Exam 1 Sympathomimetics Flashcards
What are monoamines?
- contains one amino group connected to an aromatic ring by a two carbon chain
- includes serotonin, dopamine, norepinephrine, epinephrine, (histamine)
What are catecholamines?
- monoamine with catechol group (benzene with two hydroxyl side groups at C1 and C2 (one of them is a para hydoxy to the amino group)
- includes dopamine, norepinephrine, and epinephrine
Serotonin is a derivative of which amino acid?
tryptophan
What are the derivatives of tyrosine?
norepinephrine, epinephrine, and dopamine
What is the mechanism of norepinephrine neurotransmission?
- tyrosine is transported into the noradrenergic ending or varicosity by a sodium dependent carrier (A)
- tyrosine is converted to dopa by tyrosine hydroxylase which is converted to dopamine by dopa decarboxylase
- dopamine is transported into the vesicle by the vesicular monoamine transporter (VMAT) → the carrier also transports NE and other amines into vesicles
- dopamine is converted to NE in the vesicle by dopamine-beta-hydroxylase
- release of transmitter occurs when an action potential opens voltage sensitive calcium channels and increases intracellular calcium → fusion of vesicles with the surface membrane results in expulsion of NE
- NE binds to adrenergic receptors on postsynaptic cell
- NE binds to regulatory receptors present on the presynaptic terminal
- NE diffuses out of the cleft or is re-uptaken into the cytoplasm of the terminal by the NE transmporter (NET) where it is metabolized by MAO or transported by VMAT back into vesicles
- NE can also diffuse away from the synaptic cleft to other cells where it can be degraded by COMT
What is the biosynthesis of catecholamines?
L-tyrosine → L-dopa (has extra hydroxyl group to make a catechol via tyrosine hydroxylase) → dopamine (no COOH group and is considered to be the simplest catecholamine via L-aromatic amino acid decarboxylase) → norepinephrine (added OH group via beta-hydroxylase, synthesized in the presynaptic vesicle) → epinephrine (addition of methyl group on the nitrogen via N-methyltransferase in the adrenal medulla)
What is the metabolism of norepinephrine?
norepinephrine → 3,4-dihydroxyphenylglycoaldehyde (via MAO) → 3,4-dihydroxyphenylehtylene glycol (via aldehyde reductase) → 3-methoxy-4-hydroxyphenylethylene glycol (via COMT) → VMA (via alcohol then aldehyde dehydrogenases)
What is another mechanism of the metabolism of norepinephrine?
- norepinephrine → 3,4-dihydroxymandelic acid (via MAO and aldehyde dehydrogenase) → VMA (via COMT)
- norepinephrine → normetanephrine (via COMT) → VMA (via MAO then aldehyde dehydrogenase)
What is the final product of norepinephrine metabolism?
3-methocy-4-hydroxymandelic acid (vanilylmandelic acid, VMA)
What are the two metabolic enzymes?
- COMT (catechol-O-methyltransferase) → highest activity in the liver, important for metabolism of circulating and administered catecholamines, also at nerve terminals
- MAO (monoamine oxidase) → surface membrane protein of mitochondria, high concentration in nerve terminals, liver, kidney, gut
What happens when a catechol is oxidized?
becomes an ortho-quinone → the OHs become ketones
What are the receptor mediated cardiovascular effects of norepinephrine (NE)?
- activates alpha and beta1 receptors with little affinity for beta2 receptors
- alpha1 agonist → vasoconstriction leading to rise in BP
- beta1 agonist → cardiac stimulation by increase in force and conduction
What are the receptor mediated cardiovascular effects for epinephrine?
- activates alpha and beta receptors
- alpha1 agonist → vasoconstriction leading to rise in BP
- beta1 agonist → cardiac stimulation by increasing in force, rate, and conduction
- beta2 agonist → vasodilation leading to fall in BP and bronchodilation
What are the receptor mediated cardiovascular effects of dopamine?
- at lower doses:
D1 agonist → vasodilation in renal, mesenteric, and coronary arteries increasing blood flow
beta1 agonist → cardiac stimulation by increasing force, rate, and conduction - at high doses: alpha1 agonist → vasoconstriction leading to rise in BP
What pathway does alpha1 receptors stimulate and what are the effects?
- Gq pathway
2. vasoconstriction, pupillary dilation, ejaculation, inhibition of peeing (micturition), GI inhibition
What pathway does alpha2 receptors stimulate and what are its effects?
- Gi pathway
2. vascoconstriction, prejunctional inhibition of NE release, in CNS: decrease CV SNS input
What pathway do beta1 receptors stimulate and what are the effects?
