ANS pharmacology Flashcards
locations of nicotinic receptors
NMJ, autonomic ganglia, brain
location of M1 muscarinic receptors
CNS, gastric parietal, sympathetic postganglionic cells
differences between nicotinic and muscarinic receptors, including difference in signal transduction mechanisms
nicotinic are ligand-gated ion channels, muscarinic are G protein coupled receptors.
state the significance of presynaptic versus postsynaptic cholinergic receptors
drugs that act postsynaptically are more selective than drugs that act presynaptically. because drugs that act presynaptically affect all synapses for that particular neurotransmitter
list the 3 categories of acetylcholinesterase inhibitors and the relation between the nature of the inhibitor interaction with AChE adn its duration of action-clinical utility
1) reversible, short acting (edrophonium) 2) reversible, intermediate-to-long acting (neostigmine-physostigmine) 3) irreversible, very long acting (isofluorophate-Nerve Gas)
action of cholinergic agonists
PNS stimulation
antimuscarinic agents/parasympatholytics
cholinergic antagonists that act at parasympathetic end organs
neuromuscular blockers
cholinergic antagonists that act at the neuromuscular junction (NMJ)
monoamine oxidase inhibitors
indirect-acting adrenergic agonists that increase storage and release of norepinephrine/epinephrine
sympatholytic action
just means inhibition of some aspect of synthesis-storage-release of NE
ACh synthesis and storage
Choline is taken up by active transport system that is dependent on Na+ and blocked by hemicholinium. Rate-limiting step. Synthesis occurs in the cytoplasm of the terminal and is catalyzed by choline acetyl transferase (ChAT). ACh is then stored within vesicles by a second transporter.
hemicholinium
enzyme that blocks uptake of choline
vesamicol
enzyme that inhibits ACh vesicle storage
How is ACh release modulated?
NE interacts with presynaptic alpha2-adrenergic heteroreceptors.
How is ACh action terminated?
hydrolysis catalyzed by acetylcholinesterase (AChE)
Pathway for interaction of ACh with acetylcholinesterase
Ac: esteratic site attracts acetyl group (CH3-COO) of acetylcholine. Cat: catalytic site where acetyl group is covalently bound to the serine [Ser-OH] of acetylcholinesterase while the choline group is released. Acetyl-serine-enzyme bond is hydrolyzed rapidly.
choline esters, examples, and pharmacokinetics
direct-acting muscarinic receptor agonists, including acetylcholine and bethanechol. low lipid solubility, poor oral absorption and distribution into CNS.
acetylcholine applications
not used, rapidly hydrolyzed by AChE
bethanechol and applications
synthetic analog of acetylcholine. can be modified structurally to produce selectivity for muscarinic receptors (by adding methyl group) and/or resistance to AChE (replace acetyl group with carbamyl group).
parasympathamomimetic alkaloids, examples mechanism, pharmacokinetics.
direct acting-muscarinic receptor agonists. pilocarpine. lipid soluble so well absorbed and can distribute into CNS.
pilocarpine (salagen)
muscarinic agonist
nicotine, class, mechanism.
direct-acting nicotinic neuronal (ganglionic) receptor agonists. stimulates both PNS and SNS. mechanism is dose dependent, agonist at low doses (impt - causes vasoconstriction via epinephrine released from adrenal gland activating SNS). At larger or prolonged doses it causes depolarization blockade and thus antagonism.
edrophonium
indirect-acting, reversible, short acting cholinesterase inhibitor. bond is readly reversible/not ionic so short acting.
neostigmine, physostigmine
indirect-acting, reversible, intermediate-to-long acting cholinesterase inhibitor. transfers a carbamyl group to anionic site on AChE, thereby inhibiting acetylcholinesterase. IMPT: physostigmine is distributed to CNS but neostigmine is not.
isofluorophate - nerve gas
indirect acting, irreversible cholinesterase inhibitor. covalently transfers a phosphate group to AChe, thereby inhibiting AChe.
location of M2 muscarinic receptors
cardiac cells
location of M3 muscarinic receptors
smooth muscle organs and glands
alkaloids mechanism and examples
high affinity and specificity antimuscarinic agents. atropine and scopolamine.
propantheline and glycopyrrolate, (ipratropium?)
semisynthetic-synthetic antimuscarinic agents with greater effect on GI activity. Quaternary ammonium compounds so low lipid solubility and poor oral absorption and excreted unchanged in urine.
benztropine, oxybutynin, tolterodine
semisynthetic-synthetic antimuscarinic agents with greater effect on CNS. Tertiary amines so well absorbed from GI and conjunctival membranes and eliminated by a combination of hepatic metabolism and renal excretion.
how do anti-nicotinic ganglionic blocking agents work? applications?
block neurotransmission in autonomic ganglia so affect predominant tone. since predominat tone is largely sympathetic for arteries/veins, blockage leads to vasodilation/hypotension/reduced cardiac output. not used anymore.
biosynthesis of norepinephrine
tyrosine is natural precursor and taken up by active transporter –> converted to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. DOPA converted to dopamine by L-aromatic amino acid decarboxylase (l-AAD) in cytosol –> dopamine is taken up into catecholamine storage vesicle by vesicular amine pump and converted to norepinephrine by dopamine beta-hydroxylase (DbetaH) –> (only in adrenal gland and certain CNS neurons) NE converted to epinephrine by phenylethanolamine n-methyl transferase.
metyrosine
enzyme that inhibits conversion of tyrosine to DOPA
alpha-methyl dopa/carbidopa
enzymes that inhibit conversion of DOPA to dopamine
what is the common structural property of catecholamine neurotransmitters
they all have the phenylethylamine nucleus and catechol hydroxyl (OH) groups in common.
what defines neurotransmitter group of monoamines or “biogenic” amines?
catecholamines + indoleamine 5-hydroxytryptamine (serotonin)
norepinephrine storage and release
the vesicle membrane for NE contains an active pump called VMAT.
NE transporter
This is the pump located on the presynaptic membrane that removes released NE from the synapse.
monoamine oxidase
enzyme on mitochondria that degrades NE
bretylium
enzyme that prevents release of catecholamines
How is NE terminated following synaptic action?
most impt mechanism is reuptake by NET (norepinephrine transporter).
What are some drugs that inhibit reuptake of NE?
cocaine, TCAs
action of amphetamines, pseudoephedrine
these are phenylethylamine drugs that indirectly release NE by reversing the NET transporter.
a1-receptor activation
Gq protein that activates phospholipase C –> release of IP3 (releases intracellular stores of Ca++) and DAG (activates protein kinase C)
a2-receptor activation
Gi protein that inhibits adenylyl cyclase activity –> decreases cAMP levels or opens K+ channels. Effect is to decrease Ca++ movement.
b1 and b2 receptor activation
Gs protein that stimulates adenylyl cyclase –> increased cAMP synthesis –> which activates protein kinase A. Thus increases Ca++ movement.
what is the most common mechanism of indirect acting adrenergic agonists?
increasing storage and release of NE
how is the ability of adrenergic agonists to enter the CNS determined?
lack of hydroxyl groups on phenyl ring increases drug’s lipophilicity.
How do you increase the oral effectiveness of adrenergic agonists?
non-catechols (no hydroxyl group) are resistant to first pass metabolism because they are not substrates for catechol-O-methyl transferase in the liver. Drugs with a methyl group are protected from degradation from MAO in the liver.
