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Flashcards in ANS neuropharmacology Deck (39):
1

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)

2

Which drugs are most selective

drugs that act post synaptically are most selective and thus have highest clinical utility

3

2. 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)

4

2. 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

5

2. 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

6

3. 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

7

3. 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])

8

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

9

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)

10

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

11

What general effect do adrenergic antagonists have?

Block effects of NE and Epi at α- and β-adrenergic receptors on sympathetic end organs.

12

What general effect do sympatholytic agents have?

Interference with adrenergic function in the presynaptic neuron via block of synthesis, storage or release

13

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

14

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)

15

List 3 categories of indirect cholinergic agonists, inlcuding examples and the nature of the inhibitors interaction with ACHE

1. 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.

16

Acetylcholinesterase inhibitors action

By blocking cholinesterase, ACH accumulates in the synapse and exerts increased effects at both muscarinic and nicotinic receptrs

17

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)

18

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)

19

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)

20

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)

21

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

22

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.

23

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)

24

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)

25

Termination of NE synaptic action

Reuptake by norepinephrine transporter (NET) in nerve endings is most important. Cocaine and tricyclic antidepressants inhibit NET. Amphetamines and pseudoephedrine indirectly cause release of NE by reversing NET process as they are taken up into neuron.

26

Signaling pathway of a1 adrenergic receptor

Gq protein activates Phospholipase C > formation of IP3 (releases intracellular Ca++) and DAG (activates PKC)
Gq protein activates Phospholipase C > formation of IP3 (releases intracellular Ca++) and DAG (activates PKC)

27

Signaling pathway of a2 adrenergic receptor

Gi protein inhibits Adenylyl cyclase> decreases cAMP levels or opens K+ channels (hyperpolarization) - couples to Go to decrease Ca++ movement through L- and N- type channels
Gi protein inhibits Adenylyl cyclase> decreases cAMP levels or opens K+ channels (hyperpolarization) - couples to Go to decrease Ca++ movement through L- and N- type channels

28

Signaling pathway of B1-B2 adrenergic receptor

Gs protein that stimulates adenylyl cyclase > increased cAMP levels (activates PKA) - stimulation of 1 also increases Ca++ movement through L-type Ca++ channels
Gs protein that stimulates adenylyl cyclase > increased cAMP levels (activates PKA) - stimulation of 1 also increases Ca++ movement through L-type Ca++ channels

29

Modes of action for indirect acting adrenergic agonists

1. increase storage and release (most common, pseudoephedrine/amphetamine)- drug taken up by NET, VMAT pumps it into vesicles displacing NE into cytoplasm then into synapse via reversal of NET. 2. Inhibition of neurotransmitter reuptake from the synapse

30

Describe the relationship of adrenergic drug structure to pharmacokinetics with regards to absorption

Absorption: oral effectiveness increases with Drugs that are non-catechols (ephedrine and amphetamine) b/c they are not metabolized in liver or drugs with methyl group on alpha carbon (ephedrine and amphetamine) b/c it protects from monoamine oxidase in liver

31

Describe the relationship of adrenergic drug structure to pharmacokinetics with regards to distribution, and duration of action

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 for ephedrine and amphetamine b/c not metabolized in liverDistribution: 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 for ephedrine and amphetamine b/c not metabolized in liver

32

Pharmacokinetics of norepinephrine and epi

not effective orally, don’t enter brain and short duration of action

33

List adrenergic agonists and the specific receptor they act on

Epi (a1,b1,b2), NE (a1, b1), Phenylephrine (a1), clonidine (a2), Isoproterenol (b1 and b2), dobutamine (b1), albuterol (B2), pseudoephedrine (indirect acting releaser)

34

Name the primary modes of action of adrenergic antagonists and clinical utility

1. Sympatholytic action: Interferes with presynaptic neuron function (lack of specificity limits clinical utility). 2. Adrenergic receptor blocking: block a or B receptors on postganglionic neurons (specificity means greater clinical utility). 3. Activation of a2 receptors: decreases sympathetic activity

35

List sympatholytic agents and their actions

1. inhibitors of catecholamine synthetic enzymes: Metyrosine, a-methyldopa, carbidopa, disulfiram. 2. Inhibitors of catecholamine storage: reserpine. 3. Inhibitors of catecholamine release: Bretylium, guanethidine.

36

List adrenergic receptor blockers and which receptor they block

1. Nonselective, a1 and a2: Phentolamine (reversible), phenoxybenzamine (irreversible). 2. Selective a1: Prazosin, Terazosin, Doxazosin. 3. Nonselective B1 and B2: propranolol. 4. Selective B1(cardioselective): metoprolol, atenolol (B1 selectivity is only seen at low doses)

37

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

stimulation of a2 receptors (postsynaptic) in brain stem reduces peripheral SNS activity. Stimulation of peripheral a2 (presynaptic) reduces NE release from neurons

38

Pharmacokinetics of anti-adrenergic drugs

Oral availability, propranolol has high CNS effects, atenolol has low CNS effects. Propranolol, carvedilol and metroprolol are metabolized by liver. Atenolol is metabolized by kidney.

39

Review ANS drug effects on separate sheet

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