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Pharmacology > Intro to Adrenergic Pharmacology > Flashcards

Intro to Adrenergic Pharmacology Flashcards

1
Q

What is dopamine a precursor for?
Where is dopamine present?
What clinical disorders is dopamine important in?

A

Dopamine is precursor for norepinephrine and epinephrine.

  • Present in sympathetic neurons and chromaffin cells.
  • It is an important transmitter in Schizophrenia and Parkinson’s disease.
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2
Q

What neurons is norepinephrine a primary neurotransmitter?

  • What cells produce it?
  • And what clinical disorder is norepinephrine relevant?
A
  • Primary NT of sympathetic neurons.
  • Produced by chromaffin cells
  • Important transmitter in peripheral vascular tone and some forms of hypertension.
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3
Q

Where is epinephrine primarily synthesized?

What clinical disorder does epinephrine mediate?

A
  • Epinephrine is predominantly synthesized in the chromaffin cells
  • Mediates the symptoms of pheochromocytoma.
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4
Q

Name the precursors and the products of the endogenous catecholamine production pathway

A

Tyrosine–>(Tyrosine hydroxylase)–>DOPA–>(DOPA decarboxylase)–>Dopamine–>(Dopamine Beta-hydroxylase)–>Noradrenaline–>Adrenaline
- The terminal catecholamine produced depends on the availability of specific enzymes.

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5
Q

What transports newly synthesized dopamine to vesicles for storage?

A

VMAT ( a drug target for reserpine)

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6
Q

What part of the endogenous catecholamine synthesis pathway occurs in the post ganglionic sympathetic neurons?

A

Dopamine is converted to norepinephrine (w/in the sympathetic vesicles) by dopamine Beta-hydoxylase.

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7
Q

What part of the endogenous catecholamine pathway occurs in the chromaffin cells?

A

Norepinephrine is transported/ diffused into the cytosol for conversion to epinephrine by phenyl ethanolamine N-methyl transferasee.

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8
Q

What triggers the release of endogenous catecholamines?

What triggers the termination of action?

A
  • Release is triggerd by action potential, calcium influx, AND Endocytosis (similar to AcH)
  • Termination of action potential involves three mechanisms:
    a) Reuptake - predominant (SSRI)
    b) Metabolism - minor
    c) Diffusion away from the cleft - minor
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9
Q

Where is Monoamine Oxidase Found?
What does MAO-A preferentially degrade?
What does MAO-B degrade?

A

MAO is found in the outer mitochondrial membrane of most neurons.

  • MAO-A preferentially degrades 5HT, norepinephrine and dopamine
  • MAO-B degrades dopamine more rapidly than 5HT and norepinephrine.
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10
Q

Name 3 MAO inhibitors.

What are MAO inhibitors effective in treating?

A
  • selegiline, isocarboxazid, phenelzine

- Depression

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11
Q

What is the Catechol-O-methyl transferase (COMT)?

A

A cytosolic enzyme (Metabolism/degradation) expressed primarily in the liver but also found in the brain

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12
Q

Where is the Alpha 1 receptor found and what is its effect?

A

Alpha 1 is found in post-synaptic terminals of Vascular smooth muscle (contraction), genitourinary smooth muscle (contraction), intestinal smooth muscle (relaxation), heart (increases inotropy and excitability), and liver cells (Glycogenolysis and gluconeogensis).

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13
Q

Where is the Alpha 2 receptors found and what are there actions?

A

Pancreatic beta cells (decreases insulin secretion), Platelets (aggregation), Nerves (decreases norepinephrine release), vascular smooth muscle (contraction)

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14
Q

Where are the Beta one receptors found and what are there actions?

A

Heart (increases chronotropy and inotropy; and increases AV node conduction velocity)
Renal juxtaglomerular cells (increases renin secretion)

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15
Q

Where are the Beta 2 receptors found and what are there actions?

A

Smooth muscle (relaxation), Liver (Glucogenolysis and gluconeogenesis), Skeletal muscle (glycogenolysis and K+ uptake)

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16
Q

Where are the Beta 3 receptors located and what are their effect?

A

Adipose - Lipolysis

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17
Q

What is the mechanism of action of the Alpha 1 adrenergic receptors?

A

G-protein-coupled receptor. Simulated phospholipase C leading to increase in DAG and IP3.

