1) Calcium channel blockers block L-type voltage-gated calcium channels in the heart and in the blood vessels which prevents calcium levels from increasing as much in the cells when stimulated leading to less contraction. This decreases total peripheral resistance by dilating the blood vessels and decreases cardiac output by lowering the force of contraction. Blood pressure drops because resistance and output drop; therefore, the heart does not have to work as hard which can ease problems with cardiomyopathy and coronary disease. Unlike with beta-blockers, the heart is still responsive to sympathetic nervous system stimulation, so blood pressure can be maintained more effectively. They are a class of drugs with effects on excitable cells of the body e.g. the muscle of the heart and the smooth muscles of the vessels or neuron cells. The main action of calcium channel blockers is to lower blood pressure in individuals with hypertension. Most calcium channel blockers decrease the force of contraction of the myocardium which is known as the negative inotropic effect of calcium channel blockers which is why they are used with caution in individuals with cardiomyopathy. Many calcium channel blockers also slow down the conduction of electrical activity within the heart by blocking the calcium channel during the plateau phase of the action potential of the heart which causes a lowering of the heart rate and may cause heart blocks which is known as the negative chronotropic effect of calcium channel blockers which is why they are used in individuals with atrial fibrillation or flutter in whom control of the heart rate is an issue.

Dihydropyridine calcium channel blockers often used to reduce systemic vascular resistance and arterial pressure, but is not used to treat angina because the vasodilation and hypotension can lead to reflex tachycardia.

Calcium channel blockers are easily identified by the suffix "-pine".

List of calcium channel blockers:

Amlodipine (Norvasc)
Felodipine (Plendil)
Nicardipine (Cardene, Carden SR)
Nifedipine (Procardia, Adalat)
Nimodipine (Nimotop)
Nisoldipine (Sular)
Nitrendipine (Cardif, Nitrepin)
Lacidipine (Motens)
Lercanidipine (Zanidip)
Phenylalkylamine calcium channel blockers are relatively selective for mycardium, reduces myocardial oxygen demand and reverses coronary vasospasm and is often used to treat angina. It has minimal vasodilatory effects compared with dihydropyridines.

Verapamil (Calan, Isoptin)
Gallopamil (D600)
Benzothiazepine calcium channel blockers is an intermediate class between phenylalkylamine and dihydropyridines in its selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, benzothiazepines are able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines.

Diltiazem (Cardizem)

Amlodipine is a 1,4-dihydropyridine-derivative calcium-channel blocking agent that is structurally related to felodipine, nifedipine, and nimodipine. Unlike other currently available agents in the dihydropyridine class, amlodipine has an intrinsically long duration of action.

Amlodipine is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Amlodipine in fixed combination with atorvastatin (Caduet) is used in patients for whom treatment with both amlodipine and atorvastatin is appropriate.

Long-acting dihydropyridine calcium-channel blocking agents are considered to be alternatives to diuretics for initial therapy in the management of isolated systolic hypertension (systolic blood pressure of 140 mm Hg or greater and diastolic pressure less than 90 mm Hg) in geriatric patients, since nitrendipine which is no longer commercially available in the US has been shown to affect favorably the risk of stroke over an average 2-year period.

Because of the slow onset of hypotensive effect with amlodipine, this drug is not suitable for use as acute therapy in rapidly reducing blood pressure in patients with severe hypertension in whom reduction of blood pressure is considered urgent (hypertensive urgencies) nor in hypertensive emergencies. However, long-acting antihypertensive agents may be useful when severe blood pressure elevations continue after initial management of the hypertensive crisis with an appropriate agent.

Amlodipine also is used for the management of Prinzmetal variant angina and chronic stable angina pectoris. The drug has been used alone or in combination with other antianginal agents. Amlodipine in fixed combination with atorvastatin (Caduet) is used in patients for whom treatment with both amlodipine and atorvastatin is appropriate.

As monotherapy for the management of hypertension, the usual initial adult dosage of amlodipine is 2.5 to 5 mg once daily. In geriatric patients and small frail individuals, an initial dosage of 2.5 mg once daily is recommended. This reduced initial dosage also can be used in adults when amlodipine is added to an existing antihypertensive drug regimen. Subsequent dosage of amlodipine should be adjusted according to the patient’s blood pressure response and tolerance and usually should not exceed 10 mg once daily. Generally, dosage is increased gradually at 7- to 14-day intervals until optimum control of blood pressure is maintained. However, more rapid titration of dosage can be undertaken when clinically warranted, provided response and tolerance are assessed frequently. The usual maintenance dosage of amlodipine for the management of hypertension in adults is 5 to 10 mg once daily.

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of amlodipine is recommended. Large or abrupt reductions in blood pressure generally should be avoided.

Once antihypertensive drug therapy has been initiated, dosage generally is adjusted at approximately monthly intervals (more aggressively in high-risk patients e.g. stage 2 hypertension, comorbid conditions) if blood pressure control is inadequate at a given dosage; it may take months to control hypertension adequately while avoiding adverse effects of therapy.

