Adrenergic antagonists week 2 Flashcards
What is pheochromocytoma?
What are the sx of this disease?
In what population is disease most common?
Pheochromocytoma is the most common tumor of the adrenal medulla in adults. Sympathetic paraganglioma of chromaffin cell origin (derived from neural crest cells). Catecholamine hypersecretion is the most common clincal manifestation.
Most tumors secrete Epi, NE, and DA which can cause episodic HTN.
Sx: 5 P’s
Pressure (elevated BP)
Pain (headache)
Perspiration
Palpitations (tachycardia)
Pallor
What receptors does phenoxybenzamine bind to? Describe the type of binding that occurs.
State the MOA, effects, and clinical uses of phenoxybenzamine.
Describe the relative length of action of phenoxybenzamine.
Alpha Antagonists:
A. Non-selective agents
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Phenoxybenzamine
a. MOA: Covalent binding to alpha-1>>alpha-2 and is non-surmountable. Requires re-synthesis of receptors to reinstate function.
b. Effects: Mostly related to blockade of SANS activity, when function. SANS activity is elevated. Thus, there is little effect on BP when supine, but significant orthostatic hypotension when rising and light-headedness when standing.
(1) HR and cardiac output increase reflexively through baroreceptor response to decreased BP.
(2) nasal stuffiness
(3) inhibition of ejaculation
(4) sedation reflecting its entry into the CNS
Clinical: Mostly used in the pre-surgical management of pheochromocytoma. Because its blockade is not surmountable, NE and Epi surges associated with pheochromocytoma do not produce adrenergic effects and especially the hypertension which can be profound, although it also reduces the headache and diaphoresis, which together with the hypertension/tachycardia formulate the triad of pheochromocytoma.
Why is it important to adminster an alpha blocker BEFORE a beta blocker to pheochromocytoma patients?
How is pheochromocytoma often discovered?
What is often done to pts prior to surgery and why?
Pheochromocytoma patients should never receive a beta blocker in the absence of an alpha blocker as it will produce catastrophic increases in BP (baroreceptor reflex). In addition, pre-
treatment or perioperative treatment with an alpha-antagonist can lead to significant hypotension and there are some who would advocate giving low doses of a beta blocker after the alpha blocker has been administered. Alternatively, a mixed alpha/beta agent such as labetalol. Often pheochromocytoma is often discovered serendipitously and as such patients are volume depleted due to the increase in BP and epi effects on renin/angiotensin system. Patients are often salt loaded prior to surgery to overcome the potential for hypovolemic hypotension after surgery.
What receptors does phentolamine bind to?
What is the MOA?
What are the effects of phentolamine?
What are the clinical uses of phentolamine?
Phentolamine
a. MOA: reversible, competitive inhibitor of alpha-1 = alpha-2.
b. Effects: same as phenoxybenzamine:
(1) HR and cardiac output increase reflexively through baroreceptor response to decreased BP.
(2) nasal stuffiness
(3) inhibition of ejaculation
(4) sedation reflecting its entry into the CNS
with less sedation. Its greater blockade of alpha-2 than phenoxybenzamine leads to greater cardio-stimulation since baroreceptor reflexes are more pronounced due to less attenuation of NE release acting through autoreceptors.
c. Clinical: used during surgical procedures for pheochromocytoma since it is short acting. Not widely available anymore. Nitroprusside used to treat the hypertension produced during surgery.
Name alpha-1 selective drugs.
Alpha-1 selective agents
- Prazosin , tamsulosin, terazosin, and doxazosin
Explain the MAO, effects, clinical uses, and toxicities of alpha-1 selective drugs (prazosin, tamsulosin, terazosin, doxazosin).
Alpha-1 selective agents
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Prazosin , tamsulosin, terazosin, and doxazosin
a. MAO: Specific, reversible, competitive antagonists for alpha-1.
b. Effects: marked reduction in TPR with little reflex cardiac stimulation (bc alpha-1 receptors blocked-decreased ability to vasoconstrict)
c. Clinical: can be used in management of hypertension. (1) used widely in benign prostatic hyperplasia (BPH)
d. First Aid: Toxicities: 1st-dose orthostatic hypotension, dizziness, headache
What is benign prostatic hyperplasia (BPH)?
