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Pharmacology Exam 2 > Intro to Adrenergic Pharmacology > Flashcards

Intro to Adrenergic Pharmacology Flashcards

1
Q

What are 4 dopaminergic pathways in the CNS?

A
  1. Nigrostriatal
  2. Mesocortical and mesolimbic
  3. Tubero-infundibular pathway
  4. Area postrema
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1
Q

What does degeneration of the Nigrostriatal pathway lead to?

A

Parkinson’s Disease

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2
Q

Describe the Nigrostriatal pathway

A

The nigrostriatal pathway projects from substantia nigra (pars compacta) to striatum. D1 and D2 are the predominant subtype and they are involved in the production of movement.
It is the largest dopamine pathway in the CNS (80% of total dopamine)

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2
Q

What is the largest dopamine pathway in the CNS?

A

Nigrostriatal - produces 80% of total dopamine

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3
Q

Which pathway involves DA input to the cerebral cortex and nucleus accumbens form the ventral tegmental area?

A

Mesocortical and Mesolimbic pathway

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3
Q

What brain functions are involved in the VTA?

A

cognition, motivation, drug addiction and intense emotions

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4
Q

What is the nucleus accumbens known for?

A

pleasure center

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4
Q

What is mesocortical associated with?

A

motivation and emotional resposne

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5
Q

What is mesolimbic associated with?

A

“reward”

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5
Q

What pathology are the mesocortical and mesolimbic pathways implicated in?

A

schizophrenia, addiction, and other psychotic Sx

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6
Q

What pathway projects neurons from teh arcuate and paraventricular nuclei of the hypothalamus to the anterior pituitary?

A

Tubero-infundibular pathway

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6
Q

The tubero-infundibular pathway tonically inhibits release of _________

A

Prolactin

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7
Q

What area of the brain has a high density of mostly D2 dopamine receptors and is associated with emesis?

A

Area postrema

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7
Q

What system projects from pons to the cerebral cortex, hypothalamus, and cerebellum?

A

noradrenagic system (norepinephrine)

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8
Q

What is the center in the pons linked with stress and anxiety

A

locus coeruleus

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8
Q

What are functions of the noradrenergic system?

A

-mediates teh psycho-stimulative effects of drugs of abuse such as cocaine and amphetamine and Tx of attention deficit hyperactivity disorder

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9
Q

What system recieves input from teh baroreceptors and chemoreceptors?

A

nucleus tractus solitarius

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9
Q

What is the function of the nucleus tractus solitarius?

A

regulate sympathetic peripheral outflow including BP regulation

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10
Q

What mediates inotropic and chronotropic effects of sympathetic input to the SA and AV nodes of the heart?

A

B1 adrenergic receptors

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10
Q

What does stimulation of B1 adrenergic receptors of the heart do?

A

increase the rate and force of contraction of the heart

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11
Q

What are 4 heart diseases that are treated by targeting the B1 adrenergic receptors?

A
  1. supraventricular tachyarrhythmias (class 2 antiarrhythmic agents - metoprolol, propranolol, etc)
  2. angina pectoris
  3. decompensate heart failure
  4. hypertension
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11
Q

Why might a treatment for asthma cause a pt to have side effects of tachycardia?

A

Because both require stimulation of B receptors. B2 receptors promote vasodilation of bronchioles and B1 receptors promote increased contractility in the heart.

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12
Q

What controls tone and total peripheral vascular resistance on vascular smooth muscles?

A

alpha adrenergic receptors

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12
Q

What diseases do pharmacologic agents target alpha adrenergic receptors for?

A
  1. hypertension
  2. benign prosthetic hyperplasia
  3. glaucoma
  4. pheochromocytoma
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13
Q

What causes relaxation upon stimulation in the splanchnic, coronary, renal and cerebral vasculature as well as diuresis upon stimulation?

A

D1 receptors

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13
Q

What causes vascular smooth relaxation?

A

B2 receptors

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14
Q

If you give just an a1 adrenergic receptor drug by itself with no beta blocker, what will happen?

A

the baroreceptors in the carotid sinus will increase HR because BP backs up and leads to tachycardia

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14
Q

What receptors mediate renin release on the JG apparatus in the kidneys?

A

B1 adrenergic receptors

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15
Q

What mediates natriuresis and diuresis along the PCT of the nephron?

A

DA receptors

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15
Q

what is an anti-hypertensive agent that acts in the kidney?

