• Nonspecific beta-blockers should not be administered to asthmatic or COPD patients because of the bronchoconstriction that will occur from blocking beta 2 receptors.
• Beta-blockers are also discouraged for use in patients that have CHF or severe PVD.

Side-effects of beta-blockers include:

• decreased libido and impotence
• decreased HDL
• increased triacylglycerol
• abrupt withdrawal may induce angina or even MI.
  

The response after abrupt withdrawal is due to upregulation of beta-receptors that occurs with chronic therapy.

• Note that beta-stimulation leads to arterial dilation; you would not want to block this in a patient with severe PVD.
• There is one other consideration that you should be aware of: if you are treating a patient who has high levels of circulating catecholamines (eg, a patient with a pheochromocytoma or a patient receiving iv norepinephrine (levophed)) then you must be careful when administering beta-blockers. You will go from a state of high alpha-stimulation (vasoconstriction) + high beta-stimulation (arterial dilation) to a state of high alpha stimulation (vasoconstriction) + beta-blockade (and you loose the arterial dilation). In these patients you should administer a vasodilator or alpha-blocker before you begin a beta-blocker or you may produce extreme hypertension.

ACE inhibitors reduce the activity of the renin-angiotensin-aldosterone system.

One mechanism for maintaining the blood pressure is the release of a protein called renin from cells in the kidney. This produces another protein called angiotensin, which signals the adrenal gland to produce a hormone called aldosterone. This system is activated in response to a fall in blood pressure as well as markers of problems with the salt-water balance of the body, such as decreased sodium concentration in a part of the kidney known as the distal tubule, decreased blood volume and stimulation of the kidney by the sympathetic nervous system. In such a situation, the kidneys release renin, which acts as an enzyme and cuts off all but the first 10 amino-acids residues of angiotensinogen (a protein made in the liver, and which circulates in the blood). These 10 residues are then known as angiotensin I. Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme (ACE) which removes a further 2 residues and is found in the pulmonary circulation as well as in the endothelium of many blood vessels. The system in general aims to increase blood pressure by increasing the amount of salt and water the body retains. Angiotensin is a very potent vasoconstrictor.

Common adverse drug reactions of ACE inhibitors include: hypotension, cough,or angioedema. 

Good answer. Some of these proteins are enzymes and the others are proteins that ultimately become hormones that act on specific receptors. Know which proteins are which.

Summary:

 Liver makes a protein that is an alpha-2 globulin called angiotensinogen. Renin is an enzyme that is made in the JG cells of the kidney and it hydrolyzes angiotensinogen to produce Angiotensin 1 (AT1).

Renin activity is stimulated by:

(1) low pressure baroreceptors in the kidney

(2) by sympathetic stimulation

(3) by low sodium in the nephron

When AT1 circulates throughout the body, another enzyme, located in endothelial cells all over the body but especially in the lung, named angiotensin converting enzyme (ACE) then cleaves off two carbon-terminal residues from AT1 to form AT2 (angiotensin 2). AT2 is a hormone that causes aldosterone release and also stimulates AT2 receptors causing vasoconstriction.

There are two important ways drugs may block this system:

(1) block angiotensin converting enzyme (these drugs are called ACE inhibitors)

(2) competitively block AT2 at the receptor (these drugs are called angiotensin receptor blockers or ARBs).

These two classes of drugs have very similar effects however the ARBs do not stimulate bradykinin production.

When you are treating patients, you will generally begin treatment with an ACE inhibitor and only switch to an ARB if the patient develops a chronic dry cough or angioedema. With respect to angioedema, there is not cross-sensitivity* with these drugs, and, the dry cough is thought to be mediated by bradykinin (which is not increased with ARBs); therefore, you can usually give ARBs to patients who can not tolerate ACE inhibitors.

Enalaprilat is an ACE inhibitor that is available for intravenous administration and is quite useful in treating hypertension in surgical patients.

