Sunday, December 24, 2006

medicine wk 17 - drugs for HTN

HTN
1) essential (95%)
2) non-essential, secondary (5%)
Cushing, renal vascular HTN, pheochromocytoma, meds
ACE inhibitor with HTN pt
renal bruit

lidocaine - treat post-MI(Dressler's syndrome), paraventricular tachycardia
adenosine - supraventricular tachycardia

HTN due to prostate, benign prostatic hyperplasia(BPH)
- use alpha blockers, prazosin, terazosin, doxazosin(longer half-life, t1/2)

HTN due to pheochromocytoma
- use selective alpha blockers, phenoxybenzamine, phentolamine

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ACE inhibitors, or inhibitors of Angiotensin-Converting Enzyme, are a group of pharmaceuticals that are used primarily in treatment of hypertension and congestive heart failure, in most cases as the drugs of first choice.

Clinical use

Indications for ACE inhibitors include:

In several of these indications, ACE inhibitors are used first-line as several agents in the class have been clinically shown to be superior to other classes of drugs in the reduction of morbidity and mortality.

ACE inhibitors are often combined with diuretics in the control of hypertension (usually a thiazide), when an ACE inhibitor alone proves insufficient; and in chronic heart failure (usually furosemide) for improved symptomatic control. Thus there exists, on the market, combination products combining an ACE inhibitor with a thiazide (usually hydrochlorothiazide) in a single tablet to allow easy administration by patients.

[edit] The Renin-Angiotensin-Aldosterone System

This system is activated in response to hypotension, decreased sodium delivery, decreased blood volume and sympathetic stimulation. In such a situation, the kidneys release renin which is converted to angiotensin I via angiotensinogen. Angiotensin I is then converted to angiotensin II via the angiotensin-converting-enzyme (ACE). The system in general aims to increase blood pressure.

[edit] Effects of ACE inhibitors

ACE inhibitors lower arteriolar resistance and increase venous capacitance; increase cardiac output and cardiac index, stroke work and volume, lower renovascular resistance, and lead to increased natriuresis (excretion of sodium in the urine).

Normally, angiotensin II will have the following effects:
- vasoconstriction (narrowing of blood vessels)
- cardiac hypertrophy
- stimulate the adrenal cortex to release aldosterone, a hormone which acts on kidney tubules to retain sodium and chloride ions and excrete potassium. Sodium is a "water-holding" molecule, so water is also retained. This leads to increased blood volume, hence an increase in blood pressure :D?
- stimulate the posterior pituitary into releasing vasopressin (also known as anti-diuretic hormone (ADH)) which also acts on the kidneys to increase water retention.

With ACE inhibitor use, the effects of angiotensin II are prevented, leading to decreased blood pressure.

Epidemiological and clinical studies have shown that ACE inhibitors reduce the progress of diabetic nephropathy independently from their blood pressure-lowering effect. This action of ACE inhibitors is utilised in the prevention of diabetic renal failure.

ACE inhibitors have been shown to be effective for indications other than hypertension even in patients with normal blood pressure. The use of a maximum dose of ACE inhibitors in such patients (including for prevention of diabetic nephropathy, congestive heart failure, prophylaxis of cardiovascular events) is justified because it improves clinical outcomes, independent of the blood pressure lowering effect of ACE inhibitors. Such therapy, of course, requires careful and gradual titration of the dose to prevent the patient suffering from the effects of rapidly decreasing their blood pressure (dizziness, fainting, etc).

The ACE inhibitors are contraindicated in patients with:

ACE inhibitors should be used with caution in patients with:

ACE inhibitors are ADEC Pregnancy category D, and should be avoided in women who are likely to become pregnant.[1] In the U.S., ACE inhibitors are required to be labelled with a "black box" warning concerning the risk of birth defects when taking during the second and third trimester. It has also been found that use of ACE inhibitors in the first trimester is also associated with a risk of major congenital malformations, particularly affecting the cardiovascular and central nervous systems.[6]

Potassium supplementation should be used with caution and under medical supervision owing to the hyperkalaemic effect of ACE inhibitors.

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Dressler's syndrome is a form of pericarditis that occurs in the setting of injury to the heart or the pericardium (the outer lining of the heart).

Dressler's syndrome is also known as postmyocardial infarction syndrome and postcardiotomy pericarditis.

Presentation

The syndrome consists of a persistent low-grade fever, chest pain (usually pleuritic in nature), a pericardial friction rub, and /or a pericardial effusion.The symptoms tend to occur after a few weeks or even months after infarction and tend to subside in a few days. Signs include elevated ESR.

[edit] Causes

It is believed to result from an autoimmune inflammatory reaction to myocardial neo-antigens.

Dressler's syndrome is associated with myocardial infarction (heart attack), and with open heart surgery.