A

fenoldopam

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16
Q

What mediates norepinephrine and epinephrine in lipid catabolism of adipose tissues?

A

B3 receptors

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16
Q

What does epinephrine have higher affinity for: a-receptors or B-receptors?

A

B-receptors (esp B2)

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17
Q

What are 4 major effects of epinephrine?

A
  1. positive inotropic and chronotropic effects on the heart
  2. decreased TPR in vasculature
  3. increased blood flow to muscles
  4. dilation of airways
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17
Q

What does norepinephrine hhave higher affinity for: a-receptors or B-receptors?

A

a-receptors

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18
Q

What are 3 major effects of norepinephrine?

A
  1. increase TPR in vasculature
  2. decrease capacity of capacitance vessels
  3. positive inotropic effects on the heart
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18
Q

What are 4 types of catecholamines?

A
  1. Epinephrine
  2. Norepinephrine
  3. Dopamine
  4. Isoproterenol
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19
Q

What are the major effects of Dopamine?

A

produces vasodilation of renal, splanchnic, coronary, and cerebral vascular beds

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19
Q

What receptors do dopamine bind to?

A

alpha-s, beta-s, Ds - selective for Ds

  • effects depend on receptor subtype and vary with concentration
  • at high doses, DA can interact with adrenergic receptors
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20
Q

What receptors are isoproterenol selective for?

A

B receptors; little effect on alpha receptors

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20
Q

What are the major effects of isoproterenol?

A

potent vasodilator with positive inotropic and chronotropic effects on the heart

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21
Q

What are 5 types of direct-acting sympathomimetic drugs?

A
  1. Midodrine - Tx of orthostatic HTN
  2. Phenylephrine - nasal decongestant
  3. Methyldopa, Clonidine, Tizanidine - HTN
  4. Dobutamin - diagnostic agent for heart disease
  5. Selective B2 agonists - asthma and COPD
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21
Q

What pro-drug direct-acting sympathomimetic is a selective a1 agonist used for the Tx of orthostatic HTN?

A

Midodrine

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22
Q

What direct-acting sympathomimetic drug is a pure alpha-1 selective agonist wiht a long plasma half life and resistant to COMT metabolism?

A

Phenylephrine

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22
Q

What are the effects of phenylephrine?

A

nasal decongestant, mydriatic, vasopressor, and detumescent (often used to treat priapism)

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23
Q

What direct-acting sympathomimetic drugs are selective agonists of alpha2 adrenergic receptors?

A

methyldopa, clonidine, and tizanidine

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23
Q

What sympathomimetic drugs are used for Tx of hypertension?

A

methyldopa and clonidine

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24
Q

What sympathomimetic drug is used as a muscle relaxant and for migraines?

A

tizanidine

*tizanidine is used to treat neuropathic pain because it inhibits transmission of NT in transmitting pain to the CNS

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24
Q

Describe the receptor activity for the direct-acting sympathomimetic drug Dobutamine,

A

selective overall for B1 receptors but its effects are mediated by both alpha and Beta receptors

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25
Q

What is Dobutamine used for?

A

more prominent inotropic than chronotropic effects, used in severe heart failure
- it is used in conjunction with imaging as a diagnostic agent for ischemic heart disease

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25
Q

Why is Dobutamine only used as a secondary drug?

A

It is selective for B1 receptors, but was used for asthma. Because of the selectivity for B1 receptors though, it often causes Sx of angina for susceptible pts which is why it is only used as a secondary drug.

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26
Q

What are 5 selective B2 agonists and what is their primary effect?

A
  1. metaproterenol
  2. terutaline
  3. albuterol
  4. formoterol
  5. salmeterol (a partial agonist)
    * all produce significant bronchodilation in treatment of asthma and COPD (formeterol)
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26
Q

What are side effects of selective B2 agonists?

A

hypoxia and arrhythmias

*formoterol and salmeterol are to be used only in combo with inhaled corticosteroids

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27
Q

What are 2 mixed-acting sympathomimetics?

A
  1. Ephedrin

2. Pseudoephedrine

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27
Q

Which mixed-acting sympathomimetic drug is an effective but non-specific adrenergic receptor agonsit and is occasionally used for Tx of refractory hypotension?

A

Ephedrine - stimulates release of catecholamine

*it is part of the coastguard cocktail because alleviates Sx of motion sickness in coastguards

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28
Q

What is pseudoephedrine typically used for?

