Intro to Adrenergic Pharmacology Flashcards
1
Q
What are 4 dopaminergic pathways in the CNS?
A
- Nigrostriatal
- Mesocortical and mesolimbic
- Tubero-infundibular pathway
- Area postrema
1
Q
What does degeneration of the Nigrostriatal pathway lead to?
A
Parkinson’s Disease
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)
2
Q
What is the largest dopamine pathway in the CNS?
A
Nigrostriatal - produces 80% of total dopamine
3
Q
Which pathway involves DA input to the cerebral cortex and nucleus accumbens form the ventral tegmental area?
A
Mesocortical and Mesolimbic pathway
3
Q
What brain functions are involved in the VTA?
A
cognition, motivation, drug addiction and intense emotions
4
Q
What is the nucleus accumbens known for?
A
pleasure center
4
Q
What is mesocortical associated with?
A
motivation and emotional resposne
5
Q
What is mesolimbic associated with?
A
“reward”
5
Q
What pathology are the mesocortical and mesolimbic pathways implicated in?
A
schizophrenia, addiction, and other psychotic Sx
6
Q
What pathway projects neurons from teh arcuate and paraventricular nuclei of the hypothalamus to the anterior pituitary?
A
Tubero-infundibular pathway
6
Q
The tubero-infundibular pathway tonically inhibits release of _________
A
Prolactin
7
Q
What area of the brain has a high density of mostly D2 dopamine receptors and is associated with emesis?
A
Area postrema
7
Q
What system projects from pons to the cerebral cortex, hypothalamus, and cerebellum?
A
noradrenagic system (norepinephrine)
8
Q
What is the center in the pons linked with stress and anxiety
A
locus coeruleus
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
9
Q
What system recieves input from teh baroreceptors and chemoreceptors?
A
nucleus tractus solitarius
9
Q
What is the function of the nucleus tractus solitarius?
A
regulate sympathetic peripheral outflow including BP regulation
10
Q
What mediates inotropic and chronotropic effects of sympathetic input to the SA and AV nodes of the heart?
A
B1 adrenergic receptors
10
Q
What does stimulation of B1 adrenergic receptors of the heart do?
A
increase the rate and force of contraction of the heart
11
Q
What are 4 heart diseases that are treated by targeting the B1 adrenergic receptors?
A
- supraventricular tachyarrhythmias (class 2 antiarrhythmic agents - metoprolol, propranolol, etc)
- angina pectoris
- decompensate heart failure
- hypertension
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.
12
Q
What controls tone and total peripheral vascular resistance on vascular smooth muscles?
A
alpha adrenergic receptors
12
Q
What diseases do pharmacologic agents target alpha adrenergic receptors for?
A
- hypertension
- benign prosthetic hyperplasia
- glaucoma
- pheochromocytoma
13
What causes relaxation upon stimulation in the splanchnic, coronary, renal and cerebral vasculature as well as diuresis upon stimulation?
D1 receptors
13
What causes vascular smooth relaxation?
B2 receptors
14
If you give just an a1 adrenergic receptor drug by itself with no beta blocker, what will happen?
the baroreceptors in the carotid sinus will increase HR because BP backs up and leads to tachycardia
14
What receptors mediate renin release on the JG apparatus in the kidneys?
B1 adrenergic receptors
15
What mediates natriuresis and diuresis along the PCT of the nephron?
DA receptors
15
what is an anti-hypertensive agent that acts in the kidney?
fenoldopam
16
What mediates norepinephrine and epinephrine in lipid catabolism of adipose tissues?
B3 receptors
16
What does epinephrine have higher affinity for: a-receptors or B-receptors?
B-receptors (esp B2)
17
What are 4 major effects of epinephrine?
1. positive inotropic and chronotropic effects on the heart
2. decreased TPR in vasculature
3. increased blood flow to muscles
4. dilation of airways
17
What does norepinephrine hhave higher affinity for: a-receptors or B-receptors?
a-receptors
18
What are 3 major effects of norepinephrine?
1. increase TPR in vasculature
2. decrease capacity of capacitance vessels
3. positive inotropic effects on the heart
18
What are 4 types of catecholamines?
1. Epinephrine
2. Norepinephrine
3. Dopamine
4. Isoproterenol
19
What are the major effects of Dopamine?
produces vasodilation of renal, splanchnic, coronary, and cerebral vascular beds
19
What receptors do dopamine bind to?
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
20
What receptors are isoproterenol selective for?
