Thursday, December 21, 2006

medicine wk 17 - Basics of Pharmacology - beta blockers

Pharmacology
1) cardiac drugs: Beta blockers, cardiac glycosides
2) antibiotics
3) CNS drugs
4) chemotherapy, antineoplastic drugs
5) antiviral drugs
6) antifungal drugs
7) diabetics
8) antipsychotic
9) gout
10) diuretics
11) cholesterol drugs
12) toxicology
13) GI medication
14) Parkinson's
15) asthma
16) HTN
17) renal

Beta blockers
- selective: esmolol, atenolol, metoprolol => ema
- non-selective: propranolol, pindolol

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Beta blockers (sometimes written as β-blockers) are a class of drugs used for various indications, but particularly for the management of cardiac arrhythmias and cardioprotection after myocardial infarction. Whilst once first-line treatment for hypertension, their role was downgraded in June 2006 in the United Kingdom to fourth-line as they perform less well than other drugs, particularly in the elderly, and there is increasing evidence that the most frequently used beta-blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes.[1]

Beta blockers may also be referred to as beta-adrenergic blocking agents, beta-adrenergic antagonists, or beta antagonists.

Pharmacology

Beta blockers block the action of endogenous catecholamines, epinephrine (adrenaline) and norepinephrine (noradrenaline) in particular, on β-adrenergic receptors, part of the sympathetic nervous system which mediates the "fight or flight" response.

There are three known types of beta receptor, designated β1, β2 and β3. β1-Adrenergic receptors are located mainly in the heart, kidney, and adipose tissue. β2-Adrenergic receptors are located mainly in the heart, lung, GI tract, liver, pancreas, and skeletal muscle. The role and location of β3-receptors is less well-defined.

[edit] β-Receptor antagonism

Stimulation of β1 receptors by epinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity. Stimulation of β2 receptors induces smooth muscle relaxation (resulting in vasodilation and bronchodilation amongst other actions), induces tremor in skeletal muscle, increases glycogenolysis in the liver and skeletal muscle.

Beta blockers inhibit these normal epinephrine-mediated sympathetic actions, but have minimal effect on resting subjects. That is, they reduce the effect of excitement/physical exertion on heart rate and force of contraction, dilation of blood vessels, opening of bronchi, reduce tremor, and breakdown of glycogen.

It is therefore somewhat unexpected that non-selective beta blockers have an antihypertensive effect, since they appear to cause vasoconstriction. The antihypertensive mechanism appears to involve: reduction in cardiac output (due to negative chronotropic and inotropic effects), reduction in renin release from the kidneys, and a central nervous system effect to reduce sympathetic activity.

Antianginal effects result from negative chronotropic and inotropic effects, which decrease cardiac workload and oxygen demand.

The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade – resulting in depression of sinus node function and atrioventricular node conduction, and prolonged atrial refractory periods. Sotalol, in particular, has additional antiarrhythmic properties and prolongs action potential duration through potassium channel blockade.

[edit] Intrinsic sympathomimetic activity

Some beta blockers (e.g. oxprenolol and pindolol) exhibit intrinsic sympathomimetic activity (ISA). These agents are capable of exerting low level agonist activity at the β-adrenergic receptor while simultaneously acting as a receptor site antagonist. These agents, therefore, may be useful in individuals exhibiting excessive bradycardia with sustained beta blocker therapy.

Agents with ISA are not used post-myocardial infarction as they have not been demonstrated to be beneficial. They may also be less effective than other beta blockers in the management of angina and tachyarrhythmia (Rossi, 2006).

[edit] α1-Receptor antagonism

Some beta blockers (e.g. labetalol and carvedilol) exhibit mixed antagonism of both β- and α1-adrenergic receptors, which provides additional arteriolar vasodilating action.

[edit] Other effects

Beta blockers decrease nocturnal melatonin release, perhaps partly accounting for sleep disturbance caused by some agents (Stoschitzky et al., 1999).

[edit] Clinical use

Large differences exist in the pharmacology of agents within the class, thus not all beta blockers are used for all indications listed below.

Indications for beta blockers include:

Beta blockers have also been used in the following conditions:

[edit] Congestive heart failure

Although beta blockers were once contraindicated in congestive heart failure, as they have the potential to worsen the condition, studies in the late 1990s showed their positive effects on morbidity and mortality in congestive heart failure (Hjalmarson, 2000; Leizorovicz, 2002; Packer, 2002). Bisoprolol, carvedilol and sustained-release metoprolol are specifically indicated as adjuncts to standard ACE inhibitor and diuretic therapy in congestive heart failure.

[edit] Anxiety and performance enhancement

Some people, particularly musicians, use beta blockers to avoid stage fright and tremor during public performance and auditions. The physiological symptoms of the fight/flight response associated with performance anxiety and panic (pounding heart, cold/clammy hands, increased respiration, sweating, etc.) are significantly reduced, thus enabling anxious individuals to concentrate on the task at hand.

