Pathophysiology
Recall that blood pressure, which may be defined mathematically as BP = (CO)(PR) is determined by both cardiac output and peripheral resistance (being directly proportional to both), with cardiac output being determined by preload, contractility, afterload, and heart rate and resistance being a function of and inversely proportional to the radius of the vessel.  Therefore any drug that would decrease CO and/or resistance could lower blood pressure.

Primary (Essential) Hypertension -- any hypertension of unknown etiology may be classified as primary hypertension.  It is broadly defined as a consistent systolic pressure of greater that 140 mm Hg or a consistent diastolic pressure of greater than 90 mm Hg.  Primary hypertension may be further catogorised as either essential or benign and malignant.
 
Essential (Benign) hypertension -- most often exhibits a slow, insidious onset in persons who are in their mid 30s.  Risk factors that increase the chances of developing essential hypertension include past family history, obesity, hyperlipidæmia, and smoking.  If essential hypertension does develop, then the patient is at increased risk of congestive heart failure, kidney failure, stroke, and coronary artery disease among other disease states.

Malignant hypertension -- usually a rapid onset with a poor prognosis.  Malignant hypertension is usually fatal within 5 years of diagnosis.  It may cause general cardiovascular problems that extend to arterial thickening in the kidneys and mesentery.
 Secondary Hypertension -- a hypertensive state that is due to some known cause.  Etiologies of secondary hypertension include oral contraceptives, pregnancy, renal vascular disease, chronic renal failure, renin-secreting tumours, aldosteronism, pheochromocytoma, and Cushing's syndrome.

The goal in the treatment of any hypertensive patient is to decrease blood pressures to acceptable levels, thereby reducing the risk of myocardial infarction, cerebrovascular accident, kidney failure and other sequelæ of elevated pressures.
 

Sympatholytics -- A diverse group of drug classes whose commonality is the ability to decrease sympathetic activity.

Centrally-Acting Sympatholytics
Methyldopa
Mechanism of action -- for many years it was proposed that methyldopa acted as a false neurotransmitter through its metabolism to methyldopamine and methylnoradrenaline, where it was stored in the synapse and released as the neurotransmitter with high affinity but little efficacy at adrenergic receptors.  However, it was discovered that methyldopa and/or its metabolites had nearly the same efficacy as noradrenaline at alpha-2 receptors.  Therefore it is commonly accepted that the active metabolite methylnoradrenaline acts in a manner similar to other alpha-2 agonists to decrease central sympathetic outflow by acting at pre-synaptic autoreceptors, thus reducing sympathetic-mediated increases in CO and resistance.

Hæmodynamics -- There are age-dependent changes in CO and heart rate (HR), with methyldopa causing little change in either parametre in young people but lowering both CO and HR in older patients.  Renal blood flow and baroreceptor responses are retained with methyldopa.  Blood pressure is lowered by decreases in peripheral resistance due to decreased sympathetic tone.  While methyldopa may inhibit renin release slightly, this is not thought to contribute to the efficacy of the drug.

  Alpha-2 Adrenergic Agonists -- Clonidine, Guanabenz, Guanfacine
Mechanism of action -- these agents act in a manner similar to that described above, decreasing noradrenaline release by activation of central alpha-2 autoreceptors.  NOTE that at higher doses, these agents may act peripherally to cause vasoconstriction.  Therefore, hypertension may be seen with toxic overdoses or rapid intravenous administration.

Hæmodynamics -- These agents will decrease HR and stroke volume (SV), thus decreasing CO, especially in the supine position.  Total peripheral resistance (TPR) is decreased, especially if the patient is upright.  Renal blood flow is maintained and, similar to methyldopa, renin release may be minimally inhibited.

Pseudotolerance -- Prolonged use of clonidine and guanfacine will cause reflex, renal-mediated sodium and water retention, thereby causing an increase in BP and loss of efficacy.  NOTE that guanabenz possesses intrinsic natriuretic activity and may also have anti-vasopressin actions.  Therefore, pseudotolerance is not observed with guanabenz.

