Pharm 100 - Lesson C.3
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It was not until the well conducted clinical trials of drugs in the treatment of hypertension (highblood pressure) carried out at the Veterans Administration Hospitals in the United States in the 1950’sthat it became clear that lowering of high blood pressure would lower the possibility of stroke, heartattack, heart failure and kidney damage. At the time the trials were conducted, only a few efficacious antihypertensive drugs were available, namely reserpine, hydralazine and veratrum alkaloids. Sincethe 1950’s, many new classes of efficacious antihypertensive drugs have been introduced and continueto be introduced. Moreover, our knowledge of the biology of the cardiovascular system (heart andblood vessels) continues to increase. The conscientious physician therefore has a responsibility tokeep up with new developments if she/he is to choose the appropriate drug or drugs for their patients.
What is high blood pressure (B.P.)?
- The heart is a muscular pump providing pressure for blood to circulate through blood vessels,allowing blood to provide nutrients and oxygen to all organs.
- The blood pressure must be kept withinrelatively narrow limits and the body has several mechanisms to achieve control of blood pressure. However, in some individuals, the pressure in blood vessels rises above normal, and such individualsare diagnosed as having high blood pressure.
- The definition of normal blood pressure depends on age and the normal value increases with age; in a young adult the normal value is 120/80. The upperfigure (120) is the pressure in millimetres of mercury during systole, i.e. when the heart is contracting,while the lower figure (80) is the pressure in millimetres of mercury between contractions of the heart(diastole).
- Hypertension is usually silent and the person is not aware that they have the disease. Wide scalescreening has been an ongoing process to diagnose the condition. Hypertensaion leads to- increased vascular disease, increase in heart attacks, increase in stroke and an increase in renal disease.
Classification of high blood pressure:
- When an individual has a basal diastolic pressure of 90-105 millimetres of mercury and nodetectable kidney, heart or brain problems, she/he is classified as having mild hypertension.
- Anindividual with a basal diastolic pressure of greater than 130 millimetres of mercury is classified ashaving severe hypertension.
- An individual with blood pressure intermediate in severity between mild and severe is classified as having moderate hypertension.
Why should high blood pressure be controlled?
- The reason high blood pressure should be controlled is that when blood pressure is above normalfor long periods, the possibility of stroke, heart attack, heart failure, and kidney damage is increased. Drugs can bring blood pressure down to normal so that most complications can be avoided.
- Whilethere is no controversy that blood pressure greater than 95 millimetres of mercury (diastolic) should betreated, pharmacological treatment of mild hypertension, less than 95 millimetre mercury (diastolic) is controversial. However, there is no controversy that pharmacological treatment is required for mildhypertension (less than 95 millimetre mercury diastolic) when there is damage to the kidney, heart orblood vessels
How can blood pressure be controlled?
- One way of controlling blood pressure is by instituting lifestyle changes. It has been clearlydocumented that the following lifestyle changes will lower blood pressure:
- (a) reducing weight,
- (b)regular exercise,
- (c) low salt diet, and
- (d) reduced alcohol consumption.
- There is some evidencethat increased potassium and calcium consumption may be effective in lowering blood pressure,but further studies are required. It has been shown that even when lifestyle changes by themselves are insufficient to return blood pressure to normal, their effects may still be helpful where drugs arerequired.
- A second way of controlling of high blood pressure is by using a drug or combination of drugs(pharmacological treatment).
How do drugs lower blood pressure?
- (a) By dilating (increasing the diameter) of blood vessels,
- (b) by reducing the force of the heartbeat, and
- (c) by increasing the removal of salt and water from the body.
How long does one have to take drugs?
Since antihypertensive drugs do not cure high blood pressure, the drugs may have to be takenindefinitely
Should an individual with high blood pressure follow lifestyle changes and take drugs asrecommended?
Yes, she/he certainly should. One’s wellbeing and life may depend upon it.
