Pharmacology - chapter 6 - Adrenergic agonists Flashcards
Describe the synthesis of norepinephrine.
Tyrosine is cotransported into the neuron along with sodium. There it is hydroxylated to DOPA - dihydroxypheynylalanine(rate-limiting step).
DOPA is then decarboxylated to form dopamine. Dopamine is transported into vesicles where it is hydroxylated to form norepinephrine.
Note: in the adrenal medulla, norepinephrine is methylated to yield epinephrine by phenyletanolamine N-metyltransferase(PMNT).
Where do you find the adrenergic neuron, and what is its primary neurotransmitter?
In the CNS and the sympathetic nervous system. The primary neurotransmitter of the adrenergic neuron is norepinephrine.
Reserpine?
Blocks amine transporter system than transport dopamine and norepinephrine into the synaptic vesicle.
What are the three ways by which norepinephrine is removed from the synaptic space under normal conditions?
1 Diffuse out of the synaptic space and into the general circulation.
2 Metabolized by Catechol O-methyltransferase on postsynaptic n.
3 Reuptaken and stored in presynaptic neuron.
Increased peripheral resistance, myadrisis, vasoconstriction, increased BP, increased tone of internal spchincter of the bladder… which receptor?
Alpha 1
Increased lipolysis, increased release of renin, increased myocardial contractility and tachycardia.. which receptor?
Beta uno
Inhibition of norepinephrine and ACh release, inhibition of insulin release… which receptor?
Alpha 2
Vasodilation, decreased TPR, bronchodilation, increased muscle and liver glycogenolysis, increased release of glucagon, relaxed uterine smooth muscle.. which receptor?
Beta 2
Alpha receptors: rank order of potency?
- epinephrine
- norepinephrine
- isoproterenol
epinephrine > norepinephrine»_space; isoproterenol
Beta receptors: rank order of potency?
- epinephrine
- norepinephrine
- isoproterenol
isoproterenol > epinephrine»_space; norepinephrine
What G-protein are alpha-1 receptors coupled with?
Gq protein that activate Phospholipase C pathway
Where are alpha-1 receptors primarily found?
on the postsynaptic membrane in effector organ
Where are the alpha-2 receptors primarily found?
On the presynaptic nerveendings, Beta cells of the pancreas and on certain vascular smooth muscle cells. ALpha-2 receptors are also found on the presynapthic parasympathetic membrane.
Tamsulosin?
Selective antagonist that binds to alpha-1a receptors in the urinary tract and the prostate gland.
Tamsulosin are used to treat.. ?
benign prostatic hyperplasia
Three ways of desensitizing receptors?
1 sequestration of the receptors
2 down-regulation(decreased synthesis and increased destruction)
3 inability to to couple with G-protein(phosphorylated receptor)
Effects of epinephrine? 1 Cardiovascular 2 Respiratory 3 Glucose levels 4 Lipid metabolism
1 Cardiovascular - positive ionotrophic and chronotrophic effects by binding beta-1 receptors myocardium, beta-1 receptors in the kidney cause renin release, alpha-1 receptors cause constricion of vessels in the mucos membranes, skin and viscera. Beta-2 receptors cause vasodilation in the liver and skeletal muscle.
2 Respiratory - bronchodilation by binding beta-2 receptors.
3 Glucose - beta-2 activated glycogenolysis in liver and alpha-2 coupled inhibition of insulin release in pancreas = hyperglycemia.
4 Lipids - beta-1 activated lipolysis in adipose tissue. Increased cAMP levels stimulate gormone-sensitive lipase = elevated FFA & glycerol.
Hyperthyroidism and epinephrine?
increased synthesis of adrenergic receptors on the vasculature in the hyperthyroid patient may lead to hypersensitive response. So be careful.
Cocaine and epinephrine?
Cocaine prevents reuptake into presynaptic neuron.
Diabetics and epinephrine?
Since epinephrine increase the release of stored glucose it can exaccerbate the hyperglycemia in diabetics. Therefore insulin levels may have to be increased.
Levarterenol?
Levarterenol = norepinephrine
To what receptor do norepinehrine bind most avidly?
that would be to the alpha-adrenergic receptor. MMMMMYaaaaas.. hub hub hub.
Norepinephrine effects..?
