Pharmacology Made Simple : Medications used in treatment of Heart Failure : Nebivolol

Nebivolol:

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Nebivolol is a β1 receptor blocker with nitric oxide-potentiating vasodilatory effect used in treatment of hypertension and also for left ventricular failure.

It is highly cardioselective under certain circumstances.




β1-selectivity

Beta blockers help patients with cardiovascular disease by blocking β receptors, while many of the side-effects of these medications are caused by their blockade of β2 receptors.

For this reason, beta blockers that selectively block β1 adrenergic receptors (termed cardioselective or β1-selective beta blockers) produce fewer adverse effects (for instance, bronchoconstriction) than those drugs that non-selectively block both β1 and β2 receptors.



In a laboratory experiment conducted on biopsied heart tissue, nebivolol proved to be the most β1-selective of the β-blockers tested, being approximately 3.5 times more β1-selective than bisoprolol.

However, the drug's receptor selectivity in humans is more complex and depends on the drug dose and the genetic profile of the patient taking the medication.



The drug is highly cardioselective at 5 mg.In addition, at doses above 10 mg, nebivolol loses its cardioselectivity and blocks both β1 and β2 receptors.

While the recommended starting dose of nebivolol is 5 mg, sufficient control of blood pressure may require doses up to 40 mg).

Furthermore, nebivolol is also not cardioselective when taken by patients with a genetic makeup that makes them "poor metabolizers" of nebivolol (and other drugs) or with CYP2D6 inhibitors.

As many as 1 in 10 whites and even more blacks are poor CYP2D6 metabolizers and therefore might benefit less from nebivolol's cardioselectivity although currently there are no directly comparable studies.

Vasodilator action :

Nebivolol is unique as a beta-blocker.Unlike carvedilol, it has a nitric oxide (NO)-potentiating, vasodilatory effect via stimulation of β3 receptors.Along with labetalol, celiprolol and carvedilol, it is one of four beta blockers to cause dilation of blood vessels in addition to effects on the heart.

Antihypertensive effect :

Nebivolol lowers blood pressure (BP) by reducing peripheral vascular resistance, and significantly increases stroke volume with preservation of cardiac output.

The net hemodynamic effect of nebivolol is the result of a balance between the depressant effects of beta-blockade and an action that maintains cardiac output.


Pharmacology of side-effects :

Several studies have suggested that nebivolol has reduced typical beta-blocker-related side effects, such as fatigue, clinical depression, bradycardia, or impotence.However, according to the FDA.



Contraindications:

Nebivolol is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh > B) and in patients who are hypersensitive to any component of the product.

Nebivolol is also associated with warnings regarding abrupt cessation of therapy, cardiac failure, angina and acute myocardial infarction, bronchospastic diseases, anesthesia and major surgery, diabetes and hypoglycemia, thyrotoxicosis, peripheral vascular disease, non-dihydropyridine calcium channel blockers use, as well as precautions regarding use with CYP2D6 inhibitors, impaired renal and hepatic function, and anaphylactic reactions.


Contraindications Summay :

Severe bradycardia
Heart block greater than first degree
Patients with cardiogenic shock
Decompensated cardiac failure
Sick sinus syndrome (unless a permanent pacemaker is in place)
Patients with severe hepatic impairment (Child-Pugh class B)
Patients who are hypersensitive to any component of this product.


Adverse drug reactions


Headache
Paresthesia
Dizziness
History

Pharmacology Made Simle : Antihypertensives : Amlodipine

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Amlodipine

Mechanism of action :

Amlodipine is an angioselective calcium channel blocker and inhibits the movement of calcium ions into vascular smooth muscle cells and cardiac muscle cells which inhibits the contraction of cardiac muscle and vascular smooth muscle cells.




Amlodipine inhibits calcium ion influx across cell membranes, with a greater effect on vascular smooth muscle cells. This causes vasodilation and a reduction in peripheral vascular resistance, thus lowering blood pressure. Its effects on cardiac muscle also prevent excessive constriction in the coronary arteries



The mechanisms by which amlodipine relieves angina are:

Stable angina:

Amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, thereby lowering myocardial oxygen demand, at any given level of exercise.

Variant Angina: 

Amlodipine blocks spasm of the coronary arteries and restores blood flow in coronary arteries and arterioles in response to calcium, potassium, epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro.