A

widely used as an active ingredient in nasal decongestant

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28
Q

What are 3 indirect-acting sympathomimetics that are amphetamine-like agents?

A
  1. amphetamine
  2. methamphetmine
  3. methylphenidate
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29
Q

How does amphetamine cause its effects?

A

Amphetamine causes the release of NE and DA to a lesser extent. It is a CNS stimulant and appetite suppressant. It is used as a military “go pill”.

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29
Q

What is the significance of methamphetamine?

A

It is similar to amphetamine but it has stronger CNS effects

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30
Q

What is methylphenidate effective for?

A

used for kids with ADHD

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30
Q

What are 3 indirect-acting sympathomimetic drugs that act as catecholamine reuptake inhibitors?

A
  1. Atomoxetine
  2. Duloxetine
  3. Cocaine
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31
Q

How does Atomoxetine cause its effects?

A

It is a selective inhibitor of NE reuptake transporter that is used to treat ADD. It can cause orthostatic tachycardia adn hypertension in some pts

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31
Q

How does Duloxetine cause its effects?

A

It is a serotonin and NE uptake inhibitor that is widely used as an antidepressant. It can be used with milnacipran (also a serotonin and NE uptake inhibitor) approved for the management of fibromyalgia

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32
Q

What are 4 DA agonists that are indirect-acting sympathomimetic drugs?

A
  1. Fenoldopam
  2. Bromocriptine
  3. Ropinirole
  4. Pramipexole
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32
Q

What is Fenoldopam used for?

A
  • Tx of severe hypertension

- D1 selective (partial) agonist

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33
Q

What is Bromocriptine used for?

A
  • agonist for all dopamine receptors and some serotonin receptors but with strongest effect at D2 receptors
  • mimcs dopamine in the CNS for management of Parkinson’s pituitary adenomas with excess PRL
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33
Q

What is Ropinirole used for?

A

nearly a pure D2 agonist, effective monotherapy mild Parkinson’s

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34
Q

What is Pramipexole used for?

A

D3 selective agonist effective in conjunction with levodopa for advanced Parkinson’s
-Neuroprotective effects - prevents neurodegeneration

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34
Q

What are 9 types of alpha receptor antagonists?

A
  1. Phenoxybenzamine
  2. Phentolamine
  3. Prazosin
  4. Terazosin
  5. Doxazosin
  6. Tamsulosin
  7. Alfuzosin
  8. Labetalol
  9. Chlorpromazine, Haloperidol
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35
Q

Phenoxybenzamine

A
  • irreversible blockade of alpha receptors, slightly selective for a1 than a2
  • may increase CO (peripheral a2 blockade, reflex tachycardia)
  • Tx of pheochromocytoma
  • side effects: nasal stuffiness, orthostatic hypotension, tachycardia, and inhibition of ejaculation
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35
Q

Phentolamine

A
  • potent alpha blocker for a1 and a2 equally
  • occassionally used for Tx of pheochromocytoma, reversal of local anesthesia in soft tissues
  • severe tachyarrhythmias, myocardial ischemia, erectile dysfunction
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36
Q

What is one of the main differences between phenoxybenzamine and phentolamine?

A

In phenoxybenzamine, a1 is blocked but a2 is spared, so sympa system is spared
-in phentolamine - a1 and a2 are blocked so there will be more tachycardia and increased risk of orthostatic hypotension

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36
Q

Prazosin

A
  • highly selective for a1 receptors, effective for management of HTN
  • dilate both arteries and veins, relative absence of tachycardia
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37
Q

Terazosin

A

-alpha1-selective antagonist, used for the Tx of HTN, urinary complications associated with benign prosthetic hyperplasia (BPH)

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37
Q

Doxazosin

A

For Tx of HTN and BPH, long plasma half life

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38
Q

Tamsulosin

A
  • more selective alpha1A and alpha1D receptors, incline for prostate smooth muscle contraction than vascular smooth muscles
  • effective for Tx of BPH, less orthostatic hypotension compared to others
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38
Q

Alfuzosin

A
  • alpha-selective anatagonist approved for the Tx of BPH

- may cause QT prolongation in some patients

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39
Q

Labetalol

A

-alpha1 selective and B-antagonist. effective for control of BP in pts with pre-eclampsia

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39
Q

Chlorpromazine and Haloperidol

A
  • neuroleptic with significant dopamine antagonist effects

- have alpha antagonist effects (may contribute to their side effects)

40
Q

How do beta receptor antagonists affect the cardiovascular system?

