Drugs for Management of Hypertension

Diuretics

Types:

Thiazides – Inhibits ion transporter, thus causing water retention in urine. Works at different location (distal convoluted tubule) from loop.

Loop Diuretics – generally location of action is at the loop of Henle by inhibiting reabsorption of sodium. Hence, water which usually follows sodium into ECF now follows sodium into urine.

Potassium-sparing – these kinds of diuretics are more oriented towards function than location. Hence, potassium sparing means potassium is spared from being secreted into urine.

Adverse effects are uncommon, unless high doses are used. These include increased serum cholesterol, glucose and uric acid; decreased potassium, sodium and magnesium levels and erectile dysfunction.

Beta-blockers

Work by slowing heart rate down, hence decreasing blood pressure.

They are particularly useful in hypertensive patients with effort angina, tachyarrhythmias or previous myocardial infarction where they have been shown to reduce cardiovascular morbidity and mortality.

Adverse effects reported include masking of hypoglycaemia (since you inhibit sympathetic system activity which shows symptoms), increased incidence of new onset diabetes mellitus, erectile dysfunction, nightmares and cold extremities.

Contraindications of beta-blockers are related to their cardiac mechanisms and include bradycardia, reduced exercise capacity, heart failure, hypotension, and atrioventicular (AV) nodal conduction block. Beta-blockers are therefore contraindicated in patients with sinus bradycardia and partial AV block. The side effects listed above result from excessive blockade of normal sympathetic influences on the heart.

Bronchoconstriction can occur, especially when non-selective beta-blockers are administered to asthmatic patients. Therefore, non-selective beta-blockers are contraindicated in patients with asthma or chronic obstructive pulmonary disease. Bronchoconstriction occurs because sympathetic nerves innervating the bronchioles normally activate β₂-receptors that promote bronchodilation. Blockade of these receptors can lead to bronchoconstriction.

Calcium Channel Blockers

Dihydropyridine calcium channel blockers are often used to reduce systemic vascular resistance and arterial pressure. However, the vasodilation and hypotension can lead to reflex tachycardia.

Phenylalkylamine calcium channel blockers are relatively selective for myocardium, reduce myocardial oxygen demand and reverse coronary vasospasm, and are often used to treat angina. They have minimal vasodilatory effects compared with dihydropyridines and therefore cause less reflex tachycardia, making it appealing for treatment of angina.

Benzothiazepine calcium channel blockers (Diltiazem) are an intermediate class between phenylalkylamine and dihydropyridines in their 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.

Adverse effects include initial tachycardia, headache, flushing, constipation and ankle oedema. Unlike other CCBs, Verapamil may reduce heart rate and care should be exercised when used with beta- blockers.

ACE Inhibitors

They lower arteriolar resistance and increase venous capacity; increase cardiac output, stroke volume, lower renovascular resistance, and lead to increased excretion of sodium in the urine.

Normally, angiotensin II will have the following effects:

▪ vasoconstriction (narrowing of blood vessels), which may lead to increased blood pressure

▪ stimulation of the adrenal cortex to release aldosterone, a hormone that acts on kidney tubules to retain sodium and chloride ions and excrete potassium. Sodium is a "water-holding" molecule, so water is also retained, which leads to increased blood volume, hence an increase in blood pressure.

ACE Inhibitors inhibits the production of angiotensin II from angiotensin I, thus, assisting in increasing blood pressure.

In pregnant women, ACE inhibitors taken during the first trimester have been reported to cause major congenital malformations, stillbirths, and neonatal deaths. Commonly reported fetal abnormalities include hypotension, renal dysplasia, anuria/oliguria, patent ductus arteriosus and incomplete ossification of the skull.

Adverse effects include cough (bradykinin increase but disputed) and renal failure.

Angiotensin Receptor Blockers

Angiotensin II receptor antagonists are primarily used for the treatment of HT where the patient is intolerant of ACE Inhibitor therapy. They do not inhibit the breakdown of bradykinin or other kinins, thus rarely associated with the persistent dry cough. However, may present dizziness or headache.

Hypertensive retinopathy

Hypertensive retinopathy is a retinal vascular damage due to hypertension.