What are the symptoms of BPH?
How is BPH treated? What is the most effective drug for treatment of BPH? Explain how these drugs work.
alpha blockers, particularly alpha-1 blockers, decrease tension in the urinary sphincter allowing for full emptying of the bladder (which is blocked by the enlarged prostate)
What receptors does yohimbine bind to?
State the MOA, effects, and clinical uses of yohimbine.
Alpha-2 selective antagonists
- Yohimbine is the only selective alpha-2 blocker used clinically. It can be used to treat orthostatic hypotension. As an alpha-2 antagonist it prevents released NE from acting on its auto-receptor. The absence of this negative feedback will actually increase the amount of released NE, which can then act on alpha-1 receptors as well as beta receptors.
a. MOA: competitive antagonist at alpha-2 receptors.
b. Effects: increases NE release by preventing the normal feedback inhibition of NE on its autoreceptor. Produces increased NE tone producing both alpha-1 and beta effects. Can also increase ACh release by inhibiting alpha-2 receptors located on cholinergic terminals.
c. Clinical: primarily used to manage orthostatic hypotension and erectile dysfunction.
What are the clinical uses of beta antagonists?
Beta antagonists are widely used in the management of blood pressure, angina, chronic heart failure, and following infarctions. They are also used in glaucoma (dc aqueous humor production). In addition to their beta blocking effects, some have local anesthetic effects, which reduce their effectiveness in therapy for the eye. Others are partial agonists allowing for less pronounced blockade. Beta 2 selective agents are not used clinically.
Name the nonselective B-blockers. Which is the prototypical nonselective B-blocker?
Non-selective beta blockers: there are several agents in this group with propranolol serving as the prototypical drug. Other members include nadolol, timolol, sotolol, and carvedilol.
Nonselective antagonists mostly go from N to Z (β2 with 2nd half of alphabet)
Nonselective α- and β-antagonists have modified suffixes (instead of “-olol”) (labetalol, carvedilol)
State the MOA, effects, clinical uses, and toxicities of propanolol. When is this drug contraindicated?
How does the way propanolol is metabolized affect its administration?
Propanolol
MOA: Competitive non-specific beta antagonist with some local anesthetic action. The local anesthetic effect can be useful in an eye exam when given as an eye drop as it reduces corneal sensitivity while lowering intraocular pressure by reducing aqueous humor synthesis, but its mild anesthetic properties can be problematic in other procedures.
b. Effects: reduces beta tone and thereby reduces cardiac beta-1 effects resulting in a negative inotropic and chronotropic effect. This leads to less heart work and relief from angina. Its effects on dromotropy (negative) are important in regulating arrhythmias as well. TPR often increases due to the loss of beta-2 vasodilating effects in muscle vascular beds. However, the increase in TPR is more than offset by the reduced beta-1 effects on inotropy and chronotropy. Beta-1 blockade also reduces renin release. Beta-2 blockade prevents skeletal muscle vasodilatation, bronchiole relaxation, and glycogenolysis in liver. Beta-3 blockade prevents lipolysis.
c. Clinical: reduction of heart work and decreased arrhythmias. Was at one time the most widely used drug for reducing cardiac work, but numerous other therapies have been developed (see cardiac block).
(1) widely used in the prophylaxis of migraine headache
(2) used off-label in the management of stage fright
(3) has significant CNS effects and can produce sedation
(4) reduces physiological tremor and has been used in essential tremor management
(5) Controversial use in PTSD
Toxicity:
(1) beta-2 blockade leads to reductions in bronchiole tone and increased airway resistance and is therefore contraindicated in asthmatics. This important side effect led to the development of beta-1 specific blockers.