Ganglionic Blocking Agents -- Mecamylamine, Trimethaphan
Mechanism of Action -- these agents act as nicotinic cholinergic antagonists, thus blocking the actions of acetylcholine in the sympathetic ganglia.  This decreases the activity of the peripheral sympathetic system, thus preventing peripheral vasoconstriction.

Hæmodynamics -- these agents will lower BP when standing but have minimal effect in the supine position.  They are used predominantly for controlled hypotension during surgery.  They are considered "too effective" for normal anti-hypertensive therapy.  (Additionally, they would have numerous side effects since ALL peripheral adrenergic activity would be inhibited.)

Peripheral Sympatholytics
Indirect Acting -- These agents decrease sympathetic tone by decreasing peripheral neuronal activity.
Guanethidine and Guanadrel
Mechanism of action -- These drugs are thought to be taken up by the re-uptake mechanism into pre-synaptic neurones.  They are then thought to be slowly taken up into the neurotransmitter storage vesicles.  They slowly displace the noradrenaline (which may attenuate their actions early in therapy) until ultimately all of the stored noradrenaline has been replaced with the drug, which lacks efficacy at the post-synaptic receptor.

Hæmodynamics -- These drugs act preferentially on the venous system to cause venodilatation, thus reducing preload.  They also inhibit sympathetic cardiac stimulation, thus lowering HR and CO.  These agents will blunt the baroreceptor response, thus they may cause orthostatic (postural) hypotension.  Pseudotolerance may also be observed with these agents.  These agents may also worsen CHF or even precipitate it in persons predisposed.  Side effects include decreased and/or retrograde ejaculation and diarrhœa due to inhibition of sympathetic control over these functions.

Reserpine -- The first modern antihypertensive, first used in the 1950s
Mechanism of Action -- Reserpine acts both centrally and peripherally.  It is taken up by neurones in a manner similar to that described above.  In the neurone reserpine binds tightly to synaptic storage vesicles and causes their destruction.  Consequently, the stored neurotransmitters (noradrenaline, dopamine, serotonin) leak into the cytoplasm where they are destroyed by synaptic enzymatic pathways including catecholamine O-methyl transferase (COMT) and monoamine oxidase (MAO).  Recovery from reserpine requires the synthesis of new storage vesicles and may take days or even weeks.

Hæmodynamics -- Reserpine decreases TPR, CO, HR, and renin release.  Pseudotolerance may also be observed.  Since it does cross the blood brain barrier, side effect include sedation, depression, and decreased concentration in addition to those describe for guanethidine and guanadrel above.

MAOI -- Monoamine Oxidase Inhibitors -- Pargyline
This drug, NO LONGER USED, inhibited the enzyme MAO, causing an increase in tyramine which acted as a false neurotransmitter.
 
Metyrosine
Inhibits catecholamine synthesis at its rate limiting step (the conversion of tyrosine to DOPA via tyrosine hydroxylase).  It is used in the treatment of pheochromacytoma, an adrenaline producing tumour of the adrenal gland.

Direct Acting Peripheral Sympatholytics
Beta Adrenergic Antagonists (Propranolol, nadolol, timolol, pindolol, labetalol, metoprolol, atenolol, esmolol, acebutolol, bopindolol, carteolol, oxprenolol, penbutolol, levobunolol, metipranolol, bisoprolol)
Mechanism of Action -- These agents directly block the actions of adrenaline/noradrenaline at post-synaptic beta receptors.  (RECALL that vascular beta-2 receptors cause vasodilatation -- blockade of this action would be undesirable in hypertensive patients, but also recall that adrenergic activity in the vasculature is predominanty alpha in nature -- The benefit of beta blockade is due to antagonism of beta-1 receptors on the HEART rather than the vascular effects).

