A11-12: alpha and beta receptor antagonists Flashcards
What are the 3 selective α1 receptor antagonist drugs, not including the α1A receptor antagonists?
What is their major advantage over non-selective α blockers?
Prazosine: short-acting
Terrazosine: middle-acting
Doxazosine: long-acting; ~20 hrs
Compared to non-selective α blockers, they cause less reflex tachycardia
What are the α1A antagonist drugs?
What is unique about these from the other α1 antagonists?
Alfuzosine
Tamsulosine
their α1A specificity makes them especially good for treatment of BPH (α1A in prostate mediates NE-dependent hyperplasia)
What are the indications for α1 receptor antagonists?
-
Moderate to severe hypertension
- Don’t affect bronchi, so they’re good for asthma/COPD patients with HTN
- Don’t affect glycemia, so they’re good for diabetics
- Improve lipid profile, increase HDL (obese commonly have HTN)
- α1R ATGs still have worse cardiovascular outcomes than other antihypertensives, and so they are not used as monotherapy
- Benign prostate hyperplasia patients benefit because prostatic α1A receptor causes hypertrophic effect of NE on prostate
What are the common side-effects of selective α1 receptor antagonists?
- First dose phenomenon: orthostatic hypotension + syncope. To resolve this, first dose usually given at bedtime with low dose (**likely to be on midterms**)
- Vasodilation may cause reflex tachycardia
- Nonspecific side effects: dizziness, palpitations, headache
What are the 4 different types of non-selective α antagonists?
(Just names of the categories and some examples of drugs, not details)
- α1 + α2 antagonists: Phenoxybenzamine, Phentolamine, Tolazoline
- α + 5-HT antagonists: natural and synthetic ergot alkyloids (ergotamine, LSD, bromocryptine…)
- α1 antagonist + α2 agonist, ß blocker, 5-HT1A agonist: Urapidil
- Mixed α and ß blockers: Labetalol, Carvedilopol
What are 3 non-selective α1 + α2 antagonists?
(Include indications and side effects)
Phenoxybenzamine: irreversible α blocker, so has long duration (14-48 hours). Indication: pheochromocytoma
Phentolamine: reversible α blocker, still pretty strong. Indication: pheochromocytoma (short term), maybe hypertensive crisis
Tolazoline: reversible α blocker, weaker. Indication: to vasodilate in peripheral vascular disease (e.g. Raynaud), maybe also frosbite
Side effects: orthostatic hypotension, reflex tachycardia + tachycardia from uninhibited α2 on cardiac sympathetic nerves.
What are the most important effects of the natural ergot alkaloids?
- Vasoconstriction, vasospasm: can cause gangrene due to poor perfusion. Some derivatives used to treat migraine by causing vasoconstriction.
- Powerful stimulation of pregnant uterus: can help deliver placenta or diminish loss of blood after birth
- CNS actions: paresthesia, mania, hallucinations, seizures
What receptors do ergot and ergot derivatives act on?
α: antagonist or partial agonist
5-HT: agonist, partial agonist, or antagonist. More for 5-HT1D, 5-HT1A. Less for 5-HT2 and 5-HT3.
Dopamine: agonist or partial agonist
(The derivatives affect these receptors to different degrees or in different ways)
What are some of the natural ergot alkaloid drugs?
What is important about their receptor affinity?
Drugs: Ergotamine, Ergometrine, Ergocornine, Ergocristine, Ergocriptine
Receptor affinity: binds 5-HT > α receptors
(mostly serotonin agonist, α antagonist)
This makes the drugs have an overwhelming vasoconstrictive effect, which is used in postpartum hemorrhage and migraine therapy
What are 4 examples of synthetic or semi-synthetic ergot derivatives?
- Dihydroergotoxine: more selective α antagonist than 5-HT, and so causes more vasodilation than constriction. Can be used to treat dementia
- Methylsergide: 5-HT2b1C antagonist. Inhibits relase of NO from endothelium -> migraine inhibited
- LSD (lysergic acid diethylamide, “acid”): partial agonist of 5HT receptors in CNS
- Bromocryptine, Cabergoline: more selective dopamine receptor agonists, used for hyperprolactinemia (formerly also Parkinson’s)
What receptors does Urapidil act on?