  • IP3 releases Calcium from intracellular stores and causes subsequent muscle contraction.
  • DAG - activation of PKC leading to phosphorylation of target proteins
  • MAP kinase and PI3 kinase cascades are also activated that play a role in receptor-mediated stimulation of cell growth and proliferation.
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18
Q

What is the mechanism of action of Alpha-2 adrenergic receptors?
Where are they found and what clinical significance can pharmacologic control have on them?

A

Alpha-2 adrenergic receptors inhibit adenylyl cyclase and thereby decrease cAMP levels. Very sensitive to voltage.

  • other signaling pathways include: regulation of ion channel activities (inward rectifier K+ channels and neuronal Calcium channels)
  • Expressed at both pre- and post- synaptic membranes
  • Found in the CNS, platelets, pancreatic Beta cells.
  • Used in treatment of hypertension, neuropathic pain, and fibomyalgia.
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19
Q

What is the mechanism of action of Beta-adrenergic receptors?

A

All three isoforms (B1, B2, B3) are coupled to Gs and thereby increase cAMP.
- Cellular response depends on the type of tissues and isoform of receptor (Beta1 increases cardiac contractility and heart rate, Beta2 increases dilation of smooth muscles)

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20
Q

Where are Beta adrenergic receptors found?

A

B1 - heart and kidneys
B2 - Smooth muscles, liver, and skeletal muscles
B3 Adipose tissues
They all exhibit receptor dynamism (ex. down regulation)

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21
Q

What clincal disorders might Beta Adrenergic receptors be targeted?

A

Asthma, cardiac arrhythmias, angina, hypertension, and COPD

**Beta agonists are more efficient at treating angina than AcH

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22
Q

Why do you have a decrease in cAMP if you decrease adenylyl cyclase?

A

You should know this dumbass!!

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23
Q

What is the mechanism of action of the D1 and D5 dopaminergic receptors?

A

D1* and D5 receptors are coupled to Gs with subsequent increase in cAMP.

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24
Q

Where is the D1 dopaminergic receptor found and what are its functions?

A

D1* is found in found in the kidneys, mesentery, and coronary arteries. It causes relaxation in vascular smooth muscles–> vasodilation - fenoldopam is a partial agonist at Di

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25
Q

What is the mechanism of action of D2, D3, and D4 receptors?

A

D2, D3, and D4 receptors are coupled to Gi with subsequent decrease in cAMP, an increase in potassium conductance, and a decrease in calcium influx.

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26
Q

What are the dopaminergic receptors clinically useful for?

A

Dopaminergic receptors are clinically useful for management of Parkinson’s disease, schizophenia, and shock (especially ones caused by low cardiac output)

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27
Q

What glands lack direct parasympathetic input?

A

Adrenal glands

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28
Q

What are the 4 dopaminergic pathways?

A
  • Nigrostriatal Pathway
  • Mesolimbic (mesocortical pathway)
  • Tubero-infundibular pathway
  • Area postrema
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29
Q

What is the projection of the nigrostriatal pathway?

What disorder is it relevant in?

A

The nigrostriatal pathway projects from the substantia nigra (pars compacta) to striatum (where D1 and D2 are predominant). Largest DA pathway in the CNS (80%)
- Dengeneration results in Parkinson’s disease.

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30
Q

What is the projection of the Mesolimbic pathway?

What disorders is it implicated in?

A
  • The mesolimbic pathway projects from the the ventral tegmental area (VTA) to the cerebral cortex, nucleus accumbens, etc.
  • It is implicated in schizophrenia, addiction, and other psychotic symptoms.
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31
Q

What is the projection of the Tubero-infundibular pathway?

What hormone does it effect?

A
  • Projects from the hypothalamus (arcuate and para-ventricular nuclei) to the anterior pituitary.
  • Tonically inhibits release of prolactin.
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32
Q

What is the Area postrema?

What disorder is it associated with?

A
  • The area postrema is a high density of dopamine receptors (mostly D2)
  • Associated with emesis.
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33
Q

What is the projection pathway of the noradrenergic system?
What is the effect drugs of abuse does it mediate?
What clinical issues does it treat?

A
  • Projects from the pons (locus coeruleus) to cerebral cortex, hypothalamus, cerebellum, etc.
  • Noradrenergic system mediates the psychostimulate effects of drugs of abuse such as cocaine, and amphetamine.
  • Is used in the treatment of attention deficit hyperactivity disorder.
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34
Q

Where does the nucleus tractus solitarius receive input from?
- What regulation does the nucleus tractus solitarius control?

A
  • Baroreceptors and Chemoreceptors.