Selectivity -- (metoprolol, atenolol, esmolol, acebutolol, bisoprolol, betaxolol, nebivolol) Recall that beta blockers may be either non-selective for both beta-1 and beta-2 receptors or they may preferentially block beta-1 receptors only.  This selectivity is seen primarily at low oral doses.  Loss of selectivity may be seen with high doses or intravenous administration of a beta-1 selective antagonist.

Intrinsic Sympathomimetic Activity (ISA, Partial Agonists) -- (pindolol, acebutolol, bopindolol, carteolol, oxprenolol, penbutolol, celiprolol)  Some of these drugs may exhibit agonist activity at adrenergic receptors.  This activity is predominantly seen at beta-2 receptors, which will decrease the risk of bronchoconstriction or increased peripheral resistance in those agents with ISA.  These agents are preferred in asthmatic patients.

Membrane Stabilising Activity (local anæsthetic activity, sodium channel blockade) -- (propranolol, pindolol, labetalol, metoprolol, acebutolol)  some of these agents have the ability to block sodium channels at higher doses.  As stated previously, this is not thought to contribute to their anti-arrhythmic or anti-hypertensive efficacy.

Hæmodynamics -- Beta blockers will decrease CO and renin formation and release by their actions directly on the heart and in the kidney respectively.  Lipophilic agents may also cross the blood brain barrier to decrease central sympathetic outflow.

Clinical Therapeutics -- Beta blockers should be withdrawn slowly, since rapid cessation of therapy can and often does result in rebound tachycardia, hypertension, and attacks of angina pectoris.  These agents are used for numerous other disease states and conditions including their use to decrease cardiovascular complications in non-cardiac surgeries.  NOTE that the lipid profiles of many patients are also altered due to the effects on hepatic beta receptors.  ALSO NOTE that the negative inotropic effects of beta antagonists may worsen CHF.
Beta and alpha antagonists --
Labetalol is a sterioisomer combination of a non-selective beta-antagonist with ISA and an alpha-1 antagonist.  Mechanistically and hæmodynamically, it combines the effects of cardiac beta-blockade and vascular alpha blockade.  TPR is reduced sufficiently to make labetalol effective in the treatment of hypertensive crises.

Carvedilol is similar in action to labetalol.  It is the only beta antagonist that may also be possibly effective in patients with congestive heart failure.

Alpha antagonists
Miscellaneous alpha antagonists -- mechanistically, these agents block alpha-1 and/or alpha-2 receptors directly on the vasculature, thus reducing adrenergic mediated vasoconstriction and PR.  Hæmodynamically these agents will reduce PR and cause reflex tachycardia.  Therapy should be initiated at the lowest dose and adjusted up, to minimise orthostatic hypotension, which can be severe with these agents.
Phenoxybenzamine -- an irreversible, non-selective alpha blocker (it shows some preference for alpha-1 blockade).  The drug binds covalently with the receptor.  It is used primarily in the treatment of pheochromocytoma.

Phentolamine -- Competitive and reversible inhibition of both alpha-1 and alpha-2 receptors.

Tolazoline -- Competitive and reversible inhibition of alpha-2 receptors, it is used primarily for the treatment of persistent pulmonary hypertension of neonates.

Selective alpha-1 antagonists -- Prazosin, terazosin, doxazosin
Mechanism of action -- these drugs block alpha-1 mediated vasoconstriction in the vasculature.

Hæmodynamics -- Patients will initially show a decrease in arterial resistance and an increase in venous capacitance.  They may then show reflex tachycardia and renin activity.  CO is not altered.  With longterm therapy, the HR and renin activity will return to normal, but vasodilatation persists.  The first dose may cause profound orthostatic hypotension, especially if given with diuretics and/or beta blockers.  These drugs lower supine and standing blood pressure and especially lower diastolic pressure.