Calcium channel blocker overdose is rapidly emerging as the most lethal prescription drug ingestion. Overdose by short-acting agents is characterized by rapid progression to cardiac arrest. Overdose by extended-relief formulations result in delayed onset of arrhythmias, shock, sudden cardiac collapse, and bowel ischemia.

Calcium channel blockers have the following 4 cardiovascular effects: peripheral vasodilatation, negative chronotropy (decreased heart rate), negative inotropy (decreased cardiac contractility), and negative dromotropy (decreased cardiac conduction)

Other physiologic responses to calcium channel blocker overdose include suppression of insulin release from the pancreas and decreased free fatty acid utilization by the myocardium. These factors produce hyperglycemia, lactic acidosis, and depressed cardiac contractility.

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2) Angiotensin II is a very potent chemical that causes the muscles surrounding blood vessels to contract and thereby narrows the blood vessels. The narrowing of the vessels increases the pressure within the vessels and can cause high blood pressure (hypertension). Angiotensin II is formed from angiotensin I in the blood by the enzyme, angiotensin converting enzyme (ACE). Angiotensin converting enzyme (ACE) inhibitors are medications that slow (inhibit) the activity of the enzyme, which decreases the production of angiotensin II. As a result, the blood vessels enlarge or dilate, and the blood pressure is reduced. This lower blood pressure makes it easier for the heart to pump blood and can improve the function of a failing heart. In addition, the progression of kidney disease due to high blood pressure or diabetes is slowed.

ACE inhibitors are used for controlling blood pressure, treating heart failure and preventing kidney damage in people with hypertension or diabetes. They also benefit patients who have had heart attacks. In studies, individuals with hypertension, heart failure, or prior heart attacks who were treated with an ACE inhibitor lived longer than patients who did not take an ACE inhibitor. Because they prevent early death resulting from hypertension, heart failure or heart attacks, ACE inhibitors are one of the most important group of drugs. Some individuals with hypertension do not respond sufficiently to ACE inhibitors alone. In these cases, other drugs are used in combination with ACE inhibitors.

ACE inhibitors differ in how they are eliminated from the body and their doses. Some ACE inhibitors need to be converted into an active form in the body before they work. In addition, some ACE inhibitors may work more on ACE that is found in tissues than on ACE that is present in the blood. The importance of this difference or whether one ACE inhibitor is better than another, has not been determined.

ACE inhibitors are relatively well-tolerated by most individuals. Nevertheless, they are not free of side effects, and some patients should not use ACE inhibitors. ACE inhibitors usually are not prescribed for pregnant patients because they may cause birth defects. Individuals with severe kidney problems and people who have had a severe reaction to ACE inhibitors probably should avoid them. The most common side effects are cough, elevated blood potassium levels, low blood pressure, dizziness, headache, drowsiness, weakness, abnormal taste (metallic or salty taste), and rash. It may take up to a month for coughing to subside, and if one ACE inhibitor causes cough it is likely that the others will too. The most serious, but rare, side effects of ACE inhibitors are kidney failure, allergic reactions, a decrease in white blood cells, and swelling of tissues (angioedema).

ACE inhibitors have few interactions with other drugs. Since ACE inhibitors may increase blood levels of potassium, the use of potassium supplements, salt substitutes (which often contain potassium), or other drugs that increase the body's potassium may result in excessive blood potassium levels. ACE inhibitors also may increase the blood concentration of lithium (Eskalith) and lead to an increase in side effects from lithium. There have been reports that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen, indomethacin, and naproxen may reduce the effects of ACE inhibitors; however, there is no conclusive evidence that this interaction, if it exists, is important.

List of the ACE inhibitors available in the United States:

captopril (Capoten)
benazepril (Lotensin)
enalapril (Vasotec)
lisinopril (Prinivil
Zestril) fosinopril (Monopril), ramipril (Altace)
perindopril (Aceon)
quinapril (Accupril)
moexipril (Univasc)
trandolapril (Mavik).

Angiotensin I converting enzyme is an exopeptidase that catalyses the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. ACE is also involved in the inactivation of bradykinin, a potent vasodilator. These two actions of ACE make it an ideal target in the treatment of conditions such as high blood pressure, heart failure, diabetic nephropathy and type 2 diabetes mellitus. Inhibition of ACE by ACE inhibitors results in decreased formation of Angiotensin II which is a far more potent vasoconstrictor than Angiotensin I and decreased inactivation of bradykinin.

Losartan, the first ARB Angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs), AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system. Their main use is in hypertension, diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure.

These substances are AT1-receptor antagonists which block the activation of angiotensin II AT1 receptors. Blockade of AT1 receptors directly causes vasodilation, reduces secretion of vasopressin, reduces production and secretion of aldosterone, amongst other actions – the combined effect of which is reduction of blood pressure.

Angiotensin II receptor antagonists are primarily used for the treatment of hypertension where the patient is intolerant of ACE inhibitor therapy. They do not inhibit the breakdown of bradykinin or other kinins, and are thus only rarely associated with the persistent dry cough and/or angioedema that limit ACE inhibitor therapy. More recently, they have been used for the treatment of heart failure in patients intolerant of ACE inhibitor therapy, particularly candesartan. Irbesartan and losartan have trial data showing benefit in hypertensive patients with type II diabetes, and may delay the progression of diabetic nephropathy.