How it happens?
- Acute BP elevation
- Prolonged / severe hypertension

Due to hypertension, the small blood vessels in the retina are damaged. This results in a thickened blood vessels' wall, decreasing their blood flow to the retina. Some parts of the retina which did not receive enough blood becomes damaged. Eventually, there is blood leakage, resulting in blindness if the macula is affected.

Hypertensive patients who have diabetes as well are at an increased risk of vision loss.
Smoking aggravates the adverse effect of hypertension on retina

Symptoms - headache, vision problems

Signs (through fundoscopy)
- vasocontriction of retinal blood vessels
- fluid oozing from blood vessels
- cotton wool spots & hard exudates
- swelling of optic nerve and macula
- bleeding in the back of the eye

THE ONE AND ONLY TREATMENT - treat the underlying cause, ie, hypertension

Definition of Hypertension

A condition that occurs when the pressure in the arteries is consistently above the normal range for that specific age group
If the Blood Pressure reading is consistently equal to or higher than 140 systolic and 90 diastolic or both in adults older than 18 years, then the doctor will give a diagnosis of high blood pressure or hypertension

Classification of Hypertension in Malaysia

Classification of blood pressure for adults aged 18 and older and the prevalence


Category..........Systolic(mmHg).......Diastolic(mmHg).......Prevalence in Malaysia


Optimal..............<120...................<80......................32%

Prehypertension......120-139................80-89....................37%

Hypertension

Stage 1...............140-159...............90-99....................20%

Stage 2...............160-179..............100-109....................8%
Stage 3.................180...................110.....................4%


When SBP and DBP fall into different categories, the higher category should be selected to classify the individual’s BP.

Divided into primary/essential hypertension (90%) where there is no identifiable cause and secondary hypertension (10%) where a cause can be determined (e.g. renal disease, endocrine illness, coarctation of the aorta, renovascular disease and drugs)

Prevalence and incidence

Malaysia:-

The prevalence of hypertension amongst those aged 30 years has increased from 32.9% in 1996 to 40.5% in 2004
Estimated that there are 4.8 million individuals with hypertension
Close to two thirds of individuals with hypertension were unaware that they have hypertension (Third National Health and Morbidity Survey of 2006)

The estimated figure worldwide is 1 billion individuals

America:-

High blood pressure was a primary or contributing cause of death for 326,000 Americans in 2006
About one out of three U.S. adults—31.3%—has high blood pressure
High blood pressure was listed as a primary or contributing cause of death for 326,000 Americans in 2006

Sign and Symptoms

Sign and Symptoms

1. Blood Pressure –

120/80 to 139/89 Pre Hypertension

140/90 to 159/99 Stage 1

160/100 above Stage 2

Isolated systolic hypertension >140 systolic and diastolic <90

2. Most frequent – headaches

3. Blurry or double vision

4. Drowsiness

5. Nausea

6. Dyspnea (Dangerous by then) Exertional and Paroxysmal Nocturnal Dyspnea

7. Heart palpitations

8. Fatigue

9. A flushed face

10. Nosebleeds

11. Strong need to urinate often (Especially at night)

12. Tinnitus

Severe hypertension that targets organ’s present with

- Nausea

- Vomiting

- Visual disturbance

- Chest pain

- Confusion

- Retinas are affected with narrowing of arterial diameter to less than 50% of venous diameter, copper or silver wire appearance, exudates, hemorrhages or papilledema

Hypertension could be due to other secondary endocrine diseases.

Hypertension is usually idiopathic.

End Organ Damage

End organ damage or target organ damage refers to damage happening in major organs that are circulated by the circulatory system due to hypertension, hypotension or hypovolemia.

The organs normally affected are:

The eyes- Acute BP elevation typically causes reversible vasoconstriction in retinal blood vessels, and hypertensive crisis may cause papilledema. More prolonged or severe hypertension leads to exudative vascular changes, a consequence of endothelial damage and necrosis. Other changes (eg, arteriole wall thickening) typically require years of elevated BP to develop. Smoking compounds the adverse effects of hypertension on the retina.

Hypertension is a major risk factor for other retinal disorders (eg, retinal artery or vein occlusion, diabetic retinopathy). Also, hypertension combined with diabetes greatly increases risk of vision loss. Patients with hypertensive retinopathy are at high risk of hypertensive damage to other end organs.

