hypertension pharmacology - pathopharm

principle determinants of blood pressure

arterial pressure = cardiac output x peripheral resistance

cardiac output factors

• HEART RATE

• myocardial contractility

• blood volume

• venous return

systems that help regulate bp

• sympathetic baroreceptor reflex

  • baroreceptors in aortic arch and carotid sinus sense bp changes

  • if bp is low → activates beta receptors in heart to inc cardiac output and alpha receptors for vasoconstriction

  • when bp restored, SNS stimulation subsides

• RAAS

  • can elevate bp → contraindicates hypertensive drugs

  • constricts blood vessels → reduces glomerular filtration → retains salt and water → inc. blood volume and bp

• renal regulation

  • bp falls → filtration falls → higher volume → higher bp

    • diuretics neutralize renal effects on bp

diuretic antihypertensive drugs

• thiazide

• loop diuretics

• potassium-sparing

sympatholytics (antiadrenergic drugs) antihypertensive drugs

• beta-adrenergic blockers

• alpha1 blockers

• alpha/beta blockers: carvedilol and labetalol

• centrally acting alpha1 agonists

• adrenergic neuron blockers

• calcium channel blockers

direct acting vasodilators

• hydralizine

• minoxidil

drugs that suppress RAAS

• ACE inhibitors

• Angiotensin II receptor blockers

• aldosterone antagonists

• direct renon inhibitors

  • precautions for type 2 diabetes mellitus

initial drug selection

determined by presence of absence of compelling indication

absence - thiazide diuretic recommended (low mortality and morbidity)

• if doesnt work use ACE inhibbitors, ARBS, and CCBs (not as effective at reducing mortality and morbidity)

with compelling indications (hypertension + heart failure, diabetes)

• depends on condition, may have to add more than one drug

adding drugs to regimen

when adding more than 1 drug, each drug should be fromm a diff class (has a diff mechanism of action) ex: diuretic + vasodilator

benefits- diff mechanisms at diff sites can increase chance of success & dose of each can be lower than dose of one alone (better adherence), they can offset side effects of other

dosage should be low initially then GRADUALLY INC

• no immediate threat

• lessens side effects

  • sympathetic reflexes resist less

step down therapy

after bp has been controlled at least 1 year, should try to lower dose

promoting adherence

• educate patient ( even though side effect without drug arent bad, early intervention is vital)

• teach self monitoring

• minimize side effects (side effects r usually worse than not being on drugs, making them want to stop)

• establish collaborative relationship

• simplify regimen

• other measure

drugs for hypertensive emergencies

IV ONLY IN EMERGENCIES

when diastolic exceeds 120, severity is determined by likelihood of organ damage

• sodium nitroprusside

  • drug of first choixe

  • vasodilator

  • has to be chased every 2-3 min, effects work and fade quick

• fenoldopam

  • vasodilator for short-term management of emergencies

  • helps maintain or improve renal function **

  • oral meds once bp stable

• labetalol

  • arteriolar vasodilation (blocks alpha receptors)

  • reduces tachycardia (blocks beta receptors) = good for patients w angina or MI

    • could aggravate bronchial asthma, HF, AV block, bradycardia (contraindications)

• clevidipine

  • ultrashort half-life

• diazoxide

CONTRAINDICATED drugs for hypertensive disorders of pregnancy

• ACE inhibitors

• ARBs

• DRIs

most other hypertensives can be continued

chronic hypertension and pregnancy can lead to

can lead to preemie babies that cant survive, and if does survive can have severe defects

preeclampsia and eclampsia caused by pregnancy

preeclampsia - elevated bp + proteinuria develops after 20 weeks

eclampsia - preeclampsia + seizures

interventions

• delivery of baby (dangerous)

• lower bp with drugs (hydralazine)

• magnesium sulfate (for seizures)

high ceiling loops diuretics

furosemide/lasix = most frequently prescribed loop diuretic

mechanism of action:

• acts of ASCENDING LOOP of henle to block reabsorption

pharmacokinetics

• RAPID ONSET (PO 60 min, IV 5 min)

  • dont walk away bc they will pee themselves

therapeutic uses

• pulmonary edema (HF)

• edematous states (HF)

• hypertension (vasodilation)

furosemide/lasix adverse effects

• hyponatremia, hypochloremia, dehydration

  • leads to loss of volume and relaxation of smooth muscle

• hypokalemia

• ototoxicity (hearing loss)

• hyperglycemia

• hyperuricemia (avoid use in patients w/ gout)

• use in pregnancy

• impact on lipids, calcium, magensium

use loop diuretics when

1- patients need greater diuresis and cant be achieved w thiazides

2- patients w a low GFR (thiazides dont work when GFR is low)

furosemide drug interactions

• digoxin

• ototoxic drugs (mycins)

• potassium sparing diuretics

• lithium

• antihypertensive drugs

• NSAIDS

other high ceiling loop diuretics

• ethacrynic acid (edecrin)

• bumetanide (bumex)

• torsemide (demadex)

• ALL CAN CAUSE

  • ototoxicty, hypovolemia, hypotension, hypokalemia, hyperuricemia, hyperglycemia, and disruption and lipid metabolism

thiazides and related diuretics

• aka benzothiazides

• similar to loop diuretics, but not as potent

• inc. renal excretion of sodium, chloride, potassium, and water

• elevate lvls of uric and glucose (concern for ppl w diabetes)