A
  • long term therapy with B-blockers effectively controls BP in hypertensive pts
  • modulate renal renin release, hypotension not a usual side effect
  • effective in management of angina, heart failure, and pts following ischemic heart attack
40
Q

How do beta receptor antagonists affect the respiratory system?

A
  • B1- selective agents (metroprolol, atenolol) have an advantage over non-selective B1 and B2 blockers in asthmatic pts
  • should all be avoided in asthma, but may be tolderated in some pts with COPD
41
Q

How do beta receptor antagonists affect the eyes?

A
  • beta antagonists decrease intraocular pressure - effects are more prominent in galucoma
  • decreased synthesis of aqueous humor
41
Q

How do beta receptor antagonists affect the metabolic system?

A
  • decreased sympathetic-mediated lipolysis
  • decreased hepatic glycogenolysis (at least mediated by B2) - must be used with caution in pts with IDDM
  • B agonists much safer in Type 2 DM (less frequent episodes of hypoglycemia)
  • prolonged use of B-blockers - plasma increase in VLDL and low HDL
42
Q

How do beta receptor antagonists affect the extra beta adrenergic effects?

A 
metoprolol, labetalol, propranolol exhibit membrane stabilizing properties
-sotalol is an effective class 3 antiarrhythmic drug
42
Q

Which beta antagonistic drugs are equally selective for B1 and B2?

A
  • propranolol, nadolol, timolol
  • they are prototype B-blocking drugs, low and dose-dependent bioavailability
  • available in sustained release preparations for long-term management of various cardiovascular diseases (HTN, angina, etc.)
43
Q

What is Timolol used for?

A

glaucoma

43
Q

What beta antagonists are selective for B1?

A
  • metoprolol, atenolol, and nebivolol
  • preferred in pts with DM over non-selective blockers
  • may be beneficial even in some pts with COPD, i.e. after MI
44
Q

Which drug is highly selective for B1 and exhibits additional effects of vasodilation?

A

Nebivolol

44
Q

Which beta antagonist drugs serve as partial agonists at both B1 and B2?

A

pindolol and acebutolol

  • advantages: less decrease in HR, BP, abnormalities in plasma lipids than with ordinary antagonists
  • effective in treating hypertension and angina :
45
Q

Which beta antagonist drug is a partial agonist at B1 with no effect on B2 and what is it used for?

A

Acebutolol - used for the management of hypertension, may produce less bradycardia

45
Q

What are 2 mixed alpha-beta antagonists?

A
  1. Carvedilol

2. Labetalol

46
Q

Carvedilol

A
  • more potent at B receptors than at a1
  • 1 chiral center, 2 enantiomers with different metabolic kinetics, (R)-carvedilol is degraded by CYP2D6 - increased potential for drug interactions
  • inhibits mitogenesis in vascular smooth muscles and the formation of injurious foam cells
  • especially effective for treatmetn of chronic heart failure with decreased systolic function
46
Q

Labetalol

A
  • 2 chiral centers, four enantiomers with different pharmacologic properties
  • overall drug’s effeect is a combination of the racemic mixture –> a and B antagonist effects (slight selectivity for a1)
  • Tx of hypertensive emergencies, pregnancy-induced high BP
  • may induce hepatits
47
Q

Which catecholamine is a precursor to all others and is present in sympathetic neurons and chromaffin cells?

A

Dopamine

47
Q

What 2 diseases are DA implicated in?

A

Schizophrenia and Parkinson’s Disease

48
Q

Which neurotransmitter is the primary NT of sympathetic neurons, is produced by chromaffin cells, and comprises 20% of catecholamines?

A

Norepinephrine

48
Q

What are 2 major effects of NE?

A
  1. peripheral vascular tone

2. some forms of hypertension

49
Q

What catecholamine is synthesized predominantly in chromaffin cells and comprises 80% of catecholamines?

A

Epinephrine

49
Q

What disease does epinephrine mediate the symptoms of?

A

pheochromocytoma

50
Q

What are all endogenous catecholamines synthesized from?

A

tyorsine

50
Q

What are the different steps in catecholamine production?

A
  1. Tyrosine
  2. DOPA
  3. Dopamine
  4. Norepinephrine
  5. Epinephrine
51
Q

What is the rate limiting enzyme in catecholamine synthesis?

