 28

Describe the neurotransmitter release mechanisms that represent targets for adrenergic and anti-adrenergic drug action

Answer 28

Following Ca2+ release, NE vesicles fuse with the presynaptic membrane and exocytose their contents into the synaptic cleft.