- Regulates sympathetic peripheral outflow including blood pressure regulation

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35
Q

What is the major difference between the termination of AcH and Adrenergic transmission?

A
  • AcH the major method of terminated adrenergic is by reuptake (think cocaine and amphetamines that inhibite reuptake)
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36
Q

How does an alpha one blocker work?

A
  • An alpha one blocker works by decreasing the influence of the nucleus tractus solitarius that essentially initiates a blackout from standing up to fast.
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37
Q

How does Adrenergics effect the heart?

A
  • Beta-1 adrenergic receptors in cardiac tissues (SA, AV nodes) mediate inotropic and chronotropic effects of sympathetic input, resulting in stimulation that increases the rate and force of contraction of the heart.
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38
Q

In what diseases are Beta-1 Adrenergics targeted for pharmacological resolution?

A
  • Supraventricular tachyarrhythmias (class 2 anti-arrhythmic agents - metoprolol, propranolol, etc)
  • angina pectoris
  • decompensate heart failure
  • hypertension
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39
Q

Why would you choose B1-selective blockers over other options?

A

Because of no adverse affects on the lungs.

40
Q

What is the function of Adrenergics on Blood vessels?

A

Alpha receptors on vascular smooth muscles control tone and total peripheral vascular resistance.

41
Q

What disorders are Adrenergics targeted in?

A
  • hypertension
  • benign prosthetic hyperplasia
  • glaucoma
  • pheochromocytoma
42
Q

What are the mechanism of action for the adrenergic transmission?

A

D1 receptors in the splanchnic, coronary, renal and cerebral vasculature causes relaxation upon stimulation. Activation of D1–>diuresis.
- Beta 2 receptors cause vascular smooth relaxation

43
Q

Why is alpha-1 receptor stimulation not the first choice for treatment of hypertension?

A

Alpha-1 receptor stimulation decreases blood pressure of a patient it sends signal to brain (nucleus tractus solitarius) that BP has just decreased and leads to an increase in stimulation of heart in an attempt to balance:(

44
Q

What adrenergics are located in the kidneys and what are their function?

A
  • Beta (B1) adrenergic receptors on jextaglumerular apparatus mediate renin release.
  • DA receptors along the nephron (proximal convoluted tubules) mediate natriuresis and diuresis.
45
Q

What does fenoldopam do?

A
  • it is an anti-hypertensive agent that acts as an agonist on D1 receptors.
46
Q

In men specifically, what clinical pathology can the Adrenergic system be useful in treating pharmacologically?

A

Benign prosthetic hyperplasia

47
Q

In the Adrenal Glands what mediates autonomic system is mediated by Adrenergic transmission?

A

Sympathetics

48
Q

In adipose tissues what receptor mediates norepinephrine, epinephrine- induces lipid catabolism?

A

B3

49
Q

What hormone in the Adrenergic pathway has a higher affinity for Beta receptors as opposed to Alpha receptors?

A

Epinephrine.

50
Q

What are epinephrine’s general effects?

A

POsitive inotropic and chronotropic effects on the heart, decrease in total periperal vascualr resistance, increases in blood flow to muscles, and dilation of air ways.

51
Q

What hormone in the Adrenergic pathway has a higher affinity for alpha receptors than for Beta- receptors?

A

Norepinephrine

52
Q

What are the norepinephrine’s general effects?

A

increases in total peripheral vascular resistance, decreases in capacity of capacitance vessels, exhibit positive inotropic effect on the heart

53
Q

What are the general effects of Dopamine?

A
  • produces vasodilation of renal, splanchnic, coronary, and cerebral vascular beds.
  • Binds to all catechol amine receptors, but selective for Ds
  • Its effects depends on receptor subtype and vary greatly with concentration.
54
Q

What are the general effects of isoproterenol?

What are it’s uses?

A
  • Potent vasodilator with positive inotropic and chronotropic effects on the heart.
  • Used for bradycardia and heart block.
55
Q

What receptor type is isoproterenol highly selective for?

A

Beta-adrenergic with little effects on the alpha receptors.

56
Q

What is midodrine’s mechanism of action?

What is it used to treat?

A

Midodrine is a pro-drug, metabolite that is selective Alpha1 agonist.
-Midodrine is used for treatment of orthostatic hypertension.

57
Q
  • What is Phenylephrine’s mechanism of action?

- What does Phenylephrine treat?