Detection of high blood pressure:
Elevated blood pressure does not usually cause symptoms and many cases are undetected.
Compliance with therapy:
- Many individuals find it difficult to comply with therapy since therapy includes diet, salt restriction, exercise and treatment with one or more drugs. If an individual does not have a drugpayment plan, the cost of drugs may serve as a deterrent to compliance. The adverse effects of one ora combination of drugs may also deter an individual from compliance. Finally, the fact that therapy ifrequired for a long period of time is a further deterrent.
- A considerable effort has therefore been directed at trying to improve compliance with therapy inpatients with high blood pressure. It has been shown that mastery of facts about hypertension does notimprove patient compliance. Moreover, receiving medical care in “company time” also does notimprove compliance. Further study revealed that a behaviourally-oriented strategy would improvecompliance. Thus, individuals were taught how to measure their own blood pressure and record theirown blood pressure, as well as record their pill-taking. When an individual would note their bloodpressure rising after failure to take their pills, they would take their pills in the appropriate manner.
What factors control blood pressure?
- There are three factors which control blood pressure: (1) volume of fluid in blood vessels,
- (2)resistance to blood flow in the circulation, and
- (3) the renin-angiotensin-aldosterone system.
(1) Volume of fluid in blood vessels:
Increasing the volume of fluid in the blood vessels increases blood pressure, while decreasing thevolume of fluid in blood vessels leads to a decrease in blood pressure. The volume of fluid in theblood vessels in controlled primarily by the kidney.
(2) Resistance to blood flow in the circulation:
- The resistance to blood flow in the circulation depends upon the state of constriction or dilationof arterioles (small diameter arteries). The state of constriction or dilation of arterioles and thereforethe diameter of the arterioles depends upon the activity of the sympathetic nervous system (SNS).
- Increased SNS activity results in enhanced release of the neurotransmitter, norepinephrine, fromsympathetic nerves onto receptors in arterioles. This will result in constriction of the arterioles andincreased resistance to blood flow. Conversely, diminished SNS activity will result in diminishedrelease of noradrenaline, resulting in dilation of arterioles and reduced resistance to blood flow
(3) Renin-angiotensin-aldosterone system:
- Renin, an enzyme released from the kidney, acts upon a protein present in blood, namely"2-globulin. A small portion of the protein is split off and this small portion is a peptide named angiotensin I. An enzyme known as angiotensin converting enzyme (abbreviated as ACE) actsupon angiotensin I, reducing it in size to form the peptide, angiotensin II. Angiotensin II acts uponblood vessels to cause vasoconstriction and results in elevation of blood pressure.
- In addition,angiotensin II acts upon the adrenal cortex, a portion of an organ situated on top of the kidney, causingthe liberation from the adrenal cortex of a hormone known as aldosterone. Aldosterone acts uponspecific aldosterone receptors in a portion of the kidney to cause increased retention of sodium andwater by the kidney. The retention of sodium and water by the kidney in turn leads to an elevation ofblood pressure. The process is summarized by the diagram below.
Pharmacological Agents for Treatment of Hypertension
There are five classes of pharmacological agents and only one representative example is given ineach class or subclass.
Thiazide – hydrochlorothiazide: Hydrochlorothiazide is one of many thiazide diuretics used inthe therapy of hypertension. Hydrochlorothiazide decreases blood volume by enhancing salt andwater excretion by the kidney and it also lowers the resistance of blood vessels.
2. Drugs which decrease sympathetic nervous system activity:
- (a) Beta blocker – propranolol: Causes blockade of beta-adrenergic receptors in the heart andseveral other organs.
- (b) Alpha blocker – prazosin: Block alpha-adrenergic receptors and lower blood pressure by dilating arterioles and veins.
- (c) Adrenergic neuron blocker – reserpine: Reserpine binds to and destroys storage vesicles inadrenergic neurons. This causes depletion of catecholamines (e.g. norepinephrine). As a result,blood pressure will decrease.