Kidney- High blood pressure makes the heart work harder and, over time, can damage blood vessels throughout the body. If the blood vessels in the kidneys are damaged, they may stop removing wastes and extra fluid from the body. The extra fluid in the blood vessels may then raise blood pressure even more. It’s a dangerous cycle.

High blood pressure is one of the leading causes of kidney failure, also called end-stage renal disease (ESRD). People with kidney failure must either receive a kidney transplant or have regular blood-cleansing treatments called dialysis. Every year, high blood pressure causes more than 25,000 new cases of kidney failure in the United States.

Heart- As vessel diameters grow smaller and smaller, the result is not unlike what occurs to water flow out of a hose when a small kink is placed in it. In order for it to bypass this increased resistance to flow, it must be pushed with a greater pressure or force. In much the same way, an increase in the body's blood vessel resistance to flow places a new burden upon the heart to push blood through the smaller opening. It is largely unknown why the body chooses to raise resistance to flow even after it becomes a chronic burden on the heart.

Reference:

http://kidney.niddk.nih.gov/kudiseases/pubs/highblood/
http://www.merck.com/mmpe/sec09/ch106/ch106f.html
http://www.heartfailure.org/eng_site/hf_causes_hypertension.asp#

Risk factors and Investigations

Risk factors:
• Age (male > 45) (female > 55)
• Obesity
• Gender (male>female)
• Unhealthy lifestyle. smoking, alcohol, sedentary life, a lot Na from salt, less K, stress
• Race. (in US afro Americans more affected)
• Family history
• Chronic conditions like diabetes, kidney disease, cholesterol, sleep apnea
• Pregnancy also could cause pregnancy (gestational hypertension)

http://www.nhlbi.nih.gov/health/dci/Diseases/Hbp/HBP_Causes.html
http://www.mayoclinic.com/health/high-blood-pressure/DS00100/DSECTION=risk-factors

Investigations:
To ensure that a person is a chronic hypertensive, more than just 1 BP test is required, unless the BP is exceptionally high or if end-organ damage is present.
Normally it is measured 3 times, each time a week apart. The patient must not be under the influence of caffeine or any other drugs that could alter the BP.
Another way to make a diagnosis would be home BP monitoring. A device that measures the BP every 30 minutes throughout the day and night is worn by the patient. This rules out white coat syndrome.
Source: Dr. Nik Asma

(Exclude or rule out secondary causes)

Effects of hypertension

Effects of hypertension

1. Arteriosclerosis and atherosclerosis
- Hypertension causes damage to the endothelial lining of the blood vessel. This leads to the hardening of the arteries which is called arteriosclerosis. Fats from the diet will enter the damaged cells and collect to form plaque (lipid accumulation), which is called atherosclerosis. Formation of plaque can obstruct the blood flow to various organs in the body, such as heart, brain and kidneys. The damage can cause many problems including angina, heart attack, heart failure and stroke.
- Atherosclerosis increases the risk of transient ischemic attack (TIA), or ministroke. TIA is a brief, temporary disruption of blood supply to the brain. A transient ischemic attack is often a warning that you're at risk of a full-blown stroke.
- Another potential effect is dementia. Vascular dementia, results from narrowing and blockage of the arteries that supply blood to the brain. It can also result from strokes caused by an interruption of blood flow to the brain.
2. Aneurysm
- Over time, the constant high pressure weakens the vessel wall and causes a section of the wall to enlarge and form a balloon –like bulge ( aneurysm). They can form in any arteries in the body, but most commonly in the body. An aneurysm can potentially rupture and cause internal bleeding (haemorrhage).
3. Enlarged left heart
- High blood pressure causes the heart to work harder because the heart has to pump harder against resistance. This causes the left ventricle to enlarge (left ventricular hypertrophy). This enlargement or stiffening limits the ventricle's ability to pump blood to your body. This increases the risk of heart attack, heart failure and sudden cardiac death.

