Most common form is essential HTN 

Isolated systolic HTN: Loss of elasticity of aorta as you age->only increases systolic BP->large pulse pressure of up to 100 (normal=40)->heart requires more O2 but its ability to obtain O2 has deceased, no drugs can help it, doubles risk of death due to CHD

African Americans: Higher prevalence of HTN, a volume dependent HTN rather than vasoconstrictive HTN with high plasma renin like caucasians; Use thiazide diuretic or combo w/ ACE-I, NOT ACE-I alone b/c renin is already low

Normal BP: <120/<80

Pre-HTN: 120-139/80-89; Can use non-pharmacological intervention if patient doesn't have other condtiions

Stage 1 HTN: 140-159/90-99; 1 drug

Stge 2 HTN: 160+/100+; 2 drugs

Drugs:

Diuretics: Thiazide (HTN)-almost always used in combos, Loop Diuretics (HF), K+ Sparing (resistant HTN)

B-Blockers: Not 1st line, Atenolol most common

Alpha-Beta Blockers: HF, not HTN; Carvediol most important

Ca-Channel Blockers: Amlidopine-t1/2=40 hours

Renin-Angiotensin-Aldosterone blockers: Catopril frequently used for HTN

Central Sympatholytics: Alpha-Methyldopa=only drug for HTN treatment in pregant women; Resperine-acts in periphery ("resperiphery"), not CNS

Less than 50% have BP under control b/c: Bad Dosing (BP highest early morning, but drugs dosed 1x/day only last until night), bad combos (ex: B-blocker and ACE-I: B-blocker inhibits renin release->ACE-I has nothing to do), non-compliance, systolic BP is hard to control

Vasomotor Center in CNS (Alpha 2 agonists): 

Alpha-Methyldopa: Prodrug converted to methyldopamine then methylnorepinephrine;  Only anti-HTN for pregnancy; Acts on post-synaptic alpha-2A receptors in CNS

Alpha-2A: Inhibitory, CNS and periphery, limits SNS output, located pre-synaptically in the periphery

Alpha-2B: In vasculature, cause vasoconstriction

Clonidine: Oral only(IV could cause BP rise from alpha-2B); Rebound HTN common; Increased effect with increased dose

Sympathetic (Peripheral) Ganglia:

Trimethaphan: Intolerable SE's for HTN from blocking PNS so not used except in hypertensive crisis

Sympathetic Nerve Terminals:

Resperine: Inhibits VMAT->Prevents DA uptake->Can't be converted to NE; SE=Depression so rarely used

Receptor Blockers:

Beta Blockers: Inhibit B-1 effects on heart, decrease renin release

Alpha Blockers: Non-selective ones cause Orthostatic HTN and can't be used for HT, only used for pheochromocytomas; Selective ones like prazosin and doxazosin (selective for alpha-1) can be used for HTN and improve lipid profile, but may cause HF (ALLHAT study)->Not 1st line, too powerful

Depress renal function->Increase diuresis (urine volume) and natriuresis (Na excretion)

Long term effects are due to arterial dialation over time (no one knows why)

Thiazide and Thiazide-like: Hydrochlorothiazide (HCTZ), Chlorthalidone, Metolazone, Indapamide

Loop Diuretics: Furosemide, Torsemide

K+Sparing epithelial channel blockers: Amiloride, Triamterene ("Block AT Epithelial channels)

K+Sparing aldosterone antagonists: Spironolactone, Eplerenone

Osmotic Diuretic: Mannitol

Carbonic Anhydrase inhibitor: Acetazolamide

Path through a Nephron:

Bowman's Capsule

->PCT: Mannitol (also works a little in TAL), Acetazolamide; Na+/H+ exchanger, 65% of sodium absorbed; Carbonic Anhydrase helps form carbonic acid (H2CO3), which dissociates into HCO3- that gets reabsorbed and helps sodium reabsorption; so early that renal tubule can compensate if Na+ absorption stopped here (weak diuretics act here)

Acetozolamid: Decreases reabsorption of Na+ through Carbonic Anhydrase Inhibition; More base in urine->acidosis; NaCl reabsorption increased as a response->hyperchloremia; Treats glaucoma and mountain sickness, not HTN

->Proximal Straight tubule

->Thick Ascending Limb (part of LOH): Loop Diuretics (esp Furosemide, also Torsemide; Used in HF, too powerful for HTN), 25% Na+ reabsorbed, Impremeable to H20, Na+/K+/2Cl- co-transporter out of the cell allows hyperosmolar zone to pull water out of collecting duct