- (d) Centrally-acting – clonidine: Clonidine stimulates alpha-adrenergic receptors in the brainstem.This results in decreased sympathetic nervous system outflow to blood vessels and reducedresistance of blood vessels, thus leading to decreased blood pressure.
3. Vasodilators – hydralazine:
Hydralazine causes direct relaxation of arterioles by an unknown mechanism.
4. Angiotensin converting enzyme (ACE) inhibitor – captopril:
Captopril acts on the renin-angiotensin-aldosterone system to inhibit conversion of angiotensin Ito the potent hypertensive agent, angiotensin II
5. Calcium channel blocker – nifedipine:
Nifedipine decreases the amount of calcium reaching sites in cells of vascular smooth muscle. This decrease leads to a relaxation of arterioles, a decrease in resistance of the arterioles, and alowering of blood pressure.
Canadian Hypertension Society Consensus Conference Recommendations
- The Canadian Hypertension Society meets at intervals to reach a consensus on hypertensiontherapy to act as a guide for physicians. The following recommendations are derived from the 2007 Consensus of the Canadian Hypertension Society. Only initial recommendations are given as thecomplete recommendations would be too complex for students taking this course.For more information visit the Canadian Hypertension Website (www.hypertension.ca) Click onrecommendations and then on summary.
- For therapy of hypertensive patients with no co-existing medical conditions or organ damage:
- < Start therapy with either a low-dose diuretic or a beta blocker. If there are adverse effectsor an inadequate response, try the other.
- < If response is only partial, use a combination of a diuretic and a beta blocker, ormonotherapy with an alpha blocker, ACE inhibitor, calcium channel blocker, or centrallyacting drug.
- Further details follow on diuretics, beta blockers and ACE inhibitors.
Diuretics – thiazide diuretics:
These are key drugs in the therapy of hypertension. They are efficacious when used alone andenhance the efficacy of most other antihypertensives when given concurrently. These drugs areeffective in the elderly. In recent years, it has been found that smaller doses than those usedpreviously are effective with a corresponding decrease in the incidence of adverse effects. This classof drugs is held in high regard due to their record of safety over many years and the fact that wellcontrolled clinical trials have shown that they reduce the incidence of stroke and other problemsassociated with the cardiovascular system.
Beta-adrenergic blocking drugs – propranolol:
These drugs are widely used because hypertension clinical trials show a reduction in stroke andother serious cardiovascular problems. Beta blockers are less effective than diuretics in the elderlyand in African Americans. Beta blockers can block receptors in bronchi and cause bronchospasm. Therefore, beta blockers should not be used in individuals with asthma and other obstructive lungdiseases.
Angiotensin converting enzyme (ACE) inhibitors – captopril:
One of the advantages of this group of antihypertensive agents is that they are not thought tocause sexual dysfunction, a problem seen with other antihypertensives. They can be used in asthma. They do not cause an alteration in carbohydrate metabolism or plasma concentration of lipoproteinsand can therefore be used in diabetes. There is some preliminary evidence that ACE inhibitors will reduce the incidence of heart disease in patients with high blood pressure more effectively than otherblood pressure lowering drugs. A disadvantage of ACE inhibitors is that 5-20% of patients develop abothersome dry cough. ACE inhibitors can cause fetal injury and death when used in the second andthird trimester of pregnant. They should therefore not be used during pregnancy. Elderly AfricanAmericans are more resistant to the blood pressure lowering effects of ACE inhibitors.
As our knowledge of the biology of the cardiovascular system continues to advance, thedevelopment of new and more selective antihypertensive drugs may be anticipated. This field oftherapeutics can be expected to develop rapidly and keeping up to date will present a continuingchallenge. One way to keep up to date is continued reading of periodicals such as THE MEDICALLETTER ON DRUGS AND THERAPEUTICS.
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