The angiotensin II receptor blockers have differing potencies in relation to blood pressure control, with statistically differing blood pressure effects at the maximal doses. When used in clinical practice, the particular agent used may vary based on the degree of blood pressure response required.

Angiotensin II receptor antagonists are usually well-tolerated, with common adverse drug reactions e.g. dizziness, headache, and/or hyperkalemia. Infrequent adverse drug reactions associated with therapy include first dose orthostatic hypotension, rash, diarrhea, dyspepsia, abnormal liver function, muscle cramp, myalgia, back pain, insomnia, decreased hemoglobin levels, renal impairment, pharyngitis, and/or nasal congestion.

While one of the main rationales for thei use is the avoidance of dry cough and/or angioedema associated with ACE inhibitor therapy, they may still rarely occur. Additionally, there is also a small risk of cross-reactivity in patients who have experienced angioedema with ACE inhibitor therapy.

Angiotensin II receptor antagonists: Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Tasosartan, Telmisartan, Valsartan

Losartan is a prodrug and requires activation in the liver to exert its pharmacologic activity. Losartan is used to treat hypertension, for prevention of cardiovascular morbidity and mortality, diabetic nephropathy, and for treating congestive heart failure.

Hi,

The various calcium channnel blockers are
L calcium channel blockers ( calcium current in long, large and high threshold)
i)Dihydropyridines
Amlodipine
Felodipine
Isradipine
Nicardipine
Nimodipine
Nifedipine
Nisoldipine
Nit redipine

ii) Phenylalkylamine
Verapamil
iii)Benzothiazepine
Diltiazem

T type calcium channel blockers ( T calcium current is short, small and low threshold)
Flunarazine

N type calcium channel blockers (short, high threshold current)
conotoxins (experimental use only)

P type (long and high threshold current)
conotoxins and funnel spider toxin (experimental use only)



Mechanism of action in general
The cardiac muscle and smooth muscle has L-type calcium channel as the dominant one and is known to have various drug receptors. The binding sites of dihidropyridines differ slightly from the other groups. These receptor binding sites are also stereoselective.

The drugs act via the channels in the inside of the cell membrane and and binds more effectively to channels on depolarized membranes. This binding results in reduced frequency of opening on channels in response to depolarization. The end result is marked decrease in the transmembrane calcium current leading to long lasting relaxation of smoothmuscle and reduction in contractility of heart. The non-dihydropyridines also decreases sinus node pacemaker rate and the atrioventricular conduction velocity.

The dihydropyridines (esp short acting ones like Nifedepine) can actually increase the heart rate indirectly by stimulating sympathetic activity resulting from the fall in blood pressure due to vasodilation. Verapamil and Diltiazem have prominent action on heart while dihydropyridines are prominent vasoactive agents.

Calcium enters the smooth muslce cell through Ca2+ channels (blocked by Ca-channel blockers) and forms calcium calmodulin complex which activates myosin light chain kinase (MLCK)which inturn activates mysosin light chain and which interactes with actin to bring about contraction. SO the very first step in this chain of events is blocked and the smooth muscle remains relaxed.

USES
The uses

i)Dihydropyridines
Amlodipine: Angina, Hypertension
Felodipine: Hypertension, Raynauds Phenomenon, Congestive heart failure
Isradipine: Hypertension,
Nicardipine: Angina, hypertension, Congestive heart failure
Nimodipine: Subarachnoid hemorrhage, Migraine
Nifedipine: Angina (sustained release), hypertension, migraine, cardiomyopathy, Raynauds Phenomenon, pregnancy induced hypertension
Nisoldipine: hypertension
Nitredipine: Angina, Hypertension

ii) Phenylalkylamine
Verapamil: Angina, Hypertension, migraine, cardiomyopathy,arrhythmias
iii)Benzothiazepine
Diltiazem: Angina, hypertension, raynauds phenomenon

T type calcium channel blockers ( T calcium current is short, small and low threshold)
Flunarazine: Migraine

Adverse effects:

i)Dihydropyridines
Amlodipine: Headache, peripheral edema
Felodipine: Dizziness, peripheral edema
Isradipine: Headache, fatigue
Nicardipine: Headache, peripheral edema, dizziness, flushing
Nimodipine: Headache, diarrhoea
Nifedipine: Headache,hypotension, dependent edema, flushing, nausea, constipation
Nisoldipine: Headache,hypotension, dependent edema, flushing, nausea, constipation
Nitredipine:Headache,hypotension, dependent edema, flushing, nausea, constipation

ii) Phenylalkylamine
Verapamil: Hypotension, dependent edema,myocardial depression, constipation
iii)Benzothiazepine
Diltiazem: Headache,hypotension, flushing, hypotension, bradycardia

T type calcium channel blockers ( T calcium current is short, small and low threshold)
Flunarazine: peripheral edema

To be continued with ACEIs.

Thank you

Dr Santhosh Joseph, MD


Dr. Santhosh MD