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DRUGS ACTING ON CARDIOVASCULAR SYSTEM

HYPERTENSION:
It is the most common disorder found nowadays, and is defined differently. Elevated blood pressure is said to be hypertension A sustain rise in blood pressure either systolic or diastolic is said to be hypertension Blood pressure at which there is risk to the life of subject is called hypertension WHO characterize hypertension as a situation, in which rise in blood pressure exceed 160/95 mm of Hg. Hypertension is a situation doesnt strictly relate to rise in blood pressure; it also depends upon age, sex, race and lifestyle. And variation in defining hypertension occurs due to these factors.

CLASSIFICATION:
3 years back, hypertension was classified as mild, moderate, severe and highly severe. Now it is classified as normal, pre hypertension, stage I hypertension, and stage II hypertension and the blood pressure limits are following; TYPE OF SYSTOLIC DIASTOLIC CHECKUP HYPERTENSION (mm of Hg) (mm of Hg) (Blood pressure must be checked every) Normal > 120 > 80 2 years Pre hypertension 120-139 80-90 year Stage I hypertension 140-159 90-99 2 months Stage II hypertension < 160 < 100 Week But if the Stage II blood pressure is greater than 180/110 mm of Hg, it should be managed immediately, without wasting time. Traditionally hypertension is classified into, Primary Hypertension: 90-95% of individuals have this type of hypertension. It is also called essential hypertension, as patient doesnt have any specific reason to have hypertension. It is generally due to stress, genetics and environmental factors. Secondary Hypertension: In it rise in blood pressure is due to some specific reasons like hormonal abnormalities, any disease or drugs. And to treat such hypertension causes of blood pressure elevation must be managed like checking and normalizing hormonal levels, disease must be treated and discontinuing drug therapy.

REASONS OF BLOOD PRESSURE ELEVATION:


Alteration in contractile property of arterial blood vessels Failure of response to auto regulatory mechanism If these mechanisms fail, blood pressure rises and medicines must be taken to control blood pressure.

SECONDARY HYPERTENSION:
RENAL ARTERY STENOSIS: It is a clinical situation in which narrowing of renal artery occur, which decreases renal perfusion pressure due to which rennin-angitensin aldosterone system activates which increases reabsorption of salt and water, as a result increasing blood pressure. In this situation; Surgery can be done Revascularization with or without stunt is done Angioplasty is done Drugs are given to control hypertension PHEOCHROMOCYTOMA: In this condition, tumor in adrenal gland of zona granulosa is found which increases secretion of epinephrine and norepinephrine which increase blood pressure elevation and cause hypertension. For this, -antagonist Phenoxybenzamine is given as an adjutant with tyrosine hydroxylase inhibitor metirosine, which reduces 35-80% synthesis of catecholamines if given in the dose of 14gm/ day. If tumor is non-carcinogenic surgery is done and if it is carcinogenic person has to take metirosine for his entire life. CONNS SYNDROME AND HYPERALDOSTERONISM: In these condition secretion of hormone aldosterone increases which is responsible for absorption of sodium and water. This will increase blood volume and sensitivity to vasoconstriction. Spironolactone, which is potassium-sparing diuretic, is drug of choice in this condition. HYPERTHYROIDISM: Thyroxin increases the sensitivity or chances of expression of -adrenergic receptor, increasing blood pressure. Therefore, for treating it -adrenergic receptor antagonist is given. DRUG INDUCED HYPERTENSION: Use of corticosteroids, amphetamine, licorice, MAO inhibitors, NSAIDS and oral contraceptive cause elevation of blood pressure. In this situation drug therapy should be stopped. Oral contraceptives are commonly used in our society and it can be of serious threat, as it increases chances of causing hypertension and thrombosis. So, they should be avoided and if it is necessary the use should be kept monitored.

SYSTEMS WHICH REGULATE BLOOD PRESSURE:


AUTONOMIC NERVOUS SYSTEM:
It is meant for short term management of blood pressure i.e. changes in Blood pressure due to change in posture or altered physical activity. The regulation of BP by ANS is done by baroreceptors, which detect change in blood pressure and in response to that sympathetic nervous system is activated, which increases release of norepinephrine that acts on -receptors which increase peripheral vascular resistance and when it act on 1receptors it increase heart rate, cardiac output. And combine effect of these receptors increase blood pressure.