1 cardiovascular
2 baroreceptor reflex
3 atropine treatment
1 cardiovascular - alpha-1 coupled vasoconstriction. NE cause greater vasoconstriction than does epinephrine. This is because it binds less than epinephrine to beta-2 receptors in skeltal muscles etc.
2 baroreceptor reflex - little if any cardiac stimulation is observed. This is due to that increased TPR causes a reflex bradycardia that counteracts the actions of NE on the heart.
3 atropine treatment - atropine blocks cholinergic muscarnic receptors so norepinephrine administration induce tachycardia.
Isoproterenol: receptors and primary effects?
Isoproterenol stimulates both beta-1 and beta-2 receptors. Isoproterenol causes intese stimulation of myocardium by binding beta-1 receptors. Beta-2 mediated vasodilation lowers TPR. Total effect = increased systolic pressure, lowered TPR and diastolic pressure.
Dopamine: where can we find this amazing neurotransmitter?
In the CNS, the basal ganglia and the adrenal medulla.
Effects of Dopamine on adrenergic receptors?
Dopamine binds alpha and beta receptors.
high doses induce vasoconstriction by binding alpha receptors
low doses stimulate beta-1 cardiac receptors.
Dopamine in mesenteric and renal vascular beds?
Dopamine binds to D1 and D2 receptor in the peripheral mesenteric and renal vasculature, producing vasodilation.
Dopamine therapeutical effects in treating shock?
Beta-1 receptors cause increased cardiac output.
Alpha-1 receptors cause vasoconstriction and increased TPR
Dopaminergic receptors increase blood flow to kidney and splanchnic
areas, increasing glomerular filtration rate.
Fenoldopam?
rapid acting agonist of peripheral dopaminergic receptors used to treat severe hypertension.
Dobutamine?
Beta-1 agonist used to treat congestive heart failure as well as ionotrophic support after cardiac surgery.
Oxymetazoline?
direct acting adrenergic agonist that stimulates alpha-1 & alpha-2 receptors. Used as nasal spray decongestant and as ophthalmic drops to relief redness(clear eyes).
Phenylephrine?
direct acting synthetic adrenergic agonsit that bind primarily to alpha-1 receptors. Raise blood pressure. Used as nasal spray decongestant and as ophthalmic drops to cause myosis.
Clonidine?
Alpha-2 agonist used in essential hypertension. It works centrally, decreasing sympathetic neuronal activity and adrenergic outflow.
Albuterol and terbutaline?
Short-acting beta-2 agonists used primarily as bronchodilators. Terbutaline is used as a uterine relaxant to suppress premature labor.
Monoamine oxidase inhibitors?
Inhibit MAO and its breakdown of monoamines(e.g. norepinephrine, dopamine, serotonin)
MAOi and beta-2 agonists?
there should be a 2 week gap between the use of MAOi and bet-2 agonists, due to risk of adverse cardiovascular effects.
Amphetamine?
blocks reuptake of norepinephrine - e.i. indirect adrenergic agonist.
Tyramine?
Similar actions as amphetamine, not clinically useful. Significant compound if person use MAOi, as Tyramine is found in fermented food, aged cheese and Chianti wine.
Cocaine?
Block Na/K ATPase required for cellular uptake norepinephrine.
Ephedrine and pseudoephedrine?
mixed action adrenergic agents. Induce release of stored epinephrine as well as stimulate alpha & beta receptors. Ephedrine and Pseudoephedrine are not cathecols and thus poor substrates for COMT and MAO = long duration of action.
Name five catecholamines?
1 epinephrine 2 norepinephrine 3 isoproterenol 4 dopamine 5 dobutamine
Four characteristics of catecholamines?
1 rapid onset of action
2 brief duration of action
3 not administered orally
4 do not penetrate BBB
Non-catecholamines vs. catecholamines?
Non-catecholamines have longer duration of action and can be administered orally.
type of beta receptor in adipose tissue?
Beta-3
Name eight non-catecholamine adrenergic agonists.
1 oxymetazoline work on alpha-1 2 phenylephrine work on alpha-1 3 methoxamine work on alpha-1 4 clonidine work on alpha-2 5 albuterol & terbutarol work on beta-2 6 salmeterol & formoterol work on beta-2 7 amphetamine work on alpha, beta and in CNS 8 ephedrine & pseudoephedrine work on alpha, beta and CNS
Name two sympathomimetic agents that can make noradrenaline leave the nerveterminal non-exocytotically?