A

tyrosine carboxylase: converts tyrosine to DOPA in substantia nigra

51
Q

What transports newly synthesized dopamine from the cytosol to vesicles for storage?

A

VMAT (vesicular monoamine transporter)

52
Q

What enzyme converts dopamine to norepinephrine and where does this occur?

A

dopamine B-hydroxylase converts DA to NE in postganglionic sympathetic neurons within sympathetic vesicles

52
Q

What enzyme converts NE to Epi and where does this occur?

A

NE is converted to Epi by phenyl ethanolamine N-methyl transferase in chromaffin cells - NE is transported/diffused from vesicle into cytosol for conversion to Epi

53
Q

What triggers the release of catecholamines?

A

action potential, calcium influx, and endocytosis

53
Q

What are the 3 mechanisms involved in the termination of action potential and what is the predominant form of termination?

A
  1. reuptake (major)
    2 metabolism (minor)
  2. diffusion away from cleft (minor)
54
Q

How do anti-depressants affect levels of NE in the synaptic cleft?

A

Anti-depressants inhibit transporters and therefore prolong the effect of NE in the synaptic terminal

54
Q

Distinguish between MAO-A (monoamine oxididase) and MOA-B

A
  1. MAO preferentially degrades 5HT, NE, and DA

2. MAO-B degrades DA more rapidly than 5HT and NE

55
Q

What are 3 MAO inhibitors and what clinical use are they effective for?

A
  1. selegiline
  2. isocarboxazid
  3. phenelzine
    * effective in treating depression
55
Q

What is a cytosolic enzyme expressed primarily in the liver but also in the brain?

A

catechol-o-methyl transferase (COMT)

56
Q

What is the excretion product of both the COMT and MAO degradation pathway?

A

Vanilymandelic acid (VMA)

56
Q

What disease is characterized by an increase of VMA?

A

pheochromocytoma

57
Q

What are alpha-1 adrenergic receptors coupled to and describe the pathway? What is their primary function?

A

coupled to Gq GPCR which stimulates PLC and increases levels of DAG and IP3

  • DAG activates PKC and phosphorylates target proteins
  • IP3 releases Ca2+ from IC stores and muscle contraction
  • MAP kinase and IP3 kinase cascades are also activated by a1 - receptor mediated stimulation of cell growth and proliferation
  • increases TPR of smooth muscle
57
Q

Where are alpha-1 receptors expressed?

A

*postsynaptic terminals in vascular smooth muscles: UG tract smooth muscles, prostate, heart, liver, etc.

58
Q

What are alpha-2 adrenergic receptors coupled to and describe the pathway?

A

couped to Gi GPCR which inhibits AC and decreases cAMP leevls
-inward rectifier of K+ cannels and neuronal Ca2+ channels

58
Q

What is the primary function of alpha-2 receptors?

A
  • counteracts effects of alpha-1
  • alpha-2 acts as an autoreceptor and safety valve, i.e. when NE binds to A1, excess NE will bind A2 to counteract the effects of A1 to prevent overstimulation
59
Q

Where are A2 adrenergic receptors expressed?

A

both pre-synaptic terminals mostly (as autoreceptors) and sometimes post-synaptic terminals

59
Q

What are beta adrenergic receptors coupled to and describe the pathway?

A

all 3 isoforms of B receptors (B1, B2, and B3) are coupled to Gs and increase cAMP

60
Q

What are the functions of B1, B2, and B3 resepectively?

A
  • B1 - expressed in heart and kidneys to increase heart contractility and BP (RAAS)
  • B2- expressed in liver and skeletal muscles for vasodilation
  • B3- adipose tissue to stimulate lipolysis
60
Q

What are 5 clinical applications of B receptors?

A
  1. asthma
  2. cardiac arrhythmias
  3. angina
  4. HTN
  5. COPD
61
Q

How does Atomoxetine cause its effects?

A

It is a selective inhibitor of NE reuptake transporter that is used to treat ADD. It can cause orthostatic tachycardia adn hypertension in some pts

61
Q

How does Atomoxetine cause its effects?

A

It is a selective inhibitor of NE reuptake transporter that is used to treat ADD. It can cause orthostatic tachycardia adn hypertension in some pts

62
Q

How does Duloxetine cause its effects?

A

It is a serotonin and NE uptake inhibitor that is widely used as an antidepressant. It can be used with milnacipran (also a serotonin and NE uptake inhibitor) approved for the management of fibromyalgia

62
Q

How does Duloxetine cause its effects?