Primary Causes of Hypertension

Primary Hypertension (Essential Hypertension)
1. High intake of salt (> 5.8g daily)
- The recommended daily salt intake for a healthy 19 to 50-year-old adult is only 3.8g, to replace the average amount lost daily through perspiration and to achieve a balanced diet.
Institute of Medicine of the National Academies
2. Genetic factors
- Genes for hypertension have not yet been identified.
- Current research focuses on the genetic factors affecting the
renin–angiotensin-aldosterone system (RAAS)
- RAAS is a system which regulates the Salt/Water balance and hence, blood pressure of the body.
- Approximately 30% of cases are attributed to genetic factors.
Example 1 : In the United States, the incidence of high blood pressure is greater among African Americans than among Caucasians or Asians.
Example 2 : In individuals who have one or two parents with hypertension, high blood pressure is double that of the general population.
3. Abnormality of arteries
- Reduced distensibility in peripheral arteries which leads to increased resistance of the arteries. Arteries will not be able to increase the diameter of their lumen during ventricular systole and hence, increased pressure. Vascular endothelium produces less nitric oxide (vasodilator agent) and its smooth muscle is also less sensitive to it.
- There is also an increase in the production of endothelin 1, which is a vasoconstrictor agent.
4. Age
- The older u get, the higher the likelihood that you will develop hypertension , especially the systolic pressure, because the vessel wall becomes less elastic.
5. Race
- African Americans have high blood pressure more often than whites. They develop high blood pressure at a younger age and develop more severe complications sooner.
6. Gender
- Men have a greater probability of developing high blood pressure than women.
7. Alcohol
- Drinking more than one to two drinks of alcohol per day tends to raise blood pressure in those who are sensitive to alcohol.
8. Oral Contraceptive Use
- Some women who take birth control pills tend to develop high blood pressure.
9. Drugs
- Certain drugs such as amphetamines, diet pills and medications used for cold and allergy, tend to increase blood pressure.


10. Body weight
- Obese people are 2 to 6 times more likely to develop hypertension compared to people whose weight are within the healthy range.
- Apple shaped people are at greater health risk compared to pear shaped people.

Complications

arteries

• Arteriosclerosis and atherosclerosis. High blood pressure can damage the cells of your arteries' inner lining. That launches a cascade of events that make artery walls thick and stiff, a disease called arteriosclerosis (ahr-teer-e-o-skluh-RO-sis), or hardening of the arteries. Fats from your diet enter your bloodstream, pass through the damaged cells and collect to start atherosclerosis (ath-ur-o-skluh-RO-sis). These changes can affect arteries throughout your body, blocking blood flow to your heart, kidneys, brain, arms and legs. The damage can cause many problems including chest pain (angina), heart attack, heart failure, kidney failure, stroke, peripheral arterial disease and aneurysms.
• Aneurysm. Over time, the constant pressure of blood coursing through a weakened artery can cause a section of its wall to enlarge and form a bulge (aneurysm). An aneurysm (AN-u-rizm) can potentially rupture and cause life-threatening internal bleeding. Aneurysms can form in any artery throughout your body, but they're most common in the aorta, your body's largest artery.

Heart

• Coronary artery disease. Coronary artery disease affects the arteries that supply blood to your heart muscle. Arteries narrowed by coronary artery disease don't allow blood to flow freely through your arteries, which can cause chest pain (angina). The condition also occurs when blood flow through your arteries becomes blocked, usually because of atherosclerosis. When blood can't flow freely to your heart, you can experience chest pain, a heart attack or irregular heart rhythms (arrhythmias). People with high blood pressure who have a heart attack are more likely to die of that heart attack than are people who don't have high blood pressure.
• Enlarged left heart. High blood pressure forces your heart to work harder than necessary in order to pump blood to the rest of your body. This causes the left ventricle to enlarge or stiffen (left ventricular hypertrophy) — just as your biceps get bigger when you lift weights. This enlargement or stiffening limits the ventricle's ability to pump blood to your body. This condition increases your risk of heart attack, heart failure and sudden cardiac death.
• Heart failure. Over time, the strain on your heart caused by high blood pressure can cause your heart muscle to weaken and work less efficiently. Eventually, your overwhelmed heart simply begins to wear out and fail. Damage from heart attacks adds to this problem.

