Use methyldopa in pregnancy!

Methyldopa is metabolized to an active a2 agonist, and acts as a central sympathoplegic drug

the ABCDs are used to treat hypertension:
ACE inhibitors

Beta-blockers

Ca++ channel blockers

Diuretics (thiazides)

 *vasodilators are also sometimes used (ex: nitroprusside)

Thiazide diuretics, ACE inhibitors, and Ca++ channel blockers are considered the first choice drugs unless contraindicated.

Clonidine is an alpha-2 receptor agonist.  It activates a2 receptors in the Nucleus Tractus Solitarius and Rostral Ventrolateral Medulla.  It's action here decreases the central sympathetic tone, this reduces HR, contractility, vasoconstriction, causing a decrease in the mean arterial pressure!

Methyldopa is another centrally acting sympathoplegic drug that has a similar MoA. (first metabolized to an a2 agonist)

These drugs are 2nd choice drugs in the treatment of hypertension.

Clonidine is a centrally acting sympathoplegic drug.  It often causes sedation, decreased REM sleep, bradycardia, xerostomia and sexual dysfunction.

(in fact, almost all antihypertensives can cause sexual dysfunction in males)

Methyldopa, the other centrally acting sympathoplegic (indirect) can also cause hemolytic anemia (positive coombs test), hyperprolactinemia, and hepatotoxicity.  But methyldopa is the DOC for hypertension during pregnancy.

Prazosin is an alpha-1 antagonist.  Alpha-1 antagonists are rarely used in the treatment of hypertension nowadays.  They work by selectively blocking the a1 receptors, leading to a decrease in TPR.

alpha-1 antagonists often cause postural hypotension.  This is usually after the first dose of the drug, and is termed the "first dose phenomenon".  This poses the risk of myocardial or cerebral ischemia and syncope.  Because of this, the patient is usually started on 1/2 the normal dosage. 

A1-blockers may also cause palpitations.  Urinary incontinence may result because a1-blockage causes relaxation of the sphincter.  As with most antihypertensives, sexual dysfunction may result, this can include priapism.

Beta-blockers decrease cardiac output (B1)

Beta blockers inhibit the renin-angiotensin system.  (B1 receptors stimulate renin release from the juxtaglomerular cells)

Other mechanisms include reduction in NE release and reduction of central sympathetic tone.

Propranolol is a non-specific beta-antagonist.  Labetalol is an alpha-antagonist and partial beta-agonist. 

HR: propranolol = decrease (b1)

labetalol = unchanged

CO: Propranolol = decrease (b1)

labetalol = unchanged

Venous tone: propranolol = unchanged

labetalol = decreased (a1)

Postural Hypotension: propranolol = negligible

labetalol = evident

Beta blockers are used anytime that there is hypertension with a concomitant scenario where b-blockers would be effective.  This includes:

1) hyperkinetic essential hypertension (due to increased CO, tachycardia etc.)

2) Supraventricular arrhythmias

3) Hypertrophic obstructive cardiomyopathy

4) Exertional angina

5) Post myocardial infarction

6) Hypertensive emergency (labetalol)

7) pheochromocytoma/hyperthyroidism

Nitroprusside causes an increase in HR, a decrease in venous tone, and an overall decrease in cardiac output.  This is because the decreased venous tone decreases preload, this leads to a decreased SV and an elevated HR.  The relative decrease of SV is greater than the HR increase, so CO drops slightly.

TPR also drops because of vasodilation.

Postural hypotension is prominent because of the decreased TPR.

Cyanide will accumulate if the vasodilator nitroprusside is given at too high doses.  This will lead to metabolic acidosis, arrhythmias and cardiovascular collapse.  Remember that cyanide inhibits complex IV of the electron transport chain, preventing aerobic production of ATP.  The cardiac myocytes rely completely on aerobic respiration!

Administer sodium thiosulphate or hydroxycobalamin to prevent cyanide accumulation.  Cases of cyanide poisoning can be treated with Amyl Nitrite.

Nitroprusside is administered by IV.  RBCs metabolize it, releasing cyanide, which is then converted to thiocyanate.  These two byproducts are highly toxic.  Nitric oxide is also released, which produces the vasodilatory effect, beneficial in cases of hypertension.

Administer sodium thiosulphate or hydroxycobalamin to prevent cyanide accumulation.  If there is already cyanide toxicity administer amyl nitrite to couteract/treat it.

Nitoroprusside causes vasodilation of both veins and arterioles.  This leads to a profound decrease in TPR.  It also greatly reduces the preload of the heart.  This reduced preload is the reason for many of its contraindications, which include:

impaired cerebral circulation: reduced SV and CO further impair bloodflow to the brain.

Aortic stenosis: Further reduces blood flow through stenosed aorta, and impairs ability of heart to contract against the increased afterload (Starling's Law, decreased EDV=decreased contractility).

Drugs causing reduced preload are contraindicated in hypertrophic cardiomyopathy.

Also do not use in patients that are unable to safely metabolize nitroprusside.  These patients lack the enzyme rhodanase, which detoxifies cyanide by reacting it with sulfur donors to form thiocyanate.  In these patients cyanide levels will easily reach toxicity

Use a beta-blocker (esmolol) with nitroprusside. 

You could also use a Ca++ channel blocker that works on the heart (verapamil) with nitroprusside.