• maximun diuresis a lot lower than loop diuretics (why lasix is better and used more)

hydrochlorothiazide (hydroDIURIL) mechanism and uses

acts on - early distal convoluted tubule

peaks 4-6 hours

THERAPEUTIC USES:

• essential hypertension

• edema

• diabetes insipidus (mechanism unclear)

hydrochlorothiazide adverse effects

• hyponatremia, hypochloremia, dehydration

• hypokalemia

• use in pregnancy and lactation

  • enters breast milk

• hyperglycemia

• hyperuricemia

• impact on lipids, calcium, and magnesium

hydrochlorothiazide drug interactions

DIGOXIN

augments effects of hypertensive medications

• can reduce renal excretion of lithium - be careful giving to pt. taking lithium bc lithium has narrow therapeutic window (1-1.5)

NSAIDS may blunt diuretic effect

can be combined with ototoxic agents w/o inc risk of hearing loss **

potassium-sparing diuretics

useful responses

• modest inc. in urine production

• substantial dec. in potassium excretion

rarely used alone in therapy **

aldosterone antagonist = spironolactone

nonaldosterone antagonists = triamtrene, amiloride

spironolactone/aldactone mechanism of action and therapeutic uses

action

• blocks aldosterone in the distal nephron

• retention of potassium

• excretion of sodium

• binds w receptors for other steroid hormones

therapeutic uses

• hypertension

• edematous states

• heart failure (dec. mortality in severe failure)

• primary hyperaldosteronism

• premenstrual sydrome

• acne in women

spironolactone adverse effects

hyperkalemia

benign and malignant tumors

endocrine effects

spironolactome drug interactions

• thiazide and loop diuretics’

• agents that raise potassium levels

ACE inhibitors - therapeutic uses

angiotensin- converting enzyme inhibitors

• hypertenson

• heart failure

• myocardial infarction

• diabetic and nondiabetic nephropathy

• prevention of MI, stroke, and death in patients at high cardiovascular rik

ACE inhibitors- adverse effects

• first dose hypotension

• fetal injury

• cough

• angioedema

  • life threatening reaction

  • patients report edema of tongue lips or eyes, emergency care should be sought immediately, they should never take ACE again

• hyperkalemia

• renal failure

• neutropenia

ACE inhibitors drug interactions

diuretics

antihypertensive agents

drugs that raise K+ levels

lithium

NSAIDs

ACE inhibitors preparation, dosage, administration

all oral EXCEPT for enalaprilat

All available in single drug formulations

food doesn’t matter EXCEPT W captopril and moexipril which have to be given WITHOUT FOOD, (hour after meal)

Angiotensin II receptor blockers (ARBs) mechanism of action and effects

MoA

• block AgII access

• dialate arterioles and veins

• PREVENT AGII FROM INDUCING PATHOLOGIC CHANGES IN CARDIAC STRUCTURE

• reduce potassium excretion

• Dec. aldosterone release

• Inc. renal excretion of sodium and water

• Don’t inhibit kinase II

• don’t inc. levels of bradykinin, which is why we usually start them on ARBS

angiotensin II receptor blockers - therapeutic uses

• hypertension

• heart failure

• myocardial infarction

• diabetic nephropathy

• if patient cant tolerate ACE inhibitors: protection against MI, stroke, death from cardiovascular causes in high risk pt.

• may prevent the development of diabetic retinopathy

• new data shoes that ACE inhibitors and angiotensin II receptor blockers (ARBs) are not effective for primary prevention of nephropathy in normotensive diabetic pt.

angiotensin II receptor blockers adverse effects

angioedema

fetal harm

renal faiure

ARBs don’t promote accumulation of bradykinin in the lung and therefore have a lower instance of cough

direct renin inhibitors (DRIs)

• aliskiren (tekturna)

  • binds tightly with renin and inhibits the cleavage of angiotensinogen to angiotensin I

  • side effects:

    • angioedema

    • cough

    • GI effects

    • hyperkalemia

    • fetal injuury

    • death

aldosterone antagonists - eplerenone (inspra)

eplernone (inspra)

MoA:

• selective blockade of aldosterone recpetors

theapeutic uses

• hypertension

• heart failure

pharmacokinetics

• absorption not affected by food

adverse effects

• hyperkalemia

aldosterone antagonist drug interactions

• they inhibt CYP3A4

• drugs that raise potassium levels

• use w caution when combined w lithium

aldosterone antagonists - adverse effects

• hyperkalemia

• gynecomastia (boy boobies)

• menstrual irregularities

• impotence

• hirsutism

• deepening of the voice

sacubitril/valsartan (entresto)

• new drug

• angiotensin receptor- neprilysin inhibitor

• reduce re-hospitalization and CV death by 20% when compared to enalipril

drugs with selective dilation of arterioles

hydralazine

selective dilation of veins

nitroglycerine

dilation of arterioles and veins

prazosin

hemodynamic effects of vasodilators

drugs that dilate RESISTANCE vessles (ARTERIOLES) CAUSE A DECREASE IN CARDIAC afterload

drugs that dilate CAPACITANCE vessels (veins) reduce force with which blood is returned to heart, thus