(2) beta-2 blockade reduces glucagon responsiveness to
(3) and increases hypoglycemia and should be used with caution in Type I diabetics. Beta-2 receptor agonism stimulates glycogenolysis and increases glucagon production as part of the fight-or-flight response. Beta-2 blockade thus leads to hypoglycemia. Moreover, tachycardia often accompanies an insulin-induced hypoglycemic bout and non-specific beta blockers will mask this important symptom. CONTRADICTS FIRST AID which says B2 receptors increase insulin release. Also states: Despite theoretical concern of masking hypoglycemia in diabetics, benefits likely outweigh risks; not contraindicated
3. beta-2 blockade can lead to increased VLDL and increase risk of consequences associated with elevated cholesterol (metoprolol is associated with this according to first aid)
First aid also states other toxicites include: Impotence, cardiovascular adverse effects (bradycardia, AV block, HF), CNS adverse effects (seizures, sedation, sleep alterations),
d. Pharmacokinetic considerations: Undergoes significant first-pass metabolism (CYP3A4) that is dose-dependent suggesting that at higher administered doses, biotransformation becomes saturated (Zero Order). This leads to significant inter-individual variations in bioavailability.
What are the clinical uses of timolol?
Does timolol have local anesthetic effects?
Timolol is non-selective and does not have local anesthetic effects. It is widely used in hypertension and in ocular drops to reduce intraocular pressure in the treatment of glaucoma (by decreasing aqueous humor production).
What are the clinical uses of selective B-1 blockers?
Name drugs in this class and how they work. What are the protypical drugs in this class?
Selective beta-1 blockers: are a large group of drugs used in the management of hypertension and cardiac problems since they are devoid of the broncho-
constrictive effects of the non-specific blockers where beta-2 is blocked. They are often referred to as cardio-selective blockers. They are also safer in type-I diabetics as they do not inhibit the response to hypoglycemia which is at least partially catecholamine mediated.
- Metoprolol and atenolol are prototypic for this class and have all of the effects of the non-specific blockers without the beta-2 and 3 effects.
- Esmolol is an ultrashort acting beta-1 blocker that is used in the ICU for management of arrhythmias.
Selective antagonists mostly go from A to M (β1 with 1st half of alphabet)
How do partial non-specific beta antagonists work? What is the prototypical drug of this class?
State the effects of this drug and the type of patient it is preferred in.
Partial non-specific antagonists: have the effect of mildly reducing beta tone that can be surmountable when SANS activity is high.
- Pindolol is prototypic of this class along with several others and, because of their partial beta agonist effects, they are widely used in patients with heart disease since they would have less hypotensive effects. More importantly, when there is a need for increased SANS tone (standing or fight-or-flight) blockade can be overcome by their Increased Sympathomimetic Activity (ISI). Thus, increased competition for the receptor by NE or Epi since pindolol is surmountable (partial antagonist/agonist). Its partial agonist actions at beta receptors provides some beta tone unlike the full antagonists which provide no ISI. The principle here is that as a partial agonist at the beta receptor, pindolol competes with the effects of Epi and NE at the beta receptor (antagonist action) but does not completely block the receptor (ISI). Pindolol also reduces renin release through its partial actions at beta-1 receptors.
What does it mean for an adrenergic blocker to be a mixed antagonist?
What is the protypical drug of this class? What are its effects?
What kind of patients benefit from these types of drugs?
Mixed antagonists: There are several drugs used in the management of congestive heart failure (CHF) that block both beta receptors and alpha-1 receptors. In CHF, the heart is not an efficient enough pump to meet the bodies needs.
- Carvedilol is prototypical. By blocking beta-1 receptors, it reduces cardiac work and high BP which is beneficial in CHF. The alpha-1 blockade reduces TPR and therefore cardiac work as well. Symptoms including shortness of breath, leg swelling, and exercise intolerance are often seen. Causes of heart failure include myocardial infarction and other forms of ischemic heart disease, hypertension, valvular heart disease, and cardiomyopathy. Use of drugs like carvidilol are part of a treatment regimen that includes life style changes that led to the CHF.