A
  • Phenylephrine is a pure alpha1 selective agonist with a long plasma half life.
  • It treats nasal decongestant, mydriatic, vasopressor, and detumescent (priapism)
58
Q

What are methyldopa, Clonidine, and tizanidine’s mechanism of action.

A
  • Selective agonist of (central) alpha2 adrenergic receptors
59
Q

What do methyldopa and clonidine treat?

What does tizanidine treat?

A
  • hypertension

- muscle relaxant and migraines

60
Q

What receptor is Dobutamine selective for overall?

What are its effect mediated by?

A
  • B1

- alpha and Beta

61
Q

What characteristic of dobutamine makes it useful in treatment of sever heart failure?

A
  • More prominent inotropic effect than chronotropic effect.
62
Q

What selective Beta 2 agonists produce significant bronchodilation (to treat asthma)?

A
  • Metaproterenol
  • Terbutaline
  • Albuterol
  • Formoterol (COPD treat)
  • Salmeterol
  • Ritodrine
63
Q

What are some side effects of direct-acting sympathomimetics?

A

May cause hypoxia, arrhythmias, and other side effects:

- formoterol and salmeterol are to be used only in combination with inhaled corticosteroids

64
Q

What are the mixed-acting sympathomimetics?

A

Ephedrine (non-specific) and Pseudoephedrine.

65
Q

What is ephedrine used to treat?

A

Occasionally used for treatment of refractory hypotension, by stimulating the release of catecholamines. Used in “coastguard cocktail”

66
Q

What is pseudoephedrine an active ingredient in?

A
  • Widely used in nasal decongestants.
67
Q

What are the indirect-acting sympathomimetics?

A

Amphetamines (amphetamine, methamphetamine, and methlphenidate), Catecholamine Reuptake Inhibitors (Atomoxetine, Duloxetine, Cocaine), Dopamine Agonists (Fenoldopam, Bromocriptine, Ropinirole, Pramipexole)

68
Q

What is the mechanism of action of amphetamines?

A
  • It causes the release of norepinephrine and dopamine to a lesser extent. CNS stimulant and appetite suppressant. Its use and misused (military “go pill”.
69
Q

What is the mechanism of action of methamphetamine?

A

Similar to amphetamine, stronger CNS effects. Used to treat ADD.

70
Q

What is the mechanism of action of methylphenidate?

A

Effective in some children with attention deficit hyperactivity.

71
Q

What is Atomoxetine’s mechanism of action, clinical uses, side effects?

A
  • Selective inhibitor of NE reuptake transporter
  • Used to treat ADD
  • Side effects: orthostatic tachycardia and hypertension in some patients.
72
Q

What is Duloxetine’s mechanism of action and clinical uses.

A
  • Serotonin and norepinephrine uptake inhibitor widely used as an anti-depressant.
  • Approved for management of fibromyalgia.
73
Q

What is Fenoldopam’s mechanism of action and clinical uses?

A
  • D1 selective (partial) agonist

- Treatment of sever hypertension.

74
Q

What is Bromocriptine’s mechanism of action and clinical uses?

A
  • Agonist for all dopamine receptors and some serotonin receptors, but with the strongest effect at D2 receptors.
  • Treats Parkinson’ and pituitary adenomas with excess prolactin.
75
Q

What is the mechanism of action of Pramipexole and its clinical uses?

A
  • D3 selective agonist effective in conjunction with levodopa for advanced Parkinson’s.
76
Q

What is phenoxybenzamine’s mechanism of action?

A

Irreversible blockade of apha receptors (slightly less selective for alpha1 than for alpha2)
- May increase cardiac output (via peripheral alpha2 )

77
Q

What are Phenoxybenzamine’s clinical uses and side effects?

A
  • Treats pheochromocytoma (pre-op)

- Side effects: nasal stuffiness, orthostatic hypotension, tachycardia, and inhibition of ejaculation.

78
Q

Name the Alpha Receptor Antagonists. ALL OF THEM!!

A
  • Phenoxybenzamine
  • Phentolamine
  • Prazosin
  • Terazosin
  • Doxazosin
  • Tamsulosin
  • Alfuzosin
  • Labetalol
  • Chlorpromazine, Haloperidol
79
Q

What is the mechanism of action of Prazosin and what are its clinical uses?

A
  • Dilates both arteries and veins, relative absence of tachycardia.
  • Highly selective for alpha1 receptors
  • effective for management of hypertension.
80
Q

What is the Clinical use of Terazosin?