- Gs pathway
2. cardiac stimulation, secretion of renin
What pathway do beta2 receptors stimulate and what are its effects?
- Gs pathway
2. cardiac stimulation, bronchodilation, uterine relaxation, GI inhibition, vasodilation
Epinephrine acts on what receptors?
beta1, beta2 > alpha1, alpha2
Norepinephrine acts on which receptors?
alpha1, alpha2, and beta1
What is the selectivity of alpha 1 receptors (from high to low)?
isoproterenol»_space; norepinephrine > epinephrine > phenylephrine
What is the selectivity for beta1 receptors (from high to low)?
phenylephrine»_space; norepinephrine > epinephrine > isoproterenol
What is the selectivity for beta2 receptors (from high to low)?
phenylephrine > norepinephrine»_space; epinephrine > isoproterenol
What are the two examples of direct acting adrenergic receptor agonists?
norepinephrine (Levophed) and epinephrine (Adrenaline)
What stereochemistry is best for binding when it comes to norepinephrine and epinephrine?
R configuration
What are important intramolecular interactions with norepinephrine?
H-bonding, ionic bonding → weak individually but strong with specific interactions
All alpha2 receptor compounds need what?
CNS access!
R1 on direct acting beta-phenylethylamine sympathomimetics do what?
can give selectivity for beta receptors, especially beta2 receptors
What are the R1 and R2 groups on norepinephrine, epinephrine, isoproterenol, and N-tert-butylnorepinephrine (Colterol)?
norepinephrine: R1 is H, R2 is H
epinephrine: R1 is CH3, R2 is H
isoproterenol: R1 is CH(CH3)2, R2 is H
N-tert-butylnorepinephrine: R1 is -C(CH3)3, R2 is H
Larger R groups have selectivity for which receptor?
beta2 receptors (example is N-tert-butylnorepinephrine which is selective for beta2 receptors)
What is the receptor selectivity as the chart goes down from norepinephrine, epinephrine, isoproterenol, and N-tert-butylnorepinephrine?
alpha → beta1 → beta2
What is the MAO activity as the chart goes down from norepinephrine, epinephrine, isoproterenol, and N-tert-butylnorepinephrine?
MAO activity decreases (norepinephrine has highest MAO activity while N-tert-butylnorepinephrine has the lowest MAO activity)
What is the catechol ring modification for isoproterenol and its receptor selectivity?
is a catechol selective for beta receptors
What is the catechol ring modification for metaproterenol and its receptor selectivity?
is a resorcinol (other OH group is a carbon away from the other OH group and its R group is CH(CH3)2 and is selective for beta2 receptors (no COMT since it is not a catechol)
What is the catechol ring modification for albuterol and its receptor selectivity?
is a meta-hydroxymethyl (one OH group is replaced by a hydroxymethyl group) and its R group is C(CH3)3 and is selective for beta2 receptors (no COMT since it is not a catechol)
What is the catechol ring modification for phenylephrine and its receptor selectivity?
only has a meta OH group and its R group is CH3 and is selective for alpha1 receptors
What are important things to know about norepinephrine?
- direct acting adrenergic receptor agonist
- potent alpha and beta1 receptor agonist → has effect on heart rate and vasoconstriction
- substrate for MAO and COMT
- parenteral administration
- used as a pressor
- sodium bisulfite used in preparations to prevent oxidation → since catechol groups are prone to oxidation
What are important things to know about epinephrine?
- direct acting adrenergic receptor agonist
- potent alpha, beta1, and beta2 receptor agonist
- substrate for MAO and COMT
- parenteral administration → not orally available
- sodium bisulfite used in preparations to prevent oxidation → since catechol groups are prone to oxidation
- available as many salts: hydrochloride, nitrate, bitartrate
- uses: anaphylaxis, glaucoma, in combination with local anesthetics
What is the action, clinical use, and problems associated with epinephrine (alpha and beta agonist)?
- action → at lower concentrations beta1 and beta2 predominate but at higher concentrations, alpha1 effects predominate
- clinical use → treatment of acute anaphylaxis or cardiac arrest, used in adjunct with local anesthetics
- problems → not orally active due to COMT and MAO breakdown in the liver (first pass metabolism) and can also produce unwanted effects through broad activation of adrenergic receptors
If a drug is a substrate for MAO and COMT (aka it is broken down in the liver by MAO and COMT) how does it affect its route of administration?
cannot be taken orally because of first pass metabolism
What is Dipiveferin?
it is epinephrine dipivalate, propine → adjunct of epinephrine with local anesthetic to be used to treat glaucoma → is lipophilic and activated by esterases