It is proposed that hydralazine inhibits Ca++ release from the sarcoplasmic reticulum of smooth muscle.  It's side effects include:

Muscle weakness, headache, dizziness, palpitations, myocardial ischemia.

Hyrdralazine may also precipitate immune reactions, resulting in lupoid syndrome, serum sickness, hemolytic anemia and vasculitis.

Minoxidil is a vasodilator only used in the treatment of severe hypertension that has responded poorly to other medications.  This is because of its high degree of toxicity.  It is a prodrug that must be transformed by the liver to the active molecule.  Therefore, not a good drug to choose in patients with liver disease.  It promotes the opening of K+ channels in smooth muscle membranes, leading to hyperpolarization and relaxation.  It acts only on arterioles, not veins.

Minoxidil, a vasodilator that opens K+ channels, commonly causes hypertrichosis.  This is the excessive growth of hair on the body. (diazoxide may also cause this)

It may also cause pericardial effusion. Tachycardia, palpitations, flushing are all results of the powerful vasodilatory effect.  If these are very pronounced, they may even promote cardiac failure! 

Allergic reactions, like Stevens-Johnson syndrome may result.

Because of its high toxicity, minoxidil is rarely used anymore.  However, it may be used locally to treat baldness (because it promotes hypertrichosis)

("mino" like "minotaur", which is covered in hair)

(or: both of the drugs with "OX" in the name cause excessive hair growth)

Only nitroprusside has a strong likelihood of postural hypotension.

Hydralazine, Minoxidil, Diazoxide, and fenoldopam have a negligible risk of postural hypotension.

Diazoxide should not be used in Diabetics because it causes hyperglyemia (insulin resistance). This side-effect also limits its use to acute emergencies and not chronic treatment. 

Do not use in impaired cerebral blood flow or aortic stenosis because diazoxide may cause excessive hypotension, worsening both of these conditions.

Fenoldopam is a specific D1 agonist.  It vasodilates renal and mesenteric beds.  It has a very short half life, so it cannot be used in chronic treatment, and is instead reserved only for hypertensive emergencies.

Fenoldopam is contraindicated in glaucoma

Decreased blood pressure results in a decreased GFR. More Na+ is absorbed in the proximal tubule, less Na+ reaches the macula densa.  The macula densa's job is to sense the Na+ concentration of the tubular fluid.  A lack of Na+ at the macula densa signals the juxtaglomerular cells to release renin.  Renin cleaves angiotensinogen to angiotensin I.  ACE enzymes convert angiotensin I into angiotensin II.  Angiotensin II causes preferential contraction of the efferent arterioles in the glomerulus, restoring GFR.  It also stimulates aldosterone release, promoting reuptake of salt and water by the kidney, which also restores BP and GFR.

Renin release can also be stimulated by Beta-1 receptors of the juxtaglomerular cells, and stretch receptors in the afferent arterioles.

IP3/DAG

Recall that this leads to the opening of Ca++ channels, which explains why it causes vasoconstriction, and increased release of catecholamines and aldosterone from the adrenals.

The angiotensin II receptor antagonists are the "sartans", for example Losartan. 

(AngiotensinReceptorAntagonist) 

These drugs selectively block the AT1 receptor, the receptor responsible for the majority of angiotensin II effects, resulting in vasodilation and salt/water loss.  These "sartan" drugs block angiotensin II more fully than ACE inhibitors.

Captopril

Enalaprilat

lisinopril

"___pril"

Postural hypotension (first dose phenomenon)

Dry cough

Hyperkalemia (because blocks aldosterone)

Angioedema (rare), due to bradykinin, which may lead to airway obstruction and suffocation!  The skin of the face, the throat, and the tongue swell up over the period of minutes to hours.  Remember that bradykinin is a potent vasodilator that also increases vascular permeability.  One of the actions of ACE is to breakdown bradykinin: therefore its accumulation in patients on ACE inhibitors.

Fetotoxic, so avoid in pregnancy

Captopril is an ACE inhbitors.  All ACE inhibitors ("__prils") are contraindicated in:

Pregnancy! (category D drugs)

Renal artery stenosis = requires renin-angiotensin system to maintain GFR by preferential angiotensin-II-mediated efferent arteriole constriction.  Here it is absolutely contraindicated, as you will kill the patient if you administer it.

Hyperkalemia (because it blocks aldosterone)

History of angioedema

Angiotensin II receptor antagonists, like losartan, have similar contraindications to ACE inhibitors because the effects and system they act on are the same. 

Absolutely contraindicated in renal artery stenosis!

Do not use in hyperkalemic patients.

Do not use in pregnancy (category D drugs)

They are not associated with a dry cough or angioedema because they do not prevent ACE metabolism of bradykinin.

"sartans" are often combined with thiazide diuretics

First try lifesyle modifications: weight loss, reduced dietary sodium, stop smoking, exercise more.

Then , if it doesn't respond, start on one of the first choice antihypertensives (ACE inhibitors, Diuretics, Ca++ channel blockers)

A patient with stage 2 hypertension requires treatment with a two drug combination.  One of these drugs is a thiazide diuretic.  The other can be an ACE inhibitor, AT receptor antagonist, or Ca++ channel blocker.

If this fails to achieve the blood pressure goals, add another drug of a different MoA.