A

-An alpha 1 antagonist used for treatment of hypertension and urinary complications associated with benign prosthetic hyperplasia (BPH)

81
Q

What is the clinical use of Doxazosin?

A
  • Treatment of hypertension and BPH

- Long plasma half-life

82
Q

What is the selectivity of Tamsulosin for and what are some clinical uses?

A
  • More selective for alpha1A and alpha1D receptors.
  • Used for prostate smooth muscle contraction than vascular smooth muscle.
  • Treats BPH, less orthostatic hypotension compared to others.
83
Q

What is Alfuzosin selective for?
What is its clinical uses?
What are its possible side effects?

A
  • alpha1 selective anatgonist
  • Treats BPH
  • May cause QT prolongation in some patients
84
Q

What is Labetalol’s selectivity?

What is it effect in treating?

A
  • Alpha1 selective and B- antagonist

- Effective for control of blood pressure in patients with pre-eclampsia.

85
Q

What is Chlorpromazine and Haloperidol’s mechanism of action and what are its side effects?

A
  • neuroleptic with significant dopamine antagonist effects.

- Have an alpha antagonist side effects.

86
Q

What are the general effects of the beta receptor antagonist on the cardiovascular system?

A
  • Controls BP
  • Modulate renal renin release
  • Effective in treatment of: angina, heart failure, and post ischemic heart attack.
87
Q

What are the general effect of the beta receptor antagonists on the Respiratory system?

A
  • Beta1 selective agents (metoprolol, atenolol) have an advantage over non-selective B1 and B2 blockers in asthmatic patients.
  • Should all be avoided in asthma, but may be tolerated in some patients with COPD**
88
Q

What are the Beta Receptor Antagonist’s effect in the eyes?

A
  • Beta antagonists decrease intraocular pressure, effects more prominent in glaucoma.
  • Decreases synthesis of aqueous humor.
89
Q

What are the Beta Receptor Antagonist’s effect on the metabolic system?

A
  • Decrease in sympathetic- mediated lipolysis
  • Decrease in hepatic glycogenolysis –> must be used with caution in patients with insulin-dependent diabetes mellitus.
  • beta agonists are much sager in type 2 diabetes mellitus (less frequent episodes of hypoglycemia)
  • Prolonged use of Beta-blockers–>plasma increase in VLDL and low HDL
90
Q

What are some extra beta adrenergic effects of metoprolol, labetalol, propranlol and sotalol.

A 
metaprolol, labetalol, and propranolol exhibit membrane stabilizing properties.
- Sotalol is an effective class 3 antiarrhythmic drug
91
Q

What is the mechanism of action of the Propranolol, nadolol, and timolol.
What are they used to treat?

A
  • Prototype Beta- blocking drug, low and dose dependent bioavailability.
  • Available in sustained release preparations for long-term management of various cardiovascular diseases
  • Timolol for Glaucoma
92
Q

What is the mechanism of action of Metoprolol, atenolol, nebivolol?

A
  • Preferred (over non-selective blockers) in patients with diabetes mellitus.
  • May be beneficial even in some patients with COPD (Post MI)
  • Nebivolol, highly selective for Beta1 and exhibits additional effects of vasodilation
93
Q

What is the mechanism of action for Pindolol and acebutolol and what are they effective in treating?

A
  • A partial agonist at both B1 and B2 (B1=B2),
  • Advantage: less decrease in heart rate, blood pressure, abnormalities in plasma lipids, etc than with ordinary antagonists
  • Effective in treating hypertension and angina.
94
Q

What is the mechanism of action for Acebutolol? What is a potential side effect?

A
  • A partial agonist at Beta1 with no effect on Beta2, used for the management of hypertension
  • May prouduce less bradycardia.
95
Q

Name two alpha-beta antagonists?

A

Carvedilol and Labetalol

96
Q

What is the mechanism of action of Carvedilol?

What is its clinical usage?

A

It inhibits mitogenesis in vascular smooth muscles and the formation of injurious foam cells.

  • Especially effective for treatment of chronic heart failure with decreased systolic function.
  • 1 chiral center (S form is the active form)
97
Q

What is the mechanism of action of Carvedilol?
What is its clinical usage?
What are the side effects of Carvedilol?

A
  • Two chiral centers (4 enantiomers each with different functions), overall drug’s effect is a combo of the racemic mixtures alpha and Beta
  • Treats hypertensive emergencies, pregnancy-induced high blood pressure.
  • Side effects: Hepatitis

Pharmacology (4 decks)

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