What is it indicated for?
α antagonist, weak α2 agonist, ß antagonist, 5-HT1A agonist
Strong anti-hypertensive agent, used for emergency hypertensive crisis
(not approved by the FDA and this is why it’s not in some books, but it’s used in Europe)
What are 2 examples of mixed α1 and ß antagonists?
What are they indicated for?
Labetalol (lasts 4-6 hours), Carvedilol (lasts 7-10 hours)
Labetalol: used as alternative to methyldopa in pregnancy-induced HTN. Intravenously for hypertensive crisis
Carvedilol: anti-hypertensive that also decreases lipid peroxidation and vascular wall thickening, improves lipid profile, and is beneficial for stable chronic heart failure
What are two examples of α2 antagonists drugs?
What is fundamentally different about them the other alpha and beta antagonist drugs?
Mianserin, Mirtazapine
(tetracyclic antidepressants, also antagonize 5-HT2R, antihistamine. Sedative and may help with insomnia)
Because α2 receptors essentially downregulate the effects of the sympathetic nervous system (negative feedback on presynaptic NE terminal), the effects of these drugs are mostly opposite to α1 blockers or ß blockers
What are the indications for ß blockers?
[There are a lot]
- Hypertension, especially in younger patients (more likely to have HTN from ↑ sympathetic tone)
- Supraventricular tachyarrhythmias: slows AV conduction. Part of class II anti-arrhythmics
- Angina, IHD, Post-MI: decrease O2 demands on the heart
- Chronic Congetive Heart Failure: shown to prolong lifetime, decrease remodeling of the heart (related to RAAS, and remember renin is released by ß1 receptors)
- Obstructive hypertrophic cardiomyopathy, low ejection fraction
- Others: hyperthyroidism, pheochromocytoma, portal HTN, glaucoma, anxiety, essential tremor, proliferating hemangioma in newborn, migraines…
What are the 3 categories of beta blockers?
(just the names, but I’m also including some examples on answer side)
Non-Selective: e.g. Propranolol
ß1 Selective (“cardiac selective”): e.g. Metoprolol, Atenolol
ß1 Selective + NO release: e.g. Nebivolol
What are the names of 5 different non-selective ß blockers?
[There are 12 total in the lecture, but I’m just putting the ones that seem important]
Propranolol
Nadolol
Timolol
Sotalol
Pindolol
What are the major consequences of non-selectively blocking ß receptors?
- Negative chronotrophy/inotropy (ß1)
- Decreased blood pressure (ß1) From decreased cardiac output + decreased renin release
- Bronchoconstriction (ß2)
- Impaired recovery from hypoglycemia (ß2)
- Decreased aqueous humour production in the eye
- Increased plasma VLDL, decreased HDL (worse lipid profile)
- Local vasoconstriction in the end arteries and diseased peripheral vessels (ß2)
What are some major adverse effects of ß blockers?
- Bronchoconstriction (worsens bronchial asthma)
- Cardiac decompensation (only if critically-dependent on sympathetic drive)
- Bradycardia, decreased AV conduction
- Cold extremities, worsening of peripheral vascular disease
- Hypoglycemia, hyperlipidemia
- Contributes to increased K+ level
- Sleep disturbances (nightmares), mental depression, sexual impairment
- Uterine contractions in pregnancy
Should never abruptly discontinue them; risk of tachyarrhythmias
Note that even ß1 selective blockers still have some antagonism on ß2 and can have effects related to those receptors
What are features and indications for use of propranolol?
Prototype of ß blockers. Highly lipid-soluble (must be metabolized by the liver)
Used mostly for hypertension, but also:
Hyperthyroidism: inhibits T4 -> T3 transformation
Local anesthesia: inhibits Na channels
Migraines (prophylactically) - lipophilic so it can cross BBB and reach CNS
What is the duration of action of nadolol?
Is it hydrophobic or hydrophilic?
Very long duration of action (24 hours)
Hydrophilic: Doesn’t enter CNS; not metabolized much by liver and is excreted by the kidney mostly unchanged (need to lower dose if there is reduced kidney function)
Besides the normal uses of ß blockers (e.g. hypertension, IHD),
what is a common indication for Timolol?
