Hypertension- sustained elevation of either systolic >120 or diastolic >90 IDEAL BP = 110/70 Betablocker = cardioprotective but not for

Diabetes mellitus
SYMPHATOPLEGICS: Blockers of: A. CNS = Methyldopa (Aldomet) works Brain in relay area of solitary nucleus, acts as A2 receptor agonist >reduce symphatetic tone to ur peripheral structures blood vessel thus: decreased PVR, HR, plasma renin P.O. well absorbed , IV 1) HTN heptaic metab C450excretion: parent and metabolites via urine 2) CHF 1) mild edema from increased plasma volume 2) first few weeks= sedation CAUTION: elderly, first floor ; dizziness; headache (diminishes in time as tolerance develops 3) mild bradycardia 4) flu like symptoms 5) may cause lupus-like syndrome 6) (+) Coomb's test drug induced

ANTIHYPERTENSIVES

MOA

Pharmakokinetics

Clinical Use

Side Effects

Clonidine (replaced Nifedipine) =

same as of methyldopa

PO, transdermal patch (for 1) HTN = small doses only noncompliant pts; provides initially or else manifest side aesthetic plasam; fewer effects side effects

1)high dose= causes interaction with A1 receptors => vasconstriction, incr BP 2) drowsiness, diz ziness, HA 3) mild edema 4) mild bradycardia 5) xerostomia 6) constipation

live excretion: urine (unchanged, majority) Guanabenz = not internationally marketed because SITE OF ACTIOn is unknown and extreme side effects; same as solitary nucleus ***usually combined with HTCZ(hydrochlorothiazide) diuretic B. GANGLIA PERIPHERALLY ACTING DRUGS Mecamylanine(Inversine) Which of the ff. sympthatoplegic is also recognized as as ganglionic blocker: will competitively nondepolarizing ganglionic blocker?? Mecamyline inhibit AcH at the nicotinic receptors at postganglionic autonomic neurons => vasodilatation of peripheral blood vessels, decr BP excretion: urine

2) CHF transdermal: itchiness, skin irritation and redness of the area 1) confusion, headache, nausea 2) mental depression 3) array of antimuscarinic s/e even at normal doses (when given alone)

PO excretion= 90% unchanged 1) HTN ***not commonly in urine used d/t numerous s/e

, 1) at normal dose => convulsio 2) mental changes 3) tremors 4) confusion 5) hypotension

C. NERVE TERMINAL note: differentiate Gunabenz vs Guanadrel Reserpine

*** adrenergic neuronal blocker (blocks reuptake of NE & DA in vesicles) by inhibiting an enzyme magnesium Atpase => depletion of NE and DA => decr activity of NE, DA in blood vessels & heart partial hepatic (parent and metabolites) excretion: urine, feces combined with other drugs d/t CNS side effects: diuretics, beta blockers 1) suicide 2) severe depression 3) sedation 4) bradycardia

Guanethidine and Guanadrel = differ only in formulation ***superior to Reserpine

replaces NE bound to ATP inside the vesicles => decr NE release during nerve stimulation => reduced arteriolar vasoconstriction

PO hepatic metab excretion: urine (parent and metabolites)

1) moderate & severe HTN

1) angina pectoris 2)peripheral edema 3) pulmonary edema 32% 4) fatigue 5) severe diarrhea = warrant dr to d/c treatmnt 1) severe diarrhea 2) orthostatic hypotension 3) GIT disturbances = n/v 4) body malaise severe allergic rxn, EPS, severe diarrhea

Metyrosine

*** very unique because it inhibits an enzyme PO tyrosine hydroxylase => reduced synthesis of NE => decr BP

urine = unchanged

1) secondary HTN 2) prophylaxis and treatment HTN associated with pheochromocytomectomy 3) chronic treatment for malignant pheochromocytoma

D. ALPHA/BETA BLOCKERS 1. A1-ADRENERGIC Phentolamine =

nonselective alpha adrenergic blocker => decr sytemic vascular resistance => decr BP