RENNIN ANGIOTENSIN ALDOSTERONE SYSTEM:


It is responsible for long term regulation of blood pressure which mainly depends upon cardiac output, which is regulated by volume of blood. And this system maintains homeostasis between volume of blood and ions. This mechanism is controlled by kidney, as rennin is secreted by kidney which is responsible for synthesis of angiotensin that is vasoconstrictor, it also initiate release of norepinephrine and Mineralocorticoid aldosterone which not only control peripheral vascular resistance but also control the volume of blood by increasing reabsorption of Na and water Other 2 factors which control blood pressures are

NATRIURETIC PEPTIDES:
These are of three types Atrial Natriuretic Peptides ANP, Brain Natriuretic Peptides BNP and CNP. It decreases blood pressure by natriuresis (loss of sodium) and diuresis (loss of water) and this is done by direct vasodilatory effect, decrease synthesis of sympathetic neurotransmitter and release of aldosterone.

KININ:
There are two types of kinin; kallidin and bradykinin. Kallidin is synthesized from kininogen by the action of enzyme kallikrein. And same enzyme converts prekallikrein into bradykinin. They decrease blood pressure by producing Vasodilation; property of kinin is typical as it causes constriction of large blood vessels and dilatation of small blood vessels. Hypertension is the problem of smaller blood vessels so; if large blood vessels are constricted that do not produce any effect on blood pressure. Other substances that produce effect on muscle tone of blood vessels are adenosine, vasopressin, prostaglandins etc.

MANAGEMENT OF HYPERTENSION:
NON PHARMACOLOGICAL:
Initially non pharmacological methods are applied, especially when the diastolic pressure is between 85-95mm of Hg, otherwise it is not advice able to relay only on nonpharmacological methods as it can harm the patient. DECREASE SALT INTAKE: 4-6gm of salt daily keeps blood pressure in control. And if a person is taking 12gm salt daily, by reducing it to 50% blood pressure can be reduced 10mm of Hg. And 30-60% individuals are salt sensitive. DACH: Dietary Approach to Control Hypertension include increase intake of Ca and K as, Ca control blood pressure by secretion of calcitonin gene related peptide which cause vasodilation and K controls blood pressure by vasodilation. REDUCTION IN WEIGHT OF OBESE INDIVIDUALS: Decrease in each kg weight of obese person will decrease 2.5 mm of Hg systolic and 1.5 mm of Hg diastolic blood pressure. 60-80% individuals are weight sensitive.

LIGHT PHYSICAL EXERCISE: If regular exercise of 30 minutes in most days of week is done 2-5mm of Hg blood pressure decreases. CESSATION OF SMOKING: 0.3-1mg of nicotine has a role in increasing blood pressure and cessation of smoking reduces it. MEDITATION: Reduction in stress and anxiety reduce hypertension, this technique works especially in western countries.

PHARMACOLOGOICAL:
When 3 to 6 months are passed and blood pressure is not managed through nonpharmacological means then it is advised to initiate pharmacological therapy. CRITERIA: There are some criterias set by British Hypertension Society for usage of pharmacological therapy. If the sustained blood pressure is 160/95 mm HG then the therapy should be initiated. If the systolic blood pressure is 140-159 and diastolic 90-99 mm Hg, and there is evidence of any injury related to heart or kidney etc, then anti-hypertensive therapy should be initiated. If the person is having blood pressure 140/85mm Hg and having diabetes mellitus patient should be given drugs to control it. SPECIFIC DRUGS: Specific drugs are given for treating hypertension diuretics and -blockers are 1st choice of drug until and unless these specific drugs cause any harm as incase, of dialysis diuretics are not given and in case of asthma -blockers should not be administered. Diuretics are preferred for older patients i.e. above 50 years and for patients less than that -blockers are advisable. But if blood pressure is not managed by minimal dose o these drugs it is preferred to shift over other drugs than increasing dose. Angiotensin Converting Enzyme (ACE inhibitor) or Calcium channel blockers are given in this case. And if these two drugs fail to control blood pressure so these drugs are given in combination. And if this combination is not effective then ACE inhibitors, Calcium channel blocking agents and diuretics are given in combination. And if this combination also fails then aldosterone antagonist/ spironolactones are given. CLASSIFICATION: 7 CLASSES OF CLASSIFICATION SUBEXAMPLES ANTIHYPERTENSIVE CLASSIFICATION DRUGS Weak efficacy diuretics Carbonic Anhydrase

Diuretics

Moderate efficacy diuretics High efficacy diuretics

Centrally acting drugs -antagonist -antagonist Sympatholytics Mixed acting Adrenergic neuron blockers