B receptors; little effect on alpha receptors
20
What are the major effects of isoproterenol?
potent vasodilator with positive inotropic and chronotropic effects on the heart
21
What are 5 types of direct-acting sympathomimetic drugs?
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
21
What pro-drug direct-acting sympathomimetic is a selective a1 agonist used for the Tx of orthostatic HTN?
Midodrine
22
What direct-acting sympathomimetic drug is a pure alpha-1 selective agonist wiht a long plasma half life and resistant to COMT metabolism?
Phenylephrine
22
What are the effects of phenylephrine?
nasal decongestant, mydriatic, vasopressor, and detumescent (often used to treat priapism)
23
What direct-acting sympathomimetic drugs are selective agonists of alpha2 adrenergic receptors?
methyldopa, clonidine, and tizanidine
23
What sympathomimetic drugs are used for Tx of hypertension?
methyldopa and clonidine
24
What sympathomimetic drug is used as a muscle relaxant and for migraines?
tizanidine
| *tizanidine is used to treat neuropathic pain because it inhibits transmission of NT in transmitting pain to the CNS
24
Describe the receptor activity for the direct-acting sympathomimetic drug Dobutamine,
selective overall for B1 receptors but its effects are mediated by both alpha and Beta receptors
25
What is Dobutamine used for?
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
25
Why is Dobutamine only used as a secondary drug?
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.
26
What are 5 selective B2 agonists and what is their primary effect?
1. metaproterenol
2. terutaline
3. albuterol
4. formoterol
5. salmeterol (a partial agonist)
* all produce significant bronchodilation in treatment of asthma and COPD (formeterol)
26
What are side effects of selective B2 agonists?
hypoxia and arrhythmias
| *formoterol and salmeterol are to be used only in combo with inhaled corticosteroids
27
What are 2 mixed-acting sympathomimetics?
1. Ephedrin
| 2. Pseudoephedrine
27
Which mixed-acting sympathomimetic drug is an effective but non-specific adrenergic receptor agonsit and is occasionally used for Tx of refractory hypotension?
Ephedrine - stimulates release of catecholamine
| *it is part of the coastguard cocktail because alleviates Sx of motion sickness in coastguards
28
What is pseudoephedrine typically used for?
widely used as an active ingredient in nasal decongestant
28
What are 3 indirect-acting sympathomimetics that are amphetamine-like agents?
1. amphetamine
2. methamphetmine
3. methylphenidate
29
How does amphetamine cause its effects?
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".
29
What is the significance of methamphetamine?
It is similar to amphetamine but it has stronger CNS effects
30
What is methylphenidate effective for?
used for kids with ADHD
30
What are 3 indirect-acting sympathomimetic drugs that act as catecholamine reuptake inhibitors?
1. Atomoxetine
2. Duloxetine
3. Cocaine
31
How does Atomoxetine cause its effects?
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
31
How does Duloxetine cause its effects?
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
32
What are 4 DA agonists that are indirect-acting sympathomimetic drugs?
1. Fenoldopam
2. Bromocriptine
3. Ropinirole
4. Pramipexole
32
What is Fenoldopam used for?
- Tx of severe hypertension
| - D1 selective (partial) agonist
33
What is Bromocriptine used for?
- 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
33
What is Ropinirole used for?
nearly a pure D2 agonist, effective monotherapy mild Parkinson's
34
What is Pramipexole used for?
D3 selective agonist effective in conjunction with levodopa for advanced Parkinson's
-Neuroprotective effects - prevents neurodegeneration
34
What are 9 types of alpha receptor antagonists?
1. Phenoxybenzamine
2. Phentolamine
3. Prazosin
4. Terazosin
5. Doxazosin
6. Tamsulosin
7. Alfuzosin
8. Labetalol
9. Chlorpromazine, Haloperidol
35
Phenoxybenzamine
- 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
35
Phentolamine
- 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
36
What is one of the main differences between phenoxybenzamine and phentolamine?
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
36
Prazosin
- highly selective for a1 receptors, effective for management of HTN
- dilate both arteries and veins, relative absence of tachycardia
37
Terazosin
-alpha1-selective antagonist, used for the Tx of HTN, urinary complications associated with benign prosthetic hyperplasia (BPH)
37
Doxazosin
For Tx of HTN and BPH, long plasma half life
38
Tamsulosin
- 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
38
Alfuzosin
- alpha-selective anatagonist approved for the Tx of BPH
| - may cause QT prolongation in some patients
39
Labetalol
-alpha1 selective and B-antagonist. effective for control of BP in pts with pre-eclampsia
39
Chlorpromazine and Haloperidol
- neuroleptic with significant dopamine antagonist effects
| - have alpha antagonist effects (may contribute to their side effects)
40
How do beta receptor antagonists affect the cardiovascular system?