IV & IM ONLY not well defined metab not well defined excretion, some in urine

1) dx of pheochromo 2) prophylaxis and treatment HTN associated with pheochromocytomectomy

1) reflex tachycardia 2) ortho. Hypotension 3) GIT disturbances 4) body malaise

Phenoxybenzamine =

nonselective alpha adrenergic blocker => decr sytemic vascular resistance => decr BP

PO hepatic C450 excretion= metabolites in urine, feces

1) prophylaxis and treatment similar to phentolamine s/e HTN associated with pheochromocytomectomy

2) UNIQUE USE: for BPH

2. SELECTIVE ALPHA BLOCKERS Prazosin

for all: PO 1) HTN hepatic active metabolites BPH excretion= parent & metabolites in BILE, feces

for all: 2) ***main advantage vs nonselective= causes lesser reflex tachycardia

***first dose effect= orthostatic hypotension => syncope CAUTION: careful dosing, take before bedtime 1) drowsiness, dizziness, HA 2) peripheral edema, palpitation Terazosin PO hepatic active metabolites excretion = parent & metabolites in URINE , feces Doxazosin (cardura) PO hepatic active metabolites excretion= parent & metabolites in BILE, feces

2. BETA BLOCKERS = recommended as 1st linetherapy 1) decreases primarily by decresing cardiac i.e. when concomitant dse is present e.g. CHF+ HTN output ***very efficacious but also with Contraindications Generalizations: 1)more effective in CAUCASIANS 2)more effective in young HTN Generalizations that will discourage use: 1)very severe COPD 2) Chronic CHF 2) very severe symptomatic occlusive peripheral vascular disease USE WITH CAUTION: DM, elderly, HTN with other dse, with SVTach, HTN with post M.I., HTN with angina, chronic CHF, migraine HA ) 2) decreases SANS outflow from CNS

1) Acute CHF

WARNING 1 : Taper the dose 2-3 weeks when withdrawing because ABRUPT CESSATION induces angina and M.I. WARNING 2 : alters serum lipid metabolism = decreases HDL ; increases plasma TG most causes bradycardia and CNS (fatigue,lethargy, insomina, severe CNS hallucination and hypotension, impotence) all betablockers decreases compliance d/t 1) bronchonstriction 2) hypotension 3) sexual dysfunction

2) PVD

3) inhibit RENIN from kidneys =>decr angiotensin II and aldosterone

Propanolol= prototype

full effect = after SEVERAL weeks

PO = extensive 1st pass; IV excretion = metabolites urine

1) HTN 2) angina

***Absolutely Contraindicated for asthmatics because blocks B1 receptors in heart => increasing its nonselective, blocks B2 bronchodilatation (lungs) SANS activity => decreased BP as well blocks beta receptors in JG cells => decr renin release

3) cardiac arrythmias 4) migraine 5) acute MI 6 )essential tremors (hyperthyroid Contraindication: asthma, COPD, DM, PVD

Metoprolol = selective; most commonly used

same as Propanolol

PO

1) for HTN over propanolol bec; nonselective and lesser side effecs angina CHF Acute MI

1) lesser bronchoconstriction

Atenolol= selective; most commonly used

urine

E. A/B BLOCKERS Carvedilol

beta blockade: 1) decreases heart rate

PO, VERY EXTENSIVE 1stpass 1) HTN CF450 2) CHF

bradycardia, dizziness, hypotension

2) decr plasma rennin activity excretio=; FECES only 3) incr plasma volume alpha blockade: 1) decr PVR = good for cold fingers and toes 1) decr PVR = good for cold fingers and toes Labetalol selective A1 blocking but predominantly nonselective beta blocking : beta blockade: decreases heart rate plasma rennin activity volume 1) 2) decr 3) incr plasma PO, IV

mainly for HTN

PO form = postural hypotension

hepatic metab ecxretion= parent and metabolites in urine, feces

dizziness, hypotension, n/v

fatigue

alpha blockade: 1) decr PVR = good for cold fingers and toes

VASODILATORS A. ARTERIAL VASODILATORS Hydralazine

arterial smooth muscle relaxation and vasodilation by cAMP and Calcium

PO, IM, 1) HTN PO = very extensive 1st pass hepatic acetylation

CHF

toxicity in slow acetylators like tachycardia, dizziness, nausea, flushing, redness in the face, sweating, nasal congestion, lupus-like syndromes memorize: LUPUS_LIKE inducers