Brain

• Transient ischemic attack (TIA). Sometimes called a ministroke, a transient ischemic (is-KEM-ik) attack is a brief, temporary disruption of blood supply to your brain. It's often caused by atherosclerosis or a blood clot - both of which can arise from high blood pressure. A transient ischemic attack is often a warning that you're at risk of a full-blown stroke.
• Stroke. A stroke occurs when part of your brain is deprived of oxygen and nutrients, causing brain cells to die. Uncontrolled high blood pressure can lead to stroke by damaging and weakening your brain's blood vessels, causing them to narrow, rupture or leak. High blood pressure can also cause blood clots to form in the arteries leading to your brain, blocking blood flow and potentially causing a stroke. High blood pressure can also cause an aneurysm — a bulge in the blood vessel wall that can burst, causing life-threatening bleeding in the brain.
• Dementia. Dementia is a brain disease resulting in impaired thinking, speaking, reasoning, memory, vision and movement. There are a number of causes of dementia. One cause, vascular dementia, can result from narrowing and blockage of the arteries that supply blood to the brain. It can also result from strokes caused by an interruption of blood flow to the brain. In either case, high blood pressure may be the culprit. High blood pressure that occurs even as early as middle age can increase the risk of dementia in later years.
• Mild cognitive impairment. Mild cognitive impairment is a transition stage between the changes in understanding and memory that come with aging and the more serious problems caused by Alzheimer's disease. Like dementia, it can result from blocked blood flow to the brain when high blood pressure damages arteries. This condition can affect language, attention, critical thinking, reading, writing, reaction time and memory.

Kidneys

· Kidney failure. High blood pressure is one of the most common causes of kidney failure. That's because it can damage both the large arteries leading to your kidneys and the tiny blood vessels (glomeruli) within the kidneys. Damage to either makes it so your kidneys can't effectively filter waste from your blood. As a result, dangerous levels of fluid and waste can accumulate. You might ultimately require dialysis or kidney transplantation.

· Kidney scarring (glomerulosclerosis). Glomerulosclerosis (glo-mer-u-lo-skluh-RO-sis) is a type of kidney damage caused by scarring of the glomeruli (glo-MER-u-li). The glomeruli are tiny clusters of blood vessels within your kidneys that filter fluid and waste from your blood. Glomerulosclerosis can leave your kidneys unable to filter waste effectively, leading to kidney failure.

· Kidney artery aneurysm. An aneurysm is a bulge in the wall of a blood vessel. When it occurs in an artery leading to the kidney, it's known as a kidney (renal) artery aneurysm. One potential cause is atherosclerosis, which weakens and damages the artery wall. Over time, high blood pressure in a weakened artery can cause a section to enlarge and form a bulge - the aneurysm. Aneurysms can rupture and cause life-threatening internal bleeding

Eyes

• Eye blood vessel damage (retinopathy). High blood pressure can damage the vessels supplying blood to your retina. Damaged enough, the blood vessels can leak or become blocked, resulting in retinopathy. This condition can lead to bleeding in the eye, microaneurysms, swelling of the optic nerve, blurred vision and complete loss of vision. If you also have both diabetes and high blood pressure, you're at an even greater risk.
• Fluid buildup under the retina (choroidopathy). In this condition, fluid builds up under your retina because of a leaky blood vessel in the choroid, a layer of blood vessels located under the retina. Choroidopathy (kor-oid-OP-uh-thee) can result in distorted vision or in some cases scarring that impairs vision.
• Nerve damage (optic neuropathy). This is a condition in which blocked blood flow damages the optic nerve. It can lead to the death of nerve cells in your eyes, which may cause bleeding within your eye or vision loss.

Others

• Sexual dysfunction. Although the inability to have and maintain an erection (erectile dysfunction) becomes increasingly common in men as they reach age 50, it's even more likely to occur if they have high blood pressure, too. Evidence linking high blood pressure to sexual dysfunction in women isn't conclusive.
• Bone loss. High blood pressure can increase the amount of calcium that's in your urine. That excessive elimination of calcium may lead to loss of bone density (osteoporosis), which in turn can lead to broken bones. The risk is especially increased in older women.
• Trouble sleeping. Obstructive sleep apnea — a condition where your throat muscles relax causing you to snore loudly — occurs in more than half of those with high blood pressure. It's now thought that high blood pressure itself may help trigger sleep apnea. Also, sleep deprivation resulting from sleep apnea can raise your blood pressure.

Malignant hypertension
it's a sudden rapid development of EXTREMELY high blood pressure.
Can cause:
Changes in mental status, reflexes
Strokes
Coma
Seizures
Angina
Heart attack
Kidney failure
permanent blindness