[edit] Differential diagnosis

In the setting of myocardial infarction, Dressler's syndrome occurs in about 7% of cases,[1] and typically occurs 2 to 10 weeks after the myocardial infarction occurred. This differentiates Dressler's syndrome from the much more common post myocardial infarction pericarditis that occurs in 17 to 25% of cases of acute myocardial infarction and occurs between days 2 and 4 after the infarction. Dressler's syndrome also needs to be differentiated from pulmonary embolism, another identifiable cause of pleuritic (and non-pleuritic) chest pain in people who have been hospitalized and/or undergone surgical procedures within the preceding weeks.

[edit] Treatment

Dressler's syndrome is typically treated with NSAIDs such as ASA or corticosteroids.[2]

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Benign prostatic hyperplasia (BPH) also known as Benign prostatic hypertrophy or Benign enlargement of the prostate (BEP) refers to the increase in size of the prostate in middle-aged and elderly men. To be accurate, the process is one of hyperplasia rather than hypertrophy, but the nomenclature is often interchangeable, even amongst urologists. In BPH, the prostate grows larger and presses against the urethra and bladder, interfering with the normal flow of urine. It leads to symptoms of urinary hesitancy, frequent urination, increased risk of urinary tract infections and urinary retention. There is little correlation between BPH symptoms and the presence of prostate cancer.

Symptoms

Urinary symptoms of hesitancy, sensation of incomplete voiding and frequently passing small amounts of urine are all suggestive of BPH in middle-aged and elderly men. Due to the incomplete voiding, there is stasis of bacteria in the bladder residue and an increased risk of urinary tract infections.

Incomplete voiding (emptying) of the bladder caused by BPH also provides suitable conditions for the development of urinary bladder stones. These are formed from the crystallisation of waste salts in the urine. Symptoms of bladder stone include blood in the urine and moderate to severe pain which can feel as though it is located in the penis, or around the anus, as well as the bladder. As the stone (which is often spikey) develops in size it produces increased pain and gradual reduction in mobility.

A small proportion presents with urinary retention, in which inadequate amounts of urine are passed and the bladder distends greatly. Untreated, this leads to a decrease in renal function and hydronephrosis (obstructive uropathy).

Etiology

Androgens (testosterone and related hormones) are considered to play a permissive role in BPH by most experts. This means that androgens have to be present for BPH to occur, but do not necessarily directly cause the condition. This is supported by the fact that castrated boys do not develop BPH when they age, unlike intact men. Additionally, administering exogenous testosterone is not associated with a significant increase in the risk of BPH symptoms. Dihydrotestosterone (DHT), a metabolite of testosterone is a critical mediator of prostatic growth. DHT is synthesized in the prostate from circulating testosterone.

DHT is localized principally in the stromal cells. Once synthesized, DHT can act in an autocrine fashion on the stromal cells or in paracrine fashion by diffusing into nearby epithelial cells. In both of these cell types, DHT binds to nuclear androgen receptors and signals the transcription of growth factors that are mitogenic to the epithelial and stromal cells. The importance of DHT in causing nodular hyperplasia is supported by clinical observations in which an inhibitor of 5α-reductase is given to men with this condition. Therapy with 5α-reductase inhibitor markedly reduces the DHT content of the prostate and in turn reduces prostate volume and, in many cases, BPH symptoms.

Medications

Alpha blockers (α1-adrenergic receptor antagonists) (such as doxazosin, prazosin, alfuzosin and tamsulosin) and certain antiandrogens such as the 5α-reductase inhibitors (finasteride and dutasteride) are used, often together, in suppressing the symptoms. Alpha-blockers relax smooth muscle in the prostate and bladder neck decreasing the degree of blockage of urine flow. Alpha-blockers may cause ejaculation back into the bladder (retrograde ejaculation). This is not harmful.

There is also extensive evidence of the efficacy of Serenoa repens (saw palmetto) fruit extracts in alleviating mild-to-moderate BPH symptoms. A systematic review of evidence found comparable efficacy to finasteride. (Wilt et al., 2002) Other herbal medicines that have solid research support in systematic reviews include beta-sitosterol from Hypoxis rooperi (African star grass) and Prunus africanum (pygeum) bark, while there is less substantial support for the efficacy of Cucurbita pepo (pumpkin) seed and Urtica dioica (stinging nettle) root. (Wilt et al., 2000) At least one double-blind trial has also supported the efficacy of rye flower pollen. (Buck, et al., 1990)

Sildenafil shows some symptomatic relief, suggesting a possible common etiology with erectile disfunction. (Brown 2005)

Surgery

If medical treatment fails, transurethral resection of prostate (TURP) surgery may need to be performed. This involves removing (part of) the prostate through the urethra. There are also a number of new methods for reducing the size of an enlarged prostate, some of which have not been around long enough to fully establish their safety or side effects. These include various methods to destroy or remove part of the excess tissue while trying to avoid damaging what's left. Transurethral electrovaporization of the prostate (TVP), laser TURP, visual laser ablation (VLAP), TransUrethral Microwave ThermoTherapy (TUMT), TransUrethral Needle Ablation (TUNA), ethanol injection, and others are studied as alternatives.