Currently, no beta blocker is approved for anxiolytic use by the US FDA. Still, use of beta blockers to combat the physical symptoms of anxiety is not uncommon, particularly among performers, and there are studies which confirm their efficacy as anxiolytics. (Schneier 2006)

Since they lower heart rate and reduce tremor, beta blockers have been used by some Olympic marksmen to enhance performance, though beta blockers are banned by the International Olympic Committee (IOC).[2]

[edit] Adverse effects

Common adverse drug reactions (ADRs) associated with the use of beta blockers include: nausea, diarrhoea, bronchospasm, dyspnoea, cold extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension, heart failure, heart block, fatigue, dizziness, abnormal vision, decreased concentration, hallucinations, insomnia, nightmares, depression, sexual dysfunction, erectile dysfunction and/or alteration of glucose and lipid metabolism. Mixed α1/β-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with oedema. (Rossi, 2006)

Central nervous system (CNS) adverse effects (hallucinations, insomnia, nightmares, depression) are more common in agents with greater lipid solubility, which are able to cross the blood-brain barrier into the CNS. Similarly, CNS adverse effects are less common in agents with greater aqueous solubility (listed below).

Adverse effects associated with β2-adrenergic receptor antagonist activity (bronchospasm, peripheral vasoconstriction, alteration of glucose and lipid metabolism) are less common with β1-selective (often termed "cardioselective") agents, however receptor selectivity diminishes at higher doses.

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Esmolol (tradename Brevibloc®) is a cardioselective beta1 receptor blocker with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilising activity at therapeutic dosages.

Esmolol decreases the force and rate of heart contractions by blocking beta-adrenergic receptors of the sympathetic nervous system, which are found in the heart, lungs and other organs of the body. Esmolol prevents the action of two naturally occurring substances: epinephrine and norepinephrine.

[edit] Dosing

Esmolol is given by slow intravenous injection. It is commonly used in patients during surgery to prevent or treat tachycardia, and is also used in treatment of acute supraventricular tachycardia.

[edit] Metabolism

Esmolol is rapidly hydrolysed by the esterases in the cytosol of red blood cells. Plasma cholinesterases and red cell membrane acetylcholinesterase do not have any action. This metabolism results in the formation of a free acid and methanol. The amount of methanol produced is similar to endogenous methanol production. Its elimination half-life is about 9 minutes.

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Atenolol is a drug belonging to the group of beta blockers, a class of drugs used primarily in cardiovascular diseases. Introduced in 1976, atenolol was developed as a replacement for propranolol in the treatment of hypertension. Hypertension is a clinical condition in which the arterial blood pressure in rest exceeds constantly 140/90 mm Hg (as defined by the World Health Organization). Hypertension is a risk factor for stroke, myocardial infarction (heart attack), and serious renal damage.

Propranolol is known to readily cross the blood-brain barrier (BBB) and can pass into the brain, causing side-effects such as depression and nightmares; atenolol was specifically developed to be unable to pass through the blood-brain barrier in order to prevent this effect.

Whilst atenolol, the most widely used beta-blocker in the United Kingdom, was once first-line treatment for hypertension, the role for beta-blockers in hypertension was downgraded in June 2006 in the United Kingdom to fourth-line as they perform less well than other drugs, particularly in the elderly, and there is increasing evidence that the most frequently used beta-blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes.[1]

Contraindications

  • bradycardia (pulse less than 50 bpm)
  • cardiogenic shock
  • symptomatic hypotension (blood pressure of less than 100/60 mm Hg with dizziness, vertigo etc.)
  • angina of the Prinzmetal type (vasospastic angina)
  • metabolic acidosis (a severe condition with a more acid blood than normal)
  • severe disorders in perpheral arterial circulation
  • AV-Blockage of second and third degree (a particular form of arrhythmia)
  • acutely decompensated congestive heart failure (symptoms may be fluid retention with peripheral edema and/or abdominal fluid retention (ascites), and/or lung edema)
  • sick sinus syndrome (a particular form of arrhythmia, very rarely encountered)
  • hypersensitivity and/or allergy to Atenolol
  • Caution: patients with preexisting asthma bronchiale
  • Caution: only if clearly needed during pregnancy, as atenolol may retard fetal growth and possibly causes other abnormalities. (If you are pregnant or plan to become pregnant, ask your doctor.)

[edit] Side effects

See also: Propranolol

Atenolol causes significantly fewer central nervous system side effects (depressions, nightmares) and fewer bronchospastic reactions, both due to its particular pharmacologic profile.