Ganglionic blocking agent Arterial Vasodilators balance Phenylalkylamine Dihydropyridine Calcium channel blockers Benzothizepine Diarylamino isopropyl amine Sulfhydryl containing drugs Phosphonoate containing drugs Dicarboxylate containing drugs

inhibitors, potassium sparing diuretics, osmotic diuretics Thiazides Torsemide, bumetanide, ethacrynic acid, loop diuretic Methyldopa, clonidine Prazosin. Terazosin, Phenoxybenzamine Propanolol, metoprolol, esmolol, nadolol Carvedilol, labetalol Guanethidine, reserpine (these drugs are not used anymore) Trimethaphan, mecamylamine Hydralazine, minoxidil Sodium nitroprusside Gallopamil, Calan Nifedipine, nicardipine, nimodipine Diltiazem Bepridil Captopril, zofenopril Fosinopril Lisinopril, benazepril, quinapril, perindopril, Candesartan, irbesartan,

ACE inhibitors Inhibitors of rennin angitensin system Angiotensin receptor blockers

Rennin inhibitors Vasopeptidase inhibitors Dopamine agonist

valsartan Aliskiren Omapatrilat Fenoldopam

DIURETICS:
MECHANISM OF ACTION: Initially it was thought that diuretics produce anti-hypertensive effect by loss of water which decreases volume of blood and blood pressure reduces. High efficacy diuretics (loops) are not nice effectivity in patients with normal renal function. While thiazides have nice effectivity and this rejects aforementioned hypothesis. Loss of water caused by diuretics is recovered between 3-4 weeks and there is no change in volume of blood following 3-4 weeks of administration. So it was concluded that there is some other mechanism of action for anti hypertensive effect of diuretics. Second hypothesis was that diuretics cause loss of sodium which reduces blood pressure. As sodium increase stiffness of small vessels, by increasing sensitivity of vasconstricting stimuli which increase vascular peripheral resistance, increasing blood pressure. But more recently another explanation is presented that sodium accumulates in excess amount in resistant vessels which increase peripheral vascular resistance. Diuretics cause mobility of sodium from arterial blood vessel due to which blood vessels open up and blood pressure decrease. Another theory states that thiazides activates ATP sensitive K channel causing hyperpolarization in arterial blood vessels prevent entry of calcium which results in decrease peripheral vascular resistance lowering blood pressure. INDICATIONS: Whenever, diuretics are given they lower blood pressure 10-15 mm Hg and they are effective for management of mild to moderate hypertension. Thiazide diuretics are effective when renal function is normal. Loop diuretics are effective in edematous conditions (edema cur due to any problem like liver etc) PHARMACOKINETICS: Pharmacokinetics is not involved in case of diuretics they do not undergo metabolism and are removed unchanged from the body. Their removal depends upon rate of excretion. DOSE: 12.5-25mg/day ADVERSE EFFECT: If this dose does not manage hypertension than increasing the dose above 25mg will not increase anti-hypertensive effect rather it will increase adverse effects like hypokalemia, Hyperlipidemia, hyperuricemia and hyperglycemia. Hypokalemic effect I well tolerated by most of the patients but patients suffering from MI or congestive heart failure can not tolerate it and measures must be taken for replacement of potassium thus, K sparing diuretics are given or K supplements or diet rich in K is taken such as spinach, orange, and banana etc.

DRUG INTERACTION: If diuretics are given along with NSAIDs, they inhibit the hypotensive effect of diuretics. When oral hyperglycemic agents like sulfonylurea are given their metabolism is affected and hyperglycemia occurs. So diuretics must be given with caution and dose must be adjusted.

CENTRALLY ACTING SYMPATHOLYTICS:


METHYLDOPA (ALDOMET):
MECHANISM OF ACTION: It produces anti hypertensive effect at the level of CNS. Initially it was thought that this drug inhibit synthesis of nor-epinephrine in CNS, due to which peripheral effect o norepinephrine was reduced, lowering blood pressure. Then it was found that methyldopa does not inhibit synthesis of neurotransmitter rather it has structural resemblance with dopa, precursor of the neurotransmitter. And the drug enters the synthesis pathway forming -methyl nor-epinephrine which is not active as norepinephrine itself, and act as false neurotransmitter due to which all effects of norepinephrine are prevented. Again this theory was rejected due to experiment, in which 2 groups of animals were taken and methyldopa was administered in only one group of animals. They induced electrical stimulation of sympathetic system in both groups and observed that all sympathetic effects were similar and it was concluded that -methyl norepinephrine was not a false neurotransmitter rather it acted as a neurotransmitter. Then another theory came which stated that, methyldopa is prodrug in CNS and when it is converted into -methyl norepinephrine it occupies, 2-receptor in brain and decrease discharge of norepinephrine. Here a question arises that norepinephrine is also present in CNS so why it does not produce the same effect. The answer is very simple that norepinephrine is destroyed within milliseconds and drug has comparatively longer half-life. Another fact is V-methyl norepinephrine has high affinity towards 2-recptor than norepinephrine.

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