A

It is a serotonin and NE uptake inhibitor that is widely used as an antidepressant. It can be used with milnacipran (also a serotonin and NE uptake inhibitor) approved for the management of fibromyalgia

63
Q

What are 4 DA agonists that are indirect-acting sympathomimetic drugs?

A
  1. Fenoldopam
  2. Bromocriptine
  3. Ropinirole
  4. Pramipexole
63
Q

What are 4 DA agonists that are indirect-acting sympathomimetic drugs?

A
  1. Fenoldopam
  2. Bromocriptine
  3. Ropinirole
  4. Pramipexole
64
Q

What is Fenoldopam used for?

A
  • Tx of severe hypertension

- D1 selective (partial) agonist

64
Q

What is Fenoldopam used for?

A
  • Tx of severe hypertension

- D1 selective (partial) agonist

65
Q

What is Bromocriptine used for?

A
  • agonist for all dopamine receptors and some serotonin receptors but with strongest effect at D2 receptors
  • mimcs dopamine in the CNS for management of Parkinson’s pituitary adenomas with excess PRL
65
Q

What is Bromocriptine used for?

A
  • agonist for all dopamine receptors and some serotonin receptors but with strongest effect at D2 receptors
  • mimcs dopamine in the CNS for management of Parkinson’s pituitary adenomas with excess PRL
66
Q

What is Ropinirole used for?

A

nearly a pure D2 agonist, effective monotherapy mild Parkinson’s

66
Q

What is Ropinirole used for?

A

nearly a pure D2 agonist, effective monotherapy mild Parkinson’s

67
Q

What is Pramipexole used for?

A

D3 selective agonist effective in conjunction with levodopa for advanced Parkinson’s
-Neuroprotective effects - prevents neurodegeneration

67
Q

What is Pramipexole used for?

A

D3 selective agonist effective in conjunction with levodopa for advanced Parkinson’s
-Neuroprotective effects - prevents neurodegeneration

68
Q

What are 9 types of alpha receptor antagonists?

A
  1. Phenoxybenzamine
  2. Phentolamine
  3. Prazosin
  4. Terazosin
  5. Doxazosin
  6. Tamsulosin
  7. Alfuzosin
  8. Labetalol
  9. Chlorpromazine, Haloperidol
69
Q

Phenoxybenzamine

A
  • irreversible blockade of alpha receptors, slightly selective for a1 than a2
  • may increase CO (peripheral a2 blockade, reflex tachycardia)
  • Tx of pheochromocytoma
  • side effects: nasal stuffiness, orthostatic hypotension, tachycardia, and inhibition of ejaculation
70
Q

Phentolamine

A
  • potent alpha blocker for a1 and a2 equally
  • occassionally used for Tx of pheochromocytoma, reversal of local anesthesia in soft tissues
  • severe tachyarrhythmias, myocardial ischemia, erectile dysfunction
71
Q

What is one of the main differences between phenoxybenzamine and phentolamine?

A

In phenoxybenzamine, a1 is blocked but a2 is spared, so sympa system is spared
-in phentolamine - a1 and a2 are blocked so there will be more tachycardia and increased risk of orthostatic hypotension

72
Q

Prazosin

A
  • highly selective for a1 receptors, effective for management of HTN
  • dilate both arteries and veins, relative absence of tachycardia
73
Q

Terazosin

A

-alpha1-selective antagonist, used for the Tx of HTN, urinary complications associated with benign prosthetic hyperplasia (BPH)

74
Q

Doxazosin

A

For Tx of HTN and BPH, long plasma half life

75
Q

Tamsulosin

A
  • more selective alpha1A and alpha1D receptors, incline for prostate smooth muscle contraction than vascular smooth muscles
  • effective for Tx of BPH, less orthostatic hypotension compared to others
76
Q

Alfuzosin

A
  • alpha-selective anatagonist approved for the Tx of BPH

- may cause QT prolongation in some patients

77
Q

Labetalol

A

-alpha1 selective and B-antagonist. effective for control of BP in pts with pre-eclampsia

78
Q

Chlorpromazine and Haloperidol

A
  • neuroleptic with significant dopamine antagonist effects

- have alpha antagonist effects (may contribute to their side effects)

79
Q

How do beta receptor antagonists affect the cardiovascular system?