Tyramine
Amphetamine
Catecholamines –> aldehyde –> carboxylic acid
X? Y?
Catecholamines –> aldehyde –> carboxylic acid
X= MAO Y= ADH
Major and minor metabolites excreted after degradation of NA?
Major: VMA
Minor: MHPEG
VMA is primarily made in …………?
MOPEG is primarily made in ………….?
VMA –> Peripheral tissues
MOPEG –> CNS
Autoinhibitory feedback in NA release, mechanism of action?
NA –> presynaptic alpha2 autoreceptor –> inhibtion of adenylate cyclase –> decreased cAMP levels –> Ca-channels closed –> no vesicle exocytosis
Name two inhibitors of NA synthesis?
1 methyltyrosine blocks tyrosine hydroxylase
2 carbidopa blocks DOPA decarboxylase
Amphetamine, ephedrine and tyramine are all…?
Indirect acting sympathomimetic drugs.
Reserpine mechanism of action?
Blocks VMAT(vesicular monoamine transporter) - which will leave reabsorbed NA and dopamine to be degraded by MAO in cytoplasm = decreased NA sythesis and secretion.
Beta 1-3 rceptors work by stimulating…?
Gs stimulate adenylate cyclase
Alpha2 receptors work by inhibiting ……?
Gi inhibits adenylate cyclase
Alpha1 receptors work by stimulating……?
Gq stimulate PLC
Four main effects by alpha1 activation?
1 vasoconstriction
2 relaxation of GIT smooth muscle
3 salivary secretion
4 hepatic gluconeogenesis
Four main effects of alpha2 activation?
1 inhibition of transmitter release(NA & ACh)
2 contraction of vascular smooth muscle
3 platelet aggregation
4 inhibition of insulin release
Two main effects of beta1 activation?
1 increased cardiac rate and force
2 renin release
Six main effects of beta2 activation?
1 bronchodilation 2 vasodilation 3 relaxation of GIT smooth muscle 4 hepatic glycogenonlysis and gluconeogenesis 5 skeletal muscle glycogenolysis 6 muscle tremor
Main effect of beta3 receptor activation?
Lipolysis
Name four catecholamines?
adrenaline
noradrenaline
dopamine
isoprenaline
name three alpha1 selective agonists?
phenylephrine
methoxamine
imidazolines(group)
Name three alpha2 selective sympathomimetics that act centrally and decrease blood flow to the periphery?
1 Guanidine
2 Guanfacine
3 Guanabenz
Name two beta1 selective agonist.
1 Dobutamine
2 xamoterol
Name five beta2 selective agonists
1 Salbutamol 2 Fenoterol 3 Salmeterol 4 Formeterol 5 Terbutaline
Name two beta3 selective agonists
1 amibegron
2 solabegron
Cinical use of sympathomimetics:
Four beta2-selective agonists used in asthma?
1 Salbutamol
2 Salmeterol
3 Formeterol
4 Terbutaline
Clinical use of sympathomimetics:
Three drugs used in nasal decongestion?
1 oxymethazoline
2 xylomethazoline
3 phenylephrine
Sympatholytics - alpha antagonists:
two non-selective?
1 phentolamine
2 tolazoline
Sympatholytics - alpha antagonists:
Three alpha1-selective drugs?
1 prazosin
2 doxazosin
3 terazosin
Sympatholytics - alpha antagonists:
Two alpha2-selective drugs?
1 yohimibine
2 idazoxan
Sympatholytics - alpha antagonists:
Name a alpha1A-selective drug and its clinical application?
Tamsulosin, used in BPH
Sympatholytics - beta antagonists:
common suffix?
-olol”
Sympatholytics - beta antagonists:
Name three β-adrenergic antagonists with high lipophilicity, and one area of clinical use?
1 propanolol
2 penbutolol
3 carvediol
used in migraine prophylaxis and anxiety states
Clonidine, receptor specificity?
alpha2 > alpha1
Bromocriptine?
Natural ergot alkaloid and Dopamine agonist.