***hepatic acetylation is genetically predetermined ===>

caucasians = slow acetyylators asians = fast acetylators => excertion= urine PO, topical hepatic 1)HTN metab excretion= metabolites in urine

Minoxidil

inhibits phosphodiesterase => incr. levels of cAMP => arterial smooth muscle relaxation thru Calcium modulation

2) alopecia

tachycardia, massive fluid retention hypertrichosis ECG changes pericarditis REFLEX TACHYCARDIA

Diazoxide

decreases PVR via direct vasodilatory effects IV only on the smooth muscles of the peripheral partial hepatic metab arterioles excretion: parent and metabolites in urine

1) AHE (acute hypertensive emergencies)

2) hypoglycemia in pts who have hyperinsulinemia how??? inhibits insuline release

B. ARTERIAL & VENOUS VASODILATORS Na Nitroprusside *** Cyanide is a byproduct of it =>hepatic enzyme rhodanase metabolizes it to thiocyanate ( more soluble and urine excretable) Candidates for Cyanide pOisoning: 1) alcoholics (ROH poisons rhodanase) 2)

acting directly

IV 1) AHE (acute hypertensive local metabolism by tissues emergencies) and RBCs excretions= metabolites in feces, urine, and LUNGS (exhale) ***covered with foil= easily broken down by UV light 2) CHF

Nitroglycerin advantage: 1)not light sensitive 2) does not cause cyanide toxicity 3) readily available than Na nitroprosside = cost effective

SL, PO, IV , ointment, skin patch hepatic active metabolites excretion= converted to nitric oxide intracellularly => activates guanylate cyclase => cGMP cascade => dephosphorylation of myosin light chains => relaxation of vascular smooth mushcles => vasodilatation

HA repeated admin => loss of effect (from systemic compensation ****large degree of cross tolerance b/n other organic nitrates

readily available than Na nitroprosside = cost effective

CALCIUM CHANNEL BLOCKERS Verapamil (Isoptin)

for all: 1) blocks voltage-sensitive Ca channels in heart, vascular smooth muscles => decr in Intracellular calcium

PO extensive 1st pass , IV,

1) HTN Angina anti-arryhtmics

2) 3)

for all ALL = potential for peripheral ede ALL = potential for hypotension palpitation due to reflex tachycardia i.e. NIFEDIPINE lesser with verapamil and diltiazem dizziness, HA, ALL = constipation but PRONOUNCED in VERAPAMIL

2) blocks cyclcic nucleotide PDE => incr hepatic C450 ACTIVE cGMP => decr Calcium influx => dilatation of metabolites peripheral arterioles and venules urine, feces Diltiazem PO IV hepatic C450 LESS active metabolites urine, feces Nifedipine = prototype of Ca-channel Blockers PO extensive 1st pass hepatic C450 INACTIVE metabolites urine, feces DRUGS INTERFERING WITH ANGIOTENSIN Captopril = drug prototype 1) decr BP by inhibiting enzyme for AngII (ACE) ALL PO, Enalapril has IV form 1) HTN HTN and Angina only

1) common complain = nonproductive cough (d/t bradykinin's effect of cough and skin rash) 2) TERATOGENIC

Prodrug= enalaprila

2) prevents breakdown of bradykinin

Prodrug => hepaticactive metabolite urine

2) CHF

3) hyperkalemia 4) neutropenia 5) hypotension 6) ARF same above but NO COUGH

SYMPHATETIC ANTAGONISTS Angiotensin Recept Antagonsis Losartan

Angio Receptor blockade prevents vasconstriction of AngI PO hepatic C450 urine, feces 1) HTN 2) CHF

RENIN INHIBITORS