A
  • long term therapy with B-blockers effectively controls BP in hypertensive pts
  • modulate renal renin release, hypotension not a usual side effect
  • effective in management of angina, heart failure, and pts following ischemic heart attack
80
Q

How do beta receptor antagonists affect the respiratory system?

A
  • B1- selective agents (metroprolol, atenolol) have an advantage over non-selective B1 and B2 blockers in asthmatic pts
  • should all be avoided in asthma, but may be tolderated in some pts with COPD
81
Q

How do beta receptor antagonists affect the eyes?

A
  • beta antagonists decrease intraocular pressure - effects are more prominent in galucoma
  • decreased synthesis of aqueous humor
82
Q

How do beta receptor antagonists affect the metabolic system?

A
  • decreased sympathetic-mediated lipolysis
  • decreased hepatic glycogenolysis (at least mediated by B2) - must be used with caution in pts with IDDM
  • B agonists much safer in Type 2 DM (less frequent episodes of hypoglycemia)
  • prolonged use of B-blockers - plasma increase in VLDL and low HDL
83
Q

How do beta receptor antagonists affect the extra beta adrenergic effects?

A 
metoprolol, labetalol, propranolol exhibit membrane stabilizing properties
-sotalol is an effective class 3 antiarrhythmic drug
84
Q

Which beta antagonistic drugs are equally selective for B1 and B2?

A
  • propranolol, nadolol, timolol
  • they are prototype B-blocking drugs, low and dose-dependent bioavailability
  • available in sustained release preparations for long-term management of various cardiovascular diseases (HTN, angina, etc.)
85
Q

What is Timolol used for?

A

glaucoma

86
Q

What beta antagonists are selective for B1?

A
  • metoprolol, atenolol, and nebivolol
  • preferred in pts with DM over non-selective blockers
  • may be beneficial even in some pts with COPD, i.e. after MI
87
Q

Which drug is highly selective for B1 and exhibits additional effects of vasodilation?

A

Nebivolol

88
Q

Which beta antagonist drugs serve as partial agonists at both B1 and B2?

A

pindolol and acebutolol

  • advantages: less decrease in HR, BP, abnormalities in plasma lipids than with ordinary antagonists
  • effective in treating hypertension and angina :
89
Q

Which beta antagonist drug is a partial agonist at B1 with no effect on B2 and what is it used for?

A

Acebutolol - used for the management of hypertension, may produce less bradycardia

90
Q

What are 2 mixed alpha-beta antagonists?

A
  1. Carvedilol

2. Labetalol

91
Q

Carvedilol

A
  • more potent at B receptors than at a1
  • 1 chiral center, 2 enantiomers with different metabolic kinetics, (R)-carvedilol is degraded by CYP2D6 - increased potential for drug interactions
  • inhibits mitogenesis in vascular smooth muscles and the formation of injurious foam cells
  • especially effective for treatmetn of chronic heart failure with decreased systolic function
92
Q

Labetalol

A
  • 2 chiral centers, four enantiomers with different pharmacologic properties
  • overall drug’s effeect is a combination of the racemic mixture –> a and B antagonist effects (slight selectivity for a1)
  • Tx of hypertensive emergencies, pregnancy-induced high BP
  • may induce hepatits
93
Q

Which catecholamine is a precursor to all others and is present in sympathetic neurons and chromaffin cells?

A

Dopamine

94
Q

What 2 diseases are DA implicated in?

A

Schizophrenia and Parkinson’s Disease

95
Q

Which neurotransmitter is the primary NT of sympathetic neurons, is produced by chromaffin cells, and comprises 20% of catecholamines?

A

Norepinephrine

96
Q

What are 2 major effects of NE?

A
  1. peripheral vascular tone

2. some forms of hypertension

97
Q

What catecholamine is synthesized predominantly in chromaffin cells and comprises 80% of catecholamines?

A

Epinephrine

98
Q

What disease does epinephrine mediate the symptoms of?

A

pheochromocytoma

99
Q

What are all endogenous catecholamines synthesized from?

A

tyorsine

100
Q

What are the different steps in catecholamine production?

A
  1. Tyrosine
  2. DOPA
  3. Dopamine
  4. Norepinephrine
  5. Epinephrine
101
Q

What is the rate limiting enzyme in catecholamine synthesis?

A

tyrosine carboxylase: converts tyrosine to DOPA in substantia nigra

102
Q

What transports newly synthesized dopamine from the cytosol to vesicles for storage?

A

VMAT (vesicular monoamine transporter)

103
Q

What enzyme converts dopamine to norepinephrine and where does this occur?