Calcium Channel blockers work by blocking voltage-gated calcium channels in cardiac muscle and blood vessels. This decreases intracellular calcium leading to a reduction in muscle contraction in the heart, a decrease in calcium available for each beat results in a decrease in cardiac contractility. In blood vessels, a decrease in calcium results in less contraction of the vascular smooth muscle and therefore an increase in arterial diameter resulting in vasodilation. The vasodilation then decreases total peripheral resistance, while a decrease in cardiac contractility decreases CO. Since blood pressure is determined by cardiac output and peripheral resistance, blood pressure drops.

Calcium channel blockers are especially effective against: large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. With a low blood pressure, the afterload on the heart decreases resulting in a decrease in the amount of oxygen required by the heart. This can help symptoms of ischemic heart disease such as angina pectoris. The clinical usage of calcium channel blockers is to decrease blood pressure in patients with hypertension, control heart rate, prevent cerebral vasospasm, and reduce chest pain due to angina pectoris.

Side effect of Calcium channel blockers: fluid buildup.

TRUE.

These agents decrease peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle. Orthostatic hypotension is a possible side effect for prazosin, doxazosin, and terazosin.

This is correct. Note that the mechanism of the orthostatic hypotension is that cardiac preload is decreased (because of alpha-1 blockade of capacitance veins).

In treating a hypertensive emergency, Minoxidil causes dilation of resistance vessels (arterioles) but not of capacitance vessels (venules).

It is given PO for treatment of severe to malignant hypertension that is refractory to other drugs. Reflex tachycardia, sodium and fluid retention may be severe leading to volume overload, edema, and CHF; therefore, requiring the concomitant use of a loop diuretic and a Beta blocker.

What are the most important side effects of minoxidil?

The most important side effect is hypertrichosis which is growth of body hair. This is now being used to treat male pattern baldness. This agent also produces reflex stimulation of the heart that results in the competing reflexes of increased myocardial contractility, heart rate, and oxygen consumption. These actions may prompt angina pectoris, MI, or heart failure in predisposed individuals. 

There are several important things to know.

1. Minoxidil causes hypertrichosis.

2. HR will increase reflexively when you administer a

    strong vasodilator like minoxidil.

3. Like all powerful vasodilators, minoxidil administration is associated with fluid and sodium retention.

Clinical implications -- the increased HR will increase myocardial work/O2 consumption, and, when you administer a powerful vasodilator you often need to coadminister a beta-blocker +/- a diuretic.

Clonidine is a centrally acting alpha-2 agonist used primarily for treatment of hypertension refractory to two or more other anti hypertensive drugs. Stimulation of alpha-adrenoreceptors in the brain decreases sympathetic outflow from the CNS. This results in decreased peripheral vascular resistance, renal vascular resistance, heart rate, and blood pressure. Onset of action occurs within 30-60 minutes. Clonidine is useful in renally impaired patients as it does not decrease renal blood flow or GFR. The drug's half life is 12-16 hours in normal patients, but up to 41 hours in patients with severe renal impairment. It is absorbed well after oral administration and excreted by the kidney. Clonidine should be withdrawn slowly as an abrupt withdrawal may cause rebound hypertension. The most frequent side effects are dry mouth, sedation, and dizziness.

Dexmedetomidine is a relatively selective alpha-2 agonist used intravenously for sedation in a variety in settings. Stimulation of receptors in the brain and spinal cord cause a small decrease in heart rate and blood pressure along with causing analgesia and sedation. The sedative properties of the drug are thought to be linked to its action in the locus coeruleus. This is the predominant noradrenergic nucleus in the brain and an important modulator of vigilance. Respiratoy depression is not noticed when infused within the recommended dosage range. Accordingly, an interesting property of dexmedetomidine is that it does not have to be titrated off before extubating a patient. It has a half life of approximately two hours. It is highly protein bound and is metabolized by direct glucuronidation and cytochrome P450 enzymes.

Alpha-methyldopa is a prodrug that is metabolized to methylnorepinephrine. Methylnorepinephrine acts as an agonist for alpha-2 receptors in the CNS. Like clonidine, this decreases sympathetic outflow from the CNS resulting in decreased peripheral vascular resistance and blood pressure. It is also safe for use in renal impaired patients as it does not lower renal blood flow or GFR. It is also an approved drug for use in pregnancy related hypertension as it has no effect on the fetus. Its most common side effects are sedation and drowsiness. It is metabolized in the liver and excreted in the urine.