->Macula Densa: Early Part of DCT, COX2 in macula densa cells sense low Na+ and produce prostaglandins->communicates with JG cells in afferent arteriole->Gs->cAMP->renin, Furosemides cause this to happen (bad)

->Distal Convoluted Tubule: Thiazides, Impermeable to H20, Na/Cl cotransporter (Thiazides inhibit), Na/Ca exchanger controlled by PTH that brings Na inside (lower sodium, higher Ca reabsorption->Thiazides cause excess Ca reabsorption->not for kidney stone patients, good for osteoporosis), 10% of Na+ and Cl-reabsorption

->Collecting Tubule and duct: K+Sparring aldosterone antagonists (weak on their own, used in combo w/ HCTZ), K+Sparring Epithelial Channel Diuretics (also work a little at DCT, directly block luminal side sodium channel to decrease reabsorption, can be used as monotherapy); aldosterone sensitive Na+/K+ exchanger results in Na+ reabsorption and K+ secretion->High aldosterone activity results in hypoalkemia; ADH pulls water out into hyperosmotic zone

Hyperkalemia: K+ sparring, Hypokalemia: all others

HyperCalcemia: Thiazide Diurectics, HypoCalcemia:  Loop Diuretics

Alkalosis: Loop Diuretics, Thiazide

Acidosis: K+ sparing, Carbonic anhydrase inhibiting

Increased K+ secretion->HypoKalemia (Loop Diuretics cause Hypokalemia too)

Anelgesic Aspirin Dose: Decreases thiazide effectiveness (from decreasing PG's); NSAID's have interactions w/ every antihypertensive except Ca+ Channel Blockers

Hydrochlorothiazide: Most commonly prescribed

Chlorthalidone: Best (t1/2=50-60 hours), should be most common

Metolazone: Can be used with poor renal function

Indapamide: Ineffective in lowering BP in systolic HTN

Use for: HTN (50mg dose), HF (only if patient becomes resistant to loop diuretic), Nephrolithiasis due to idiopathic hypercalciuria (kidney stones from too much Calcium in urine), Nephrogenic diabetes insipidus-can't concentrate urine b/c kidney doesn't respond to ADH (thiazides cause water retention in this case!)

SE: Hypokalemia, Hyponatremia, HyperGLUC (Glucose, Lipidemia, Urecemia, Calcemia)

Drug interactions: NSAIDS, Lithium-blood level increases w/ thiazides, Quinidine-prolongs QT interval (anti-arrhythmic) which increases the effect of hypokalemia prolonging QT interval->Torsades, Digitalis (digoxin)-hypokalemia from thiazides causes excessive inhibition of Na/K pump in the heart->arrhythmias

Can treat both HTN and HF as 1st line

RAAS drugs: ACE Inhibitors, Angiotension Receptor blockers (ARB's), and direct renin inhibitor.

ACE'I's ("pril's"): Catopril (prototype), lisinopril (top prescribed), enalapril, ramapril

You get: Build up of Ang I, Build up of renin (no negative feedback from ang II to stop making renin), decreased Ang II->less vasoconstriciton->decreased TPR->decreased BP and less aldosterone relese->less aldosterone release leads to less water retention, Increased kinins->bradykinins->vasodilation and NO production (Cough!), Increaed K+ level (don't combine with potassium sparing drug->even more hyperkalemia->heart block) and Decreased Na+ (from decreased aldosterone)

NO BARORECEPTOR REFLEX->No increase in HR or CO (ang II normally increases SNS but now it can't->cancels out sympathetic compensation from baroreceptors->No change in catecholamines)

Drugs ("prils")(mechanism of action same for all):

Captopril: Prototype, Administered in active form->quick onset and short t1/2; Greatest efficacy on empty stomach

Enalapril: Pro-drug with longer onset of action and t1/2

Enalaprilat: Active metabolite of enalapril; Comes in IV form in hypertensive crisis

Lisinopril: Not a pro-drug, but has a t1/2 of 11 hours

Ramipril: HOPE study-Less mortality and morbidity in patients with cardiovascular disease

SE's: No orthostatic hypotension (b/c no effect on veins); dose related loss of taste, neutropenia; Cough; angioneurotic edema; Hyperkalemia; Hypotension

Low Na+ diet enhances effects

African Americans: ACE-I's don't work as well, bigger age-related treatment difference

Use: 1st line in stage 1 HTN in non-african americans; people with HTN and HF, patients with LVH, patients with HTN with diabetes