Other uses of alpha-antagonists -- These agents are also used to treat benign prostatic hypertrophy.  Their actions on alpha receptors in the bladder neck and prostate (the bladder itself is relatively free of alpha receptors) will cause relaxation of the smooth muscle, thus increasing urine output.
 

Alpha -1 Agonists -- Midodrine (ProAtamine®) is a relatively new drug that acts as an AGONIST at alpha-1 receptors.  It is indicated for the treatment of orthostatic hypotension in patients with persistently low blood pressure.  It may cause hypertension, especially with sitting or supine positions.  It should ONLY be used when orthostatic hypotension causes chronic weakness, dizziness, or fainting.

Hydralazine
Mechanism of Action -- For a time, the mechanism of action for hydralazine was proposed to be hyperpolarisation of vascular smooth muscle or a decrease in calcium mobilisation, either of which would prevent vascular constriction.  However recent metabolic studies suggest that it forms, in vivo, nitric oxide.  Therefore, it is likely that hydralazine acts as a prodrug, mimicking endothelial derived relaxation factor to cause vasodilatation.

Hæmodynamics -- Hydralazine causes vasodilatation to reduce peripheral resistance.  This action occurs primarily in coronary, cerebral, and renal vessels and primarily in arterioles.  Reflex tachycardia and increases in renin activity occur with hydralazine.

Minoxidil
Mechanism of Action -- Minoxidil acts as a potassium channel agonist, opening the channel and allowing potassium efflux.  This results in hyperpolarisation of the cell.  This hyperpolarisation will delay and/or prevent the acheivement of an action potential and subsequent inability for the vascular smooth muscle to contract.

Hæmodynamics -- Minoxidil's primary effects include arteriolar dilatation, especially in skin, skeletal muscle, the gastrointestinal tract, and heart.  It has minimal venous effects.  Reflex increases in CO and positive inotropy and well as increased renin secretion may be seen with minoxidil.

Clinical applications -- In addition to its use as a third or fourth line antihypertensive, minoxidil is used to treat male pattern baldness.  It is assumed that its efficacy is related to the increased cutaneous blood flow near the hair follicles.
 

Sodium Nitroprusside
Mechanism of Action -- Sodium nitroprusside is metabolised in vivo to form nitric oxide, thus acting as EDRF to cause vasodilatation.

Hæmodynamics -- Sodium nitroprusside will cause both arterio- and veno-dilatation.  In patients with left heart failure, CO may increase (presumably due to decreased afterload), while in patients without heart failure, no change is seen in CO.

Clinical applications -- Sodium nitroprusside is only used in hypertensive crises.  It should be infused slowly by pump mechanisms and the patient should be monitored closely.  A second metabolic product is cyanide, which may cause toxicity (although this is rare).  (NOTE: cyanide toxicity is treated with combination therapy of amyl nitrite, sodium nitrite, and sodium thiosulphate -- these items should be kept at hand during infusion of nitroprusside.)

Diazoxide
Mechanism of Action -- Diazoxide enhances ATP mediated potassium efflux, causing hyperpolarisation as previously described.

Hæmodynamics -- Diazoxide causes arteriolar dilatation.  It may also cause reflex tachycardia.  It may also cause sodium and water retention.

Clinical applications -- Diazoxide is only used for hypertensive emergencies.  It is also used to treat hypoglycæmia (through its actions on potassium channels in the beta cells of the islets of Langerhans).

Mechanism of Action -- These agents block calcium channels in both the heart and the vasculature, thus blocking calcium influx.  This prevents vasoconstriction and also directly decreases CO (through a negative inotropic effect).

Hæmodynamics -- These agents preferentially dilate arterioles, thus reducing PR.  They also decrease CO.  The dihydropyridines will cause reflex tachycardia.  (Refer to section on anti-anginal agents.)

Clinical Applications -- The calcium antagonists are equipotent with the beta blockers and diuretics in their anti-hypertensive activity.  However they do NOT alter exercise tolerance as the beta blockers do, nor do they alter lipid profiles, urate levels, or electrolytes as the diuretics may.
 