Clonidine = Catapres, dexmedetomidine = Precedex, alpha-methyldopa = Aldomet. Pay attention to the similarities of these three drugs. The mechanism of action of each of these is the same -- alpha-2 adrenergic agonists. Make sure you understand that alpha-1 agonists, beta-1 agonists, and beta-2 agonists all enhance sympathetic tone; but, alpha-2 agonists have opposite effects. - JM

Alpha-2 receptors are located primarily on presynaptic nerve endings. They can also be found on the beta cells in the pancreas and certain vascular smooth muscle cells.

Alpha-2 receptors act as inhibitory autoreceptors for norepinephrine. Norepinephine is released from a sympathetic adrenergic nerve and crosses the synaptic cleft to interact with alpha-1 receptors on the postsynaptic target cell. A portion of the norepinephrine moves back to the presynaptic membrane and stimulates alpha-2 receptors. This stimulation causes a feedback inhibition of the ongoing release of norepinephrine from that particular neuron.

Outline the mechanism of action and metabolism of hydralazine.

There are pharmacogenetic differences in the way individuals metabolize hydralazine. Discuss how response and toxicity will vary among "slow-acetylators" and "fast-acetylators".

MOA:Hydralazine limits release of calcium from the sarcoplasmic reticulum of smooth muscle. This results in vessel relaxation. These effects are more prominent and arteries and arterioles. This decreases PVR, causing a drop in blood pressure. There is a reflex elevation in heart rate, and so hydralazine is often given in combination with a beta blocker.

Hydralazine undergoes polymorphic acetylation in the liver. Slow-acetylators may have as much as three times bioavailable drug following oral administration than fast-acetylators. Accordingly, slow-acetylators should be given lower doses of hydralazine to avoid these toxic effects.

Remember that acetylation is a non-oxidative, phase II reaction and there are pharmacogenetic differences in how patients metabolize this drug. Besides hydralazine, procainamide is also metabolized by acetylation and the same people who are slow-acetylators of hydralazine will be slow acetylators of procainamide.

So far we have discussed three pharmacogenetic differences in drug metabolism:

(1) succinylcholine and patients with abnormal pseudocholinesterase

(2) CYP2D6 changes and codeine

(3) slow and fast acetylators and procainamide and hydralazine.

About 10 - 30% of patients of asian descent are slow acetylators, about 60% of patients from India are slow acetylators and about 50% of caucasians and patients of african descent are slow acetylators.

How is this clinically important?

(1) You will give hydralazine intravenously to many patients. About half of these patients will be slow acetylators (and you will have no idea who they are). Give hydralazine slowly and follow blood pressure. The initial hydralazine dose will be the same in fast and slow acetylators however the duration of action of hydralazine will be much longer in slow acetylators.

(2) After an oral dose, slow acetylators will have higher plasma hydralazine levels than fast acetylators. What you will notice clinically is that slow acetylators seem to be more sensitive to po hydralazine than fast acetylators. The reason is that less hydralazine makes it past the liver in fast acetylators compared to slow acetylators (ie, there is more first-pass metabolism in fast acetylators). The way you avoid problems with oral dosing is to start with small doses and gradually increase the dose. You will expect that about half your patients (the fast acetylators) will need larger dosages.

One last point, when you think about the pharmacology of vasodilators like hydralazine, remember that these drugs may cause tachycardia and fluid/electrolyte retention and you might need to coadminister a beta-blocker and/or a diuretic.

Nitroprusside – Is administered IV resulting in prompt vasodilation with reflex tachycardia. It will reduce BP in all patients regardless of the cause of hypertension. It acts equally on arterial and venous smooth muscle; therefore, the effects on the veins can reduce cardiac preload. It is metabolized rapidly with a half life of minutes and requires continuous infusion to maintain its hypotensive action. There are only a few adverse effects such as hypotension by overdose. Nitroprusside metabolism results in cyanide ion production; however, cyanide toxicity is rate and can be treated with a sodium thiosulfate infusion to produce thiocyanate which is less toxic and eliminated by the kidneys. This cannot be given PO due to its hydrolysis to cyanide, it is light sensitive and must be protected from light when in solution.