Glaucoma: used topically.
Decreases secretion of aqueous humour by blocking ß receptor in ciliary body. Unlike other ß blockers, Timolol doesn’t work on Na channels and so has no local anesthetic effect, and this is why it can be used for eyedrops.
Lasts 12-24 hours, and so it’s good for chronic management. Pilocarpine is preferred for emergency lowering of intraocular pressure.
Unlike cholinergic drugs, Timolol doesn’t affect pupil size or accommodation.
Besides being a non-selective ß blocker,
what other important class of drugs is Sotalol a part of?
Class III Anti-arrhythmics: instead of inhibiting Na+ channels, it inhibits a K+ channel (delayed rectifier)
Prolongs the refractory time of the heart, and so it can be used to maintain normal sinus rhythm in patients who tend to get atrial fibrillation, PSVT, etc.
[it’ll be covered more in cardiac drugs.. remember that ß blockers are class II antiarrhythmics]
Which ß blockers have intrinsic sympathomimetic activity (ISA)?
What does this effect mean?
Pindolol is the main one to know, but also acebutolol (ß1 selective), oxyprenolol, alprenolol, and celiprolol (ISA at ß2)
These drugs work as partial agonists of ß receptors, meaning that they inhibit endogenous catecholamines when they are present. Makes the drugs safer for people with existing bradycardia, and also causes less abnormalities with plasma lipids.
[+ Celiprolol may cause less bronchoconstriction]
What are the names of six important ß1 selective antagonists?
+ some basic info about each of them
(not including the one that also increases NO release, nor some of the others that are on lecture slide)
Metoprolol: either hypertension or migraine prophylaxis
Atenolol: doesn’t penetrate CNS, maybe won’t cause nightmares
Esmolol: very short duration (10 minutes), only used in emergencies (e.g. PSVT)
Bisoprolol: long duration of action (18-22 hours), can give 1x a day
Betaxolol: used for normal ß blocker reasons or for glaucoma in eyedrops (also doesn’t act on Na channels; no local anesthetic effect)
Acebutolol: partial agonist / ISA activity like Pindolol
What drug is ß1 selective + releases nitric oxide (NO)?
Nebivolol:
Besides ß blocking, also causes direct systemic vasodilator effect
(Racemic mixture: one isomer is selective ß1 blocker; another isomer induces NO release)
Used as antihypertensive
What are some contraindications for ß blockers?
- Severe bradycardia
- Severe hypotension
- Second grade AV block
- Vasospastic disorders: Prinzmetal angina, Raynaud (exacerbates)
- Psoriasis (unclear why, but it gets worse)
- Unstable diabetes (worsens hypoglycemia)
- Pregnancy (might worsen placental perfusion)
- Severe asthma or COPD: non-selective ß blockers are mostly contra-indicated, and ß1 blockers may be used cautiously
Of these non-cardiovascular indications for ß blockers, which drugs are typically used for:
Hyperthyroidism?
Glaucoma?
Migraine?
Anxiety?
Essential Tremor?
Hyperthyroidism: usually propranolol
Glaucoma: timolol, betaxolol
Migraine: propranolol, metoprolol
Anxiety: pindolol, propranolol
Essential tremor (i.e. not from Parkinson’s): usually propranolol (must be lipid soluble to reduce tremor)
What beta blocker has an ultrashort half-life?
What are some beta blockers with long half-lives?
Ultrashort acting: Esmolol (ß1 selective), lasts 10 minutes
Long half-life (>10 hours): Nadolol, Betaxolol, Bisoprolol, Nebivolol
What are 2 beta blockers with the highest lipid solubility?
What are some with very low lipid solubility?
What are some important consequences of lipid solubility here?
High lipid solubility: Propranolol, Nebivolol
Low lipid solubility: Atenolol, Sotalol, Acebutolol
Only lipid soluble ß blockers can be used for CNS indications (e.g. tremor), but low lipid-soluble drugs won’t have as many CNS adverse effects (e.g. nightmares)
- Lipophilic* drugs must be metabolized by liver for excretion (might increase plasma level in liver diseases)
- Hydrophilic* drugs are excreted unchanged (might increase plasma level in kidney diseases)