Indirect Antagonists -- Angiotensin Converting Enzyme Inhibitors (captopril, enalapril, enalaprilat, lisinopril, benazepril, fosinopril, quinapril, ramipril, spirapril, moexipril, trandolapril)
Mechanism of Action -- These agents inhibit the conversion of angiotensin I to angiotensin II by inhibiting ACE.  This has multiple effects.  ATII has direct vasoconstrictive properties, thus ACEI will prevent vasoconstriction.  (NOTE that ATII has both rapid and slow pressor responses with the latter presumably important in long term control of blood pressure.)    ATII also causes the release of aldosterone and ADH (vasopressin).  Additionally, ATII will increase sympathetic tone both centrally and peripherally by causing the release of noradrenaline.  Aldosterone causes sodium and water retention as does ADH which also has vasoconstrictive actions.  Moreover, ATII may also increase thirst and thus water intake.  All of these these actions are also indirectly inhibited by ACEI.

Hæmodynamics -- These agents act primarily by preventing vasoconstriction, but their indirect diuretic effect may also contribute to their efficacy.

Clinical Applications -- ACEI are typically less effective in African-Americans, however this may be overcome by the co-administration of diuretics.  They are also used to slow diabetic nephropathy and renal failure.  They produce a dry cough as a side effect, presumably through inhibition of metabolism of bradykinin (which causes cough and is also metabolised by ACE).  Additionally, potassium retention associated with decreased aldosterone activity may occur.

Direct Angiotensin Antagonists (losartan, valsartan, candesartan, telmisartan)
Mechanism of Action -- These agents directly block angiotensin at its receptor.  There exists two receptors, AT1 and AT2.  The AT1 receptor is the predominant form in adults and is a G_q/11 coupled receptor.

Hæmodynamics -- The hæmodynamic effects of these agents is similar to that of the ACEI.

Clinical Applications -- Similar to ACEI with the exception of relatively little or no cough.  Additionally, since AT1 receptors have been associated with cellular growth, especially in the vasculature and myocardium, these agents could worsen CHF (NOTE that this has not been proven conclusively, but the possibility exists.)

Mechanisms of Action -- These will be discussed in depth in the next section.

Hæmodynamic effects -- These agents will decrease blood volume, through their diuretic effect, thus decreasing fluid load and TPR.  The primary effect is mediated through the loss of sodium.  There may be reflex increases in renin activity.

Selection of therapy -- Most clinicians agree that first line choices in hypertensive therapy are diuretics, beta blockers, calcium antagonists, and ACEIs.  Beta adrenergic antagonists work well with younger patients and those with a history of angina, MI, and arrhythmias.  Calcium antagonists seem to work better in the elderly and African-Americans.  ACEI are preferred for patients with CHF and younger patients, although the potential for worsening of CHF (as discussed above) may limit their use in this respect in the future.

Hypertensive Crises -- This emergent situation often presents secondary to encephalopathy, intracranial hæmorrhage, left ventricular failure, myocardial infarction, eclampsia, and severe burns.  It most often is treated with parenteral therapy followed by accelerated oral doses.
 

Weight Reduction -- Obesity can cause both insulin-mediated sodium retention and increased sympathetic tone, which will increase TPR and BP.  Weight loss will reduce these effects.

Sodium Restriction -- This is especially effective in patients over 40 y/o.  The primary beneficial effect is less fluid retention, therefore less TPR.

Alcohol Restriction -- Ethanol may increase calcium transport into the vasculature, thus enhancing vasoconstriction.  Mild consumption appears permissible.

Exercise -- Decreases blood volume and catecholamine levels and increases atrial natriuretic factor (thus increasing sodium loss).

Miscellaneous -- Other treatment modalities include relaxation therapy, biofeedback, and potassium therapy.