Nitroprusside (SNP) reduces BP but there is often a reflex increase in heart rate and contractility. So even though blood pressure is reduced, these changes in HR and contractility may lead to increased shearing forces (dP/dT) on arterial walls. This can be clinically important when you are caring for a patient with an intracranial aneurysm or with an aortic aneurysm/dissection (cases where you do not want to risk rupture of the arterial vessel). SNP is an excellent drug to use when you need to lower blood pressure rapidly, but make sure you have a beta-blocker (eg, esmolol) handy when treating patients with fragile arteries.

Labetalol – is an alpha and beta blocker given as an IV bolus or infusion. It does not cause reflex tachycardia but the major limitation is a longer half life which precludes rapid titration.

Fenoldopam - is a peripheral dopamine-1 receptor agonist that is given IV infusion. Fendldopam maintains or increase renal perfusion while it lowers BP, can safely be used in all hypertensive emergencies and may be particularly beneficial in patients with renal insufficiency. It is contraindicated in pt with glaucoma.

Fenoldopam (Corlopam), a DA-1 agonist, is good for hypertensive patients with diminished renal function or else those patients at risk of renal injury (eg, a typical 85 y/o patient having heart surgery) Note that on average, dopamine stimulates DA-1 receptors at doses of about 3 mcg/kg/min, beta-receptors at doses greater than about 5 mcg/kg/min and alpha receptors at doses above 10 mcg/kg/min. Renal-dose dopamine is highly variable. 2-3 mcgs may be fine for one patient but inadequate for another (due to extremely erratic dopamine kinetics in critically ill patients). If you really want to stimulate DA-1 receptors for renal protection or for dilation of splanchnic vasculature, you should consider fenoldopam instead of low-dose dopamine.

Nicardipine – is a calcium channel blocker which can be given as an iv infusion. Major limitation in treating hypertensive emergency is its long half-life of about 8 hours, which precludes rapid titration.
Nicardipene and labetalol do not raise CBF as much as nitroprusside: this is an advantage when taking care of some neuro patients. Nicardipene should especially be considered for patients with cerebrovascular diseases when vasospasm is a concern.

Here is an outline of my general approach for treating perioperative hypertension:
1. Make sure the patient is really hypertensive (check transducer, blood pressure cuff size, etc). You do not want to be treating artifacts.

2. Rule out light anesthesia or pain. If someone is hypertensive because of problems like pain, "light" anesthesia, or bladder distention, then you do not want to treat this with antihypertensive medications.

3. Consider whether your patient might have one of these 3 specific causes of hypertension: malignant hyperthermia, thyrotoxicosis or pheochromocytoma. These are uncommon problems, however, patients with one of these conditions should not be treated symptomatically for hypertension.

4. At this point consider your patient's cardiac output. (a) Geriatric patients who are hypertensive generally have very high SVR and normal or low CO. You often do not want to reduce CO in these patients. Treat these patients with a vasodilator. Vasodilators that you should have readily accessible include hydralazine, nitroglycerin, nitroprusside, enalaprilat, fenoldopam and nicardipene. Minoxidil is not often used but can be quite useful in some severely hypertensive patients. Be very careful when administering beta-blockers to old patients or to young patients who may have a low cardiac output. Also, be careful when giving nicardipene or any other calcium entry blocker to patients with a low CO and/or low EF.

(b) Young hypertensive patients usually have high SVR and high CO. A vasodilator + a beta-blocker is often effective therapy in these patients. Labetalol conveniently provides vasodilation and beta-blockade. Dexmedetomidine may also be effective monotherapy in these patients. Otherwise choose one of the vasodilators listed above + a beta-blocker like esmolol or metoprolol.

How much beta-blocker should you give? In a typical hypertensive adult, pick a target heart rate between 60 - 100 bpm and keep carefully giving beta-blocker until you reach that HR.