A

dopamine B-hydroxylase converts DA to NE in postganglionic sympathetic neurons within sympathetic vesicles

104
Q

What enzyme converts NE to Epi and where does this occur?

A

NE is converted to Epi by phenyl ethanolamine N-methyl transferase in chromaffin cells - NE is transported/diffused from vesicle into cytosol for conversion to Epi

105
Q

What triggers the release of catecholamines?

A

action potential, calcium influx, and endocytosis

106
Q

What are the 3 mechanisms involved in the termination of action potential and what is the predominant form of termination?

A
  1. reuptake (major)
    2 metabolism (minor)
  2. diffusion away from cleft (minor)
107
Q

How do anti-depressants affect levels of NE in the synaptic cleft?

A

Anti-depressants inhibit transporters and therefore prolong the effect of NE in the synaptic terminal

108
Q

Distinguish between MAO-A (monoamine oxididase) and MOA-B

A
  1. MAO preferentially degrades 5HT, NE, and DA

2. MAO-B degrades DA more rapidly than 5HT and NE

109
Q

What are 3 MAO inhibitors and what clinical use are they effective for?

A
  1. selegiline
  2. isocarboxazid
  3. phenelzine
    * effective in treating depression
110
Q

What is a cytosolic enzyme expressed primarily in the liver but also in the brain?

A

catechol-o-methyl transferase (COMT)

111
Q

What is the excretion product of both the COMT and MAO degradation pathway?

A

Vanilymandelic acid (VMA)

112
Q

What disease is characterized by an increase of VMA?

A

pheochromocytoma

113
Q

What are alpha-1 adrenergic receptors coupled to and describe the pathway? What is their primary function?

A

coupled to Gq GPCR which stimulates PLC and increases levels of DAG and IP3

  • DAG activates PKC and phosphorylates target proteins
  • IP3 releases Ca2+ from IC stores and muscle contraction
  • MAP kinase and IP3 kinase cascades are also activated by a1 - receptor mediated stimulation of cell growth and proliferation
  • increases TPR of smooth muscle
114
Q

Where are alpha-1 receptors expressed?

A

*postsynaptic terminals in vascular smooth muscles: UG tract smooth muscles, prostate, heart, liver, etc.

115
Q

What are alpha-2 adrenergic receptors coupled to and describe the pathway?

A

couped to Gi GPCR which inhibits AC and decreases cAMP leevls
-inward rectifier of K+ cannels and neuronal Ca2+ channels

116
Q

What is the primary function of alpha-2 receptors?

A
  • counteracts effects of alpha-1
  • alpha-2 acts as an autoreceptor and safety valve, i.e. when NE binds to A1, excess NE will bind A2 to counteract the effects of A1 to prevent overstimulation
117
Q

Where are A2 adrenergic receptors expressed?

A

both pre-synaptic terminals mostly (as autoreceptors) and sometimes post-synaptic terminals

118
Q

What are beta adrenergic receptors coupled to and describe the pathway?

A

all 3 isoforms of B receptors (B1, B2, and B3) are coupled to Gs and increase cAMP

119
Q

What are the functions of B1, B2, and B3 resepectively?

A
  • B1 - expressed in heart and kidneys to increase heart contractility and BP (RAAS)
  • B2- expressed in liver and skeletal muscles for vasodilation
  • B3- adipose tissue to stimulate lipolysis
120
Q

What are 5 clinical applications of B receptors?

A
  1. asthma
  2. cardiac arrhythmias
  3. angina
  4. HTN
  5. COPD
121
Q

What is the mechanism of D1 and D5 receptors?

A

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

122
Q

Where are D1 receptors found and what is their primary function?

A

D1 receptors are expressed in the kidneys, mesentary, and coronary arteries. They cause RELAXATION in vascular smooth muscles and lead to vasodilation

123
Q

______ is a partial agonist at D1

A

fenoldopam

124
Q

What are D2, D3, and D4 receptors coupled to?

A

Gi GCPR:

  • decrease in cAMP
  • increase in K+ conductance
  • decrease in Ca2+ influx
125
Q

What are 3 diseases that benefit from pharmacological management of dopaminergic receptors?

A
  1. Parkinson’s disease
  2. Schizophrenia
  3. shock (esp ones caused by low CO)
126
Q

What kind of drugs are D2 agonists?

A

antipsychotics

Pharmacology Exam 2 (5 decks)

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