Newer techniques involving lasers in urology have emerged in the last 5-10 years. Starting with the VLAP technique involving the ND:YAG laser with contact on the prostatic tissue. A similar technology called Photoselective Vaporization of the Prostate (PVP) with the GreenLight (KTP) laser have emerged very recently. This procedure involves a high powered 80 Watt KTP laser with a 550 micrometre laser fiber inserted into the prostate. This fiber has an internal reflection with a 70 degree deflecting angle. It is used to vaporize the tissue to the prostatic capsule. KTP lasers target haemoglobin as the chromophore and have typically have a penetration depth of 2.0mm (four times deeper than holmium).

Another procedure termed Holmium Laser Ablation of the Prostate(HoLAP) has also been gaining acceptance around the world. Like KTP the delivery device for HoLAP procedures is a 550um disposable side-firing fiber that directs the beam from a high powered 100 Watt laser at a 70degree from the fiber axis. The holmium wavelength is 2,140nm, which falls within the infrared portion of the spectrum and is invisible to the naked eye. Where KTP relies on haemoglobin as a chromophore, water within the target tissue is the chromophore for Holmium lasers. The pentration depth of Holmium lasers is <0.5mm>

Both wavelengths, KTP and Holmium, ablate approximately one to two grams of tissue per minute.

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Etiology of Essential Hypertension

Environment

A number of environmental factors have been implicated in the development of hypertension, including salt intake, obesity, occupation, alcohol intake, family size, excessive noise exposure.[2], and crowding.

Salt Sensitivity

Sodium is the environmental factor that has received the greatest attention. It is to be noted that approximately 60% of the essential hypertension population is responsive to sodium intake.

Role of Renin

Renin is an enzyme secreted by the juxtaglomerular cells of the kidney and linked with aldosterone in a negative feedback loop.The range of plasma renin activities observed in hypertensive subjects is broader than in normotensive individuals. In consequence, some hypertensive patients have been defined as having low-renin and others as having high-renin essential hypertension.

Insulin Resistance

Insulin is a polypeptide hormone secreted by the pancreas. Its main purpose is to regulate the levels of glucose in the body, it also has some other effects. Insulin resistance and/or hyperinsulinemia have been suggested as being responsible for the increased arterial pressure in some patients with hypertension. This feature is now widely recognized as part of syndrome X, or the metabolic syndrome.

Sleep Apnea

Sleep apnea is a common, under recognized cause of hypertension. It is best treated with weight loss and nocturnal nasal positive airway pressure.

Genetics

Hypertension is one of the most common complex genetic disorders, with genetic heritability averaging 30%. Data supporting this view emerge from animal studies as well as in population studies in humans. Most of these studies support the concept that the inheritance is probably multifactorial or that a number of different genetic defects each have an elevated blood pressure as one of their phenotypic expressions.

More than 50 genes have been examined in association studies with hypertension, and the number is constantly growing.

Other Etiologies

There are some anecdotal or transient causes of high blood pressure. These are not to be confused with the disease called hypertension in which there is an intrinsic physiopathological mechanism as described above.

[edit] Etiology of Secondary Hypertension

Only in a small minority of patients with elevated arterial pressure can a specific cause be identified. These individuals will probably have an endocrine or renal defect that if corrected would bring blood pressure back to normal values.

Renal Hypertension

Hypertension produced by diseases of the kidney. A simple explanation for renal vascular hypertension is that decreased perfusion of renal tissue due to stenosis of a main or branch renal artery activates the renin-angiotensin system.

Adrenal Hypertension

Hypertension is a feature of a variety of adrenal cortical abnormalities. In primary aldosteronism there is a clear relationship between the aldosterone-induced sodium retention and the hypertension.
In patients with pheochromocytoma increased secretion of catecholamines such as epinephrine and norepinephrine by a tumor (most often located in the adrenal medulla) causes excessive stimulation of [adrenergic receptors], which results in peripheral vasoconstriction and cardiac stimulation. This diagnosis is confirmed by demonstrating increased urinary excretion of epinephrine and norepinephrine and/or their metabolites (vanillylmandelic acid).

Hypercalcemia

Coarctation of the Aorta

Diet

Certain medications, especially NSAIDS (Motrin/ibupofen) and steroids can cause hypertension. Ingestion of imported licorice (Glycyrrhiza glabra) can cause secondary hypoaldosteronism, which itself is a cause of hypertension.

  • Age. Over time, the number of collagen fibers in artery and arteriole walls increases, making blood vessels stiffer. With the reduced elasticity comes a smaller cross-sectional area in systole, and so a raised mean arterial blood pressure.

[edit] Pathophysiology

Most of the secondary mechanisms associated with hypertension are generally fully understood, and are outlined at secondary hypertension. However, those associated with essential (primary) hypertension are far less understood. What is known is that cardiac output is raised early in the disease course, with total peripheral resistance (TPR) normal; over time cardiac output drops to normal levels but TPR is increased. Three theories have been proposed to explain this:

Is is also known that hypertension is highly heritable and polygenic (caused by more than one gene) and a few candidate genes have been postulated in the etiology of this condition.[3] [4] [5]

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