- 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
How do beta receptor antagonists affect the respiratory system?
- 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
How do beta receptor antagonists affect the eyes?
- beta antagonists decrease intraocular pressure - effects are more prominent in galucoma
- decreased synthesis of aqueous humor
41
How do beta receptor antagonists affect the metabolic system?
- 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
How do beta receptor antagonists affect the extra beta adrenergic effects?
```
metoprolol, labetalol, propranolol exhibit membrane stabilizing properties
-sotalol is an effective class 3 antiarrhythmic drug
```
42
Which beta antagonistic drugs are equally selective for B1 and B2?
- 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
What is Timolol used for?
glaucoma
43
What beta antagonists are selective for B1?
- 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
Which drug is highly selective for B1 and exhibits additional effects of vasodilation?
Nebivolol
44
Which beta antagonist drugs serve as partial agonists at both B1 and B2?
pindolol and acebutolol
- advantages: less decrease in HR, BP, abnormalities in plasma lipids than with ordinary antagonists
- effective in treating hypertension and angina :
45
Which beta antagonist drug is a partial agonist at B1 with no effect on B2 and what is it used for?
Acebutolol - used for the management of hypertension, may produce less bradycardia
45
What are 2 mixed alpha-beta antagonists?
1. Carvedilol
| 2. Labetalol
46
Carvedilol
- 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
Labetalol
- 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
Which catecholamine is a precursor to all others and is present in sympathetic neurons and chromaffin cells?
Dopamine
47
What 2 diseases are DA implicated in?
Schizophrenia and Parkinson's Disease
48
Which neurotransmitter is the primary NT of sympathetic neurons, is produced by chromaffin cells, and comprises 20% of catecholamines?
Norepinephrine
48
What are 2 major effects of NE?
1. peripheral vascular tone
| 2. some forms of hypertension
49
What catecholamine is synthesized predominantly in chromaffin cells and comprises 80% of catecholamines?
Epinephrine
49
What disease does epinephrine mediate the symptoms of?
pheochromocytoma
50
What are all endogenous catecholamines synthesized from?
tyorsine
50
What are the different steps in catecholamine production?
1. Tyrosine
2. DOPA
3. Dopamine
5. Norepinephrine
6. Epinephrine
51
What is the rate limiting enzyme in catecholamine synthesis?
tyrosine carboxylase: converts tyrosine to DOPA in substantia nigra
51
What transports newly synthesized dopamine from the cytosol to vesicles for storage?
VMAT (vesicular monoamine transporter)
52
What enzyme converts dopamine to norepinephrine and where does this occur?
dopamine B-hydroxylase converts DA to NE in postganglionic sympathetic neurons within sympathetic vesicles
52
What enzyme converts NE to Epi and where does this occur?
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
What triggers the release of catecholamines?
action potential, calcium influx, and endocytosis
53
What are the 3 mechanisms involved in the termination of action potential and what is the predominant form of termination?
1. reuptake (major)
2 metabolism (minor)
3. diffusion away from cleft (minor)
54
How do anti-depressants affect levels of NE in the synaptic cleft?
Anti-depressants inhibit transporters and therefore prolong the effect of NE in the synaptic terminal
54
Distinguish between MAO-A (monoamine oxididase) and MOA-B
1. MAO preferentially degrades 5HT, NE, and DA
| 2. MAO-B degrades DA more rapidly than 5HT and NE
55
What are 3 MAO inhibitors and what clinical use are they effective for?
1. selegiline
2. isocarboxazid
3. phenelzine
* effective in treating depression
55
What is a cytosolic enzyme expressed primarily in the liver but also in the brain?
catechol-o-methyl transferase (COMT)
56
What is the excretion product of both the COMT and MAO degradation pathway?
Vanilymandelic acid (VMA)
56
What disease is characterized by an increase of VMA?
pheochromocytoma
57
What are alpha-1 adrenergic receptors coupled to and describe the pathway? What is their primary function?
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
Where are alpha-1 receptors expressed?
*postsynaptic terminals in vascular smooth muscles: UG tract smooth muscles, prostate, heart, liver, etc.
58
What are alpha-2 adrenergic receptors coupled to and describe the pathway?
couped to Gi GPCR which inhibits AC and decreases cAMP leevls
-inward rectifier of K+ cannels and neuronal Ca2+ channels
58
What is the primary function of alpha-2 receptors?