Don't use with: Poor renal function, bilateral renal artery stenosis (Ang II constricts efferent arteriole to increase GFR and this is needed in renal failure/renal stenosis patients)

Some Ang II can still be made through alternative pathway (ang I to ang II via chymase)

Blocks binding of Angiotensin II to AT1 receptors (completely blocks Ang II effects unlike ACE I's); possibly increases Ang II binding at AT2 receptors->vasodilation

NO bradykinin effect->No cough or angioedema

Equal efficacy to ACE-I's

Drugs ("Sartans")

Losartan: Prototype, t1/2=2 hours, but active metabolite has t1/2=6-9 hours

Valsartan: Food effect-most effective on empty stomach

Telmisartan: Longest t1/2, 24 hours

Asilsartan: Newest ARB, may not have additional benefits

Aliskiren: Binds renin, t1/2=24 hours

Renin may or may not contribute HTN, effectiveness unknown

None of the ACE-I SE's (like ARB's)

Block L-ype Ca channel

Use dependent: stronger effect with increasing frequency of stimulation

Non-DHP's: Dilitazem and Verapamil; Least selective-affect both arterioles and heart-slow HR and decreases contractility, slows conduction through SA and AV nodes, impairs muscle contraction via inhibiting actin-myosin cross bridge formation

DHP's ("AN DHP"): Nimidopine and amlodipine; Selective for arterioles

Clevidipine: short acting, t1/2=10 mins, IV for HTN emergencies 

Verapamil: Relaxes smooth muscle in GI tract->constipation, Interacts with digoxin (blocks its efflux pump)

Nifedipine: Short acting, sympathetic surge->MI

Amiodipine: Long t1/2 from slow hepatic degradation, high bioavailability (no 1st pass effect like others), doesn't cause baroreceptor reflex and SNS surge like the others that could lead to MI; Peripheral Edema (unrelated to kidneys so diuretics won't counteract this effect), equivalent to clorthalodone in ALLHAT study

Use for: HTN (as monotherapy or combo), Angina, Cardiac Arrhythmias (non-DHP's for a-fib and a-flutter), NOT HF (causes cardiac depression)

Advantages: Effective in isolated systolic HTN (b/c they can increase compliance of large arteries), no tolerance from renal fluid retention, no increased renin release, don't effect lipid or glucose metabolism (like thiazides or B blockers), no effect on postural HTN, don't interact with NSAIDS

3rd line for HTN

Decrease renin release b/c JG cells use B1 receptors

Propanolol: 1st gen, non-selective, interact w/ NSAID's (block PG synthesis which is how B blockers work)

Atenolol, Metoprolol, Esmolol: 2nd gen, B1 cardioselective, decrease in HR and CO (lower MAP) causes decreased BP-MAPxTPR=BP (TPR actually increases->initially no decreased BP b/c of this, but then TPR decreases and BP can derease)

Atenolol: Used for HTN, short t1/2->dangerously high morning BP

Metoprolol: Used for Angina

Esmolol: Quick onset, short t1/2, IV during anesthesia to relieve hyperactive SNS that causes arrhythmias

Pindolol: 3rd gen, Beta blocker with intrinsic sympathomimetic activity; Partial agonist of Beta 1 receptor with 30% of NE's activity->increases HR a little, but not as much as NE; Used for treating HTN in patients with HR <45

Labetalol, Carvedilol: 4th gen, Beta blockers with alpha blocking or vasodilating effects, decreases TPR

Labetalol: Blocks B1 and B2 5x less than alpha 1 receptor; Used for resistant HTN

Carvedilol: Used for HF; Blocks B1, B2, and alpha 1 equally; Anti-oxidant and anti-inflammatory; Dialates veins->orthostatic HTN

Nebvilolol: Newest, Most selective B1 blocker, HTN in asthma patients; Anti-oxidant and vasodilator, less SE's

SE's: CNS effects, CHF, Bronchospasm, Metabolic effects: Inuslin insensitivity and hyperglycemia->DM, Raise TG and lower HDL

The ones that are most lipid soluble are metabolized by liver, least lipid soluble are metabolized by kidney

Use for: MI and HTN, angina and HTN, heart failure and HTN; Not 1st line for just HTN

Associated with higher incidence of stroke (high BP variability)

Hydralazine: Selective for arterioles; Short acting

Minoxidil: K+-ATP Channel Opener->Vasodilation of arterioles, Rogaine

Nitroprusside: Serves as a source of NO to dilate venules and arterioles (venules best); Used in hypertensive emergency; Cyanide toxicity

Sildenafil