A11. Alpha-receptor antagonists

Question 1

List the alpha 1 receptor blockers.

Answer 1

1. Antihypertensives: Prazosin, Terazosin, Doxazosin, Alfuzosin.
2. Atypical antidepressants: Trazodone, Nefazodone, Vilazodone.
3. Others: 1st generation H1 antihistamines, many antipsychotics.

Question 2

What are the indications for Prazosin, Terazosin and Doxazosin?

Answer 2

1. They are all α1 receptor blockers that are good Antihypertensives.
2. Prazosin (short acting), Terazosin (middle acting), Doxazosin (long acting)
3. Indicated for moderate to severe hypertension
4. Don’t affect bronchi, so they’re safer for asthma and COPD patients than β blockers
5. Can be used in hypertension and diabetes because they don’t affect glycemia.
6. Because they don’t block α2, they’re safer than the non-selective α blockers (α2 helps inhibit the sympathetic nervous system on the heart too)
7. α1 antagonism also inhibits ejaculation.

Question 3

What are the indications for α1A antagonists (Alfuzosin, Tamsulosin)?

Answer 3

1. They are good for hypertension + in people with benign prostate hyperplasia.
2. These drugs specifically inhibit hypertrophic effect of NE at prostatic α1A receptor.

Question 4

What are the side effects of the Antihypertensive Alpha 1 R blockers?

Answer 4

1. Can cause orthostatic hypotension, may be strong even after only first dose (“first dose effect”).
2. Vasodilation → reflex tachycardia.

Question 5

What are the indications for Atypical anti-depressants (Trazodone, Nefazodone, Vilazodone) that are Alpha 1 R antagonists?

Answer 5

1. Anti-depressant effect is from inhibition of SERT and 5-HT2A.
2. Strongly sedative drugs, can be also used in depression with insomnia.
3. α1 inhibition is more of a side effect for these drugs, but it does contribute to sedative effect.
4. Vilazodone is also a 5-HT1A partial agonist, contributes to anxiolytic effect.

Question 6

What are the others of the Alpha 1 receptor blockers?

Answer 6

1st generation H1 antihistamines, many antipsychotics..

Question 7

List the Alpha 2 blockers.

Answer 7

1. Yohimbine
2. Atypical antidepressants: Mirtazepine, Mianserine.

Question 8

What are the indications and contraindications for Yohimbine?

Answer 8

1. Yohimbine is not really important medically, was used as a sexual stimulant before sildenafil and other PDE inhibitors came out.
2. Contraindicated in cardiovascular disease, psych conditions, and renal dysfunction - may worsen these syndromes.

Question 9

What are the indications for the Atypical antidepressants (Mirtazapine, Mianserine) with alpha 2 antagonism?

Answer 9

1. Mirtazapine (newer, more used)
2. Mianserine (older, less used)
3. Other effects besides α2 blockade: inhibit 5-HT2 receptors + inhibit H1 (sedative)
4. Inhibition of 5-HT2 could theoretically cause anxiety, insomnia (in combination with ↑ sympathetic activity from α2 blockade). However, they are typically sedative due to H1 antagonism.
5. Causes weight gain.
6. Don’t cause sexual dysfunction like SSRIs and other antidepressants (similarly, bupropion also doesn’t cause sexual dysfunction).

Question 10

List the non-selective alpha R antagonists.

Answer 10

Alpha 1 and alpha 2 blockers:

1. Phenoxybenzamine
2. Phentolamine
3. Tolazoline

Alpha and 5HT: natural ergot alkaloids

1. Ergot
2. Ergotamine, Ergometrine, Ergocomine, Ergocristine, Ergocriptine.
3. Semisynthetic: Dihydroergotoxine, Methylsergide.
4. Derivatives without alpha effects: LSD, Bromocriptine.

Mixed alpha and beta blockers:

1. Urapidil
2. Labetalol
3. Carvedilol

Question 11

What are the indications for Phenoxybenzamine?

Answer 11

1. Phenoxybenzamine: binds irreversibly α1 + α2 → strong effect.
2. Strong enough to be useful to block the hypertensive episodes in pheochromocytoma.
3. other effects: H1 antihistamine effect, serotonin receptor blocking effects (sometimes used for carcinoid tumors)

Question 12

What are the side effects of phenoxybenzamine?

Answer 12

1. Orthostatic hypotension
2. Tachycardia (Reflex tachycardia): is due to vasodilation + inhibition of α2 presynaptically. lose the negative feedback → increased NE level in synaptic cleft where it acts on β1 receptors.

Question 13

What are the indications for Phentolamine?

Answer 13

1. Phentolamine binds reversibly alpha 1 + alpha 2.
2. Still used some.
3. Also indicated for pheochromocytoma.
4. Maybe also indicated to reverse drug-related hypertension (e.g. amphetamine overdose, sudden clonidine withdrawal)

Question 14

What are the side effects of Phentolamine?

Answer 14

1. orthostatic hypotension
2. tachycardia

Question 15

What are the indications for Tolazoline?

Answer 15

1. Tolazoline has higher affinity for α2 than α1.
2. But a lot of other effects (inhibits MAO, parasympathomimetic), but final effect is vasodilation.
3. Indicated for Raynaud disease.

Question 16

What are the effects of α + 5-HT blockers?

Answer 16

Come from natural ergot alkaloids. Derived from wheat fungi (ergot):

1. Cause smooth muscle contraction. severe vasoconstriction → poor blood supply, particularly important in the uterus
2. Agonists on serotonin 1B, 1D
3. Antagonist or partial agonist on α1
4. but by changing structure and forming dihydro-derivatives, can get α > 5-HT and use as anti hypertensive.

Question 17

What are the indications for Ergotamine, ergometrine, ergocornine, ergocristine and ergocriptine?

Answer 17

1. target 5-HT > α
2. can help with delivering placenta, diminishing loss of blood via vasoconstriction

Question 18

What happens in Ergot posioning and what are the treatment options?

Answer 18

Ergot poisoning causes widespread vasoconstriction. Treatment is strong nitrates, especially nitroprusside.

Question 19

What are the indications for semisynthic alpha+ 5HTR antagonists?

Answer 19

1. dihydroergotoxine (α > 5-HT)
2. methylsergide: 5-HT2b1C antagonist: inhibits release of NO from endothelium → inhibits migraine.
3. Not as commonly used nowadays.

Question 20

What are the indications and side effects of the Derivatives without α effect?

Answer 20

1. LSD: hallucinogen via serotonin effect
2. Bromocriptine: dopamine agonist, used for hyperprolactinemia (in past for Parkinsons disease).
3. Causes pulmonary fibrosis in the lung run.

Question 21

What are the indications for Mixed α and β blockers.

Answer 21

As opposed to mainly cardiac effects of β blockers, these drugs also cause peripheral vasodilation (reduced TPR). Can rapidly lower blood pressure, more powerful anti-hypertensives than β blockers.

Question 22

What are the indiactions for Urapidil?

Answer 22

1. α1 ATG, α2 AG, β blocker + 5-HT1A agonist
2. very strong central anti-hypertensive agent
3. used in emergencies, hypertensive crisis

Question 23

What are the indications for Labetalol?

Answer 23

1. α and β blocker
2. also administered IV in hypertensive crisis
3. especially useful in pregnancy-related hypertensive crisis (e.g. preeclampsia)

Question 24

What are the indications for Carvedilol?

Answer 24

1. α and β blocker.
2. orally for chronic hypertension treatment.
3. anti-oxidant effect and improves lipid profile (increases HDL).
4. can be useful in chronic heart failure due to this effect.