* 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
Where are A2 adrenergic receptors expressed?
both pre-synaptic terminals mostly (as autoreceptors) and sometimes post-synaptic terminals
59
What are beta adrenergic receptors coupled to and describe the pathway?
all 3 isoforms of B receptors (B1, B2, and B3) are coupled to Gs and increase cAMP
60
What are the functions of B1, B2, and B3 resepectively?
- 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
What are 5 clinical applications of B receptors?
1. asthma
2. cardiac arrhythmias
3. angina
4. HTN
5. COPD
61
How does Atomoxetine cause its effects?
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
How does Atomoxetine cause its effects?
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
How does Duloxetine cause its effects?
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
How does Duloxetine cause its effects?
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
What are 4 DA agonists that are indirect-acting sympathomimetic drugs?
1. Fenoldopam
2. Bromocriptine
3. Ropinirole
4. Pramipexole
63
What are 4 DA agonists that are indirect-acting sympathomimetic drugs?
1. Fenoldopam
2. Bromocriptine
3. Ropinirole
4. Pramipexole
64
What is Fenoldopam used for?
- Tx of severe hypertension
| - D1 selective (partial) agonist
64
What is Fenoldopam used for?
- Tx of severe hypertension
| - D1 selective (partial) agonist
65
What is Bromocriptine used for?
- 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
What is Bromocriptine used for?
- 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
What is Ropinirole used for?
nearly a pure D2 agonist, effective monotherapy mild Parkinson's
66
What is Ropinirole used for?
nearly a pure D2 agonist, effective monotherapy mild Parkinson's
67
What is Pramipexole used for?
D3 selective agonist effective in conjunction with levodopa for advanced Parkinson's
-Neuroprotective effects - prevents neurodegeneration
67
What is Pramipexole used for?
D3 selective agonist effective in conjunction with levodopa for advanced Parkinson's
-Neuroprotective effects - prevents neurodegeneration
68
What are 9 types of alpha receptor antagonists?
1. Phenoxybenzamine
2. Phentolamine
3. Prazosin
4. Terazosin
5. Doxazosin
6. Tamsulosin
7. Alfuzosin
8. Labetalol
9. Chlorpromazine, Haloperidol
69
Phenoxybenzamine
- 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
Phentolamine
- 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
What is one of the main differences between phenoxybenzamine and phentolamine?
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
Prazosin
- highly selective for a1 receptors, effective for management of HTN
- dilate both arteries and veins, relative absence of tachycardia
73
Terazosin
-alpha1-selective antagonist, used for the Tx of HTN, urinary complications associated with benign prosthetic hyperplasia (BPH)
74
Doxazosin
For Tx of HTN and BPH, long plasma half life
75
Tamsulosin
- 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
Alfuzosin
- alpha-selective anatagonist approved for the Tx of BPH
| - may cause QT prolongation in some patients
77
Labetalol
-alpha1 selective and B-antagonist. effective for control of BP in pts with pre-eclampsia
78
Chlorpromazine and Haloperidol
- neuroleptic with significant dopamine antagonist effects
| - have alpha antagonist effects (may contribute to their side effects)
79
How do beta receptor antagonists affect the cardiovascular system?
- 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
How do beta receptor antagonists affect the respiratory system?
- 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
How do beta receptor antagonists affect the eyes?
- beta antagonists decrease intraocular pressure - effects are more prominent in galucoma
- decreased synthesis of aqueous humor
82
How do beta receptor antagonists affect the metabolic system?
- 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
How do beta receptor antagonists affect the extra beta adrenergic effects?
```
metoprolol, labetalol, propranolol exhibit membrane stabilizing properties
-sotalol is an effective class 3 antiarrhythmic drug
```
84
Which beta antagonistic drugs are equally selective for B1 and B2?
- 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
What is Timolol used for?
glaucoma
86
What beta antagonists are selective for B1?
- 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
Which drug is highly selective for B1 and exhibits additional effects of vasodilation?
Nebivolol
88
Which beta antagonist drugs serve as partial agonists at both B1 and B2?
pindolol and acebutolol
- advantages: less decrease in HR, BP, abnormalities in plasma lipids than with ordinary antagonists
- effective in treating hypertension and angina :
89
Which beta antagonist drug is a partial agonist at B1 with no effect on B2 and what is it used for?
Acebutolol - used for the management of hypertension, may produce less bradycardia
90
What are 2 mixed alpha-beta antagonists?
1. Carvedilol
| 2. Labetalol
91
Carvedilol
- 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
Labetalol
- 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
Which catecholamine is a precursor to all others and is present in sympathetic neurons and chromaffin cells?
Dopamine
94
What 2 diseases are DA implicated in?
Schizophrenia and Parkinson's Disease
95
Which neurotransmitter is the primary NT of sympathetic neurons, is produced by chromaffin cells, and comprises 20% of catecholamines?
Norepinephrine
96
What are 2 major effects of NE?
1. peripheral vascular tone
| 2. some forms of hypertension
97
What catecholamine is synthesized predominantly in chromaffin cells and comprises 80% of catecholamines?
Epinephrine
98
What disease does epinephrine mediate the symptoms of?
pheochromocytoma
99
What are all endogenous catecholamines synthesized from?
tyorsine
100
What are the different steps in catecholamine production?
1. Tyrosine
2. DOPA
3. Dopamine
5. Norepinephrine
6. Epinephrine
101
What is the rate limiting enzyme in catecholamine synthesis?
tyrosine carboxylase: converts tyrosine to DOPA in substantia nigra
102
What transports newly synthesized dopamine from the cytosol to vesicles for storage?
VMAT (vesicular monoamine transporter)
103
What enzyme converts dopamine to norepinephrine and where does this occur?
dopamine B-hydroxylase converts DA to NE in postganglionic sympathetic neurons within sympathetic vesicles
104
What enzyme converts NE to Epi and where does this occur?
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
What triggers the release of catecholamines?
action potential, calcium influx, and endocytosis
106
What are the 3 mechanisms involved in the termination of action potential and what is the predominant form of termination?
1. reuptake (major)
2 metabolism (minor)
3. diffusion away from cleft (minor)
107
How do anti-depressants affect levels of NE in the synaptic cleft?
Anti-depressants inhibit transporters and therefore prolong the effect of NE in the synaptic terminal
108
Distinguish between MAO-A (monoamine oxididase) and MOA-B
1. MAO preferentially degrades 5HT, NE, and DA
| 2. MAO-B degrades DA more rapidly than 5HT and NE
109
What are 3 MAO inhibitors and what clinical use are they effective for?
1. selegiline
2. isocarboxazid
3. phenelzine
* effective in treating depression
110
What is a cytosolic enzyme expressed primarily in the liver but also in the brain?
catechol-o-methyl transferase (COMT)
111
What is the excretion product of both the COMT and MAO degradation pathway?
Vanilymandelic acid (VMA)
112
What disease is characterized by an increase of VMA?
pheochromocytoma
113
What are alpha-1 adrenergic receptors coupled to and describe the pathway? What is their primary function?
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
Where are alpha-1 receptors expressed?
*postsynaptic terminals in vascular smooth muscles: UG tract smooth muscles, prostate, heart, liver, etc.
115
What are alpha-2 adrenergic receptors coupled to and describe the pathway?
couped to Gi GPCR which inhibits AC and decreases cAMP leevls
-inward rectifier of K+ cannels and neuronal Ca2+ channels
116
What is the primary function of alpha-2 receptors?
* 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
Where are A2 adrenergic receptors expressed?
both pre-synaptic terminals mostly (as autoreceptors) and sometimes post-synaptic terminals
118
What are beta adrenergic receptors coupled to and describe the pathway?
all 3 isoforms of B receptors (B1, B2, and B3) are coupled to Gs and increase cAMP
119
What are the functions of B1, B2, and B3 resepectively?
- 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
What are 5 clinical applications of B receptors?
1. asthma
2. cardiac arrhythmias
3. angina
4. HTN
5. COPD
121
What is the mechanism of D1 and D5 receptors?
D1 and D5 are coupled to Gs with subsequent increase in cAMP
122
Where are D1 receptors found and what is their primary function?
D1 receptors are expressed in the kidneys, mesentary, and coronary arteries. They cause RELAXATION in vascular smooth muscles and lead to vasodilation
123
______ is a partial agonist at D1
fenoldopam
124
What are D2, D3, and D4 receptors coupled to?
Gi GCPR:
- decrease in cAMP
- increase in K+ conductance
- decrease in Ca2+ influx
125
What are 3 diseases that benefit from pharmacological management of dopaminergic receptors?
1. Parkinson's disease
2. Schizophrenia
3. shock (esp ones caused by low CO)
126
What kind of drugs are D2 agonists?
antipsychotics