It was the main beta-blocker identified as carrying a higher risk of provoking type 2 diabetes, leading to its downgrading in the United Kingdom in June 2006 to fourth-line agent in the management of hypertension.[1]

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Metoprolol is a selective beta1 receptor blocker used in treatment of several diseases of the cardiovascular system. It is marketed under the brand name Lopressor® by Novartis, and Toprol® (in the USA); Seleken® or Selokeen® (elsewhere); as Minax® by Alphapharm (in Australia), as Betaloc® by AstraZeneca and as Corvitol® by Berlin-Chemie AG.

It should be noted that Lopresor® refers to metoprolol tartrate, while Toprol® refers to metoprolol succinate, the sustained-release formulation.

Pharmacology

  • Cardioselective
  • Lipophilic
  • Without intrinsic sympathomimetic activity (ISA)
  • Without membrane stabilizing activity
  • Short half-life must be taken at least twice daily or SR preparations

[edit] Indications

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Propranolol (INN) (IPA: [proˈprænəloʊl]) is a non-selective beta blocker mainly used in the treatment of hypertension. It was the first successful beta blocker developed. Propranolol is commonly marketed by AstraZeneca under the trade name Inderal.

Pharmacology

Main article: Beta blocker

Propranolol is a non-selective beta blocker, that is, it blocks the action of epinephrine on both β1- and β2-adrenergic receptors. It has little intrinsic sympathomimetic activity (ISA) but has strong membrane stabilising activity.

[edit] Pharmacokinetics

Propranolol is rapidly and completely absorbed, with peak plasma levels achieved approximately 1–3 hours after ingestion. Co-administration with food appears to enhance bioavailability. Despite complete absorption, propranolol has a variable bioavailability due to extensive first-pass metabolism. Hepatic impairment will therefore increase its bioavailability. The main metabolite 4-hydroxypropranolol, with a longer half-life (5.2–7.5 hours) than the parent compound (3–4 hours), is also pharmacologically active.

Propranolol is a highly lipophilic drug achieving high concentrations in the brain. The duration of action of a single oral dose is longer than the half-life indicates and may be up to 12 hours, if the single dose is high enough (e.g. 80 mg). Effective plasma concentrations are between 10–100 ng/mL.

Toxic levels are associated with plasma concentrations above 2000 ng/ml

Clinical use

[edit] Indications

Propranolol is indicated for the management of various conditions including (Rossi, 2006):

Whilst once first-line treatment for hypertension, the role for beta-blockers was downgraded in June 2006 in the United Kingdom to fourth-line as they perform less well than other drugs, particularly in the elderly, and there is increasing evidence that the most frequently used beta-blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes.[1]

It is also used to lower portal vein pressure in portal hypertension and prevent oesophageal variceal bleeding.

Propranolol is currently being investigated as a potential treatment for post-traumatic stress disorder [1].

[edit] Precautions/contraindications

Propranolol should be used with caution in patients with:

(Rossi, 2006)

Propranolol is contraindicated in patients with:

(Rossi, 2006)

[edit] Adverse effects

Adverse drug reactions (ADRs) associated with propranolol therapy are similar to other lipophilic beta blockers (see beta blocker).

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Pindolol is a beta blocker drug.

Pharmacology

Pindolol is a nonselective beta blocker in terms of cardioselectivity, but possesses ISA (Intrinsic Sympathomimetic Activity). This means that pindolol particularly in high doses exerts effects like epinephrine or isoproterenole (increased pulse rate, increased blood pressure, bronchodilation), but these effects are limited. Pindolol also shows membrane stabilizing effects like quinidine, possibly accounting for its antiarrhythmic effects. It acts on serotonin (5-HT1A) receptors in the brain resulting in increased postsynaptic serotonin concentrations.

[edit] Pharmacokinetics

Pindolol is rapidly and well absorbed from the GI tract. It undergoes some first-pass-metabolization leading to an oral bioavailability of 50 to 95%. Patients with uremia may have a reduced bioavailability. Food does not alter the bioavailability, but may increase the resorption. Following an oral single dose of 20mg peak plasma concentrations are reached within 1 to 2 hours. The effect of Pindolol on pulse rate (lowering) is evident after 3 hours. Despite the rather short halflife of 3 to 4 hours, hemodynamic effects persist for 24 hours after administration. Plasma halflives are increased to 3 - 11.5 hours in patients with renal impairment, to 7 - 15 hours in elderly patients, and from 2.5 to 30 hours in patients with liver cirrhosis. Approximately 2/3 of pindolol are metabolized in the liver giving hydroxylates, which are found in the urine as gluconurides and ethereal sulfates. The remaining 1/3 of pindolole is excreted in urine in unchanged form.

[edit] Uses

  • Angina pectoris and hypertension. The use of pindolol in the treatment of instable angina may be less effective compared to beta blockers without ISA.
  • In some other countries also arrhythmias and prophylaxis of acute stress reactions.
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