Pharmacokinetics

The nitrogen-containing ring is oxidized, and two of the side chains are hydrolyzed.

Amlodipine is well absorbed by the oral route with a mean oral bioavailability around 60%; the half-life of amlodipine is about 30 h to 50 h, and steady-state plasma concentrations are achieved after 7 to 8 days of daily dosing.
Its long half-life and high bioavailability are largely in part of its high pKa (8.6); it is ionized at physiological pH, and thus can strongly attract proteins.




Side effects :

Some common dose-dependent side effects of amolodipine include vasodilatory effects, peripheral edema, dizziness, palpitations, and flushing.

Peripheral edema (fluid accumulation in the tissues) occurs at rate of 10.8% at a 10-mg dose (versus 0.6% for placebos), and is three times more likely in women than in men.

It causes more dilation in the arterioles and precapillary vessels than the postcapillary vessels and venules.

The increased dilation allows for more blood, which is unable to push through to the relatively constricted postcapillary venules and vessels; the pressure causes much of the plasma to move into the interstitial space.

Amlodipine-association edema can be avoided by adding ACE inhibitors or angiontensin II receptor antagonist.

Common but not dose-related side effects are fatigue , nausea , abdominal pain , and somnolence.

Side effects occurring less than 1% of the time include: blood disorders, impotence, depression, peripheral neuropathy, insomnia, tachycardia, gingival enlargement, hepatitis, and jaundice.



Overdose

Amlodipine overdose toxicity can result in widening of blood vessels, severe low blood pressure, and fast heart rate.

Toxicity is generally managed with fluid replacement, monitoring ECG results, vital signs, respiratory system function, glucose levels, kidney function, electrolyte levels, and urine output.Vasopressors are also administered when low blood pressure is not alleviated by fluid resuscitation.



Combination therapy

Amlodipine can be given as a combination therapy with a variety of medications:

Amlodipine/atorvastatin, where amlodipine is given for hypertension or CAD and atorvastatin prevents cardiovascular events, or if the person also has high cholesterol.

Amlodipine/aliskiren or amlodipine/aliskiren/hydrochlorothiazide if amlodipine alone cannot reduce blood pressure. Aliskiren is a renin inhibitor, which works to reduce primary hypertension (that with no known cause) by binding to renin and preventing it from initiating the renin–angiotensin system (RAAS) pathway to increase blood pressure.

Hydrochlorothiazide is a diuretic and decreases overall blood volume.

Amlodipine/benazepril if either drug has failed individually, or amlodipine alone caused edema. Benazepril is an ACE inhibitor and blocks the conversion of angiotensin I to angiotensin II in the RAAS pathway.

Amlodipine/olmesartan or amlodipine/olmesartan/hydrochlorothiazide if amlodipine is insufficient in reducing blood pressure. Olmesartan is an angiotensin II receptor antagonist and blocks part of the RAAS pathway.

Amlodipine/perindopril if using amlodipine alone caused edema. Perindopril is a long-lasting ACE inhibitor.
Amlodipine/telmisartan, where telmisartan is an angiotensin II receptor antagonist.
Amlodipine/valsartan or amlodipine/valsartan/hydrochlorothiazide, where valsartan is an angiotensin II receptor antagonist.

Contraindications

The only absolute contraindication to amlodipine is an allergy to amlodipine or any other dihydropyridines.

Other situations occur, however, where amlodipine generally should not be used.

In patients with cardiogenic shock, where the heart's ventricles are not able to pump enough blood, calcium channel blockers exacerbate the situation by preventing the flow of calcium ions into cardiac cells, which is required for the heart to pump.

While use in patients with aortic stenosis (narrowing of the aorta where it meets the left ventricle) since it does not inhibit the ventricle's function is generally safe, it can still cause collapse in cases of severe stenosis.

In unstable angina (excluding variant angina), amlodipine can cause a reflex increase in cardiac contractility (how hard the ventricles squeeze) and heart rate, which together increase the demand for oxygen by the heart itself.

Patients with severe hypotension can have their low blood pressure exacerbated, and patients in heart failure can get pulmonary edema. Those with impaired liver function are unable to metabolize amlodipine to its full extent, giving it a longer half-life.

Amlodipine's safety in pregnancy has not been established, although reproductive toxicity at high doses is known. Whether amlodipine enters the milk of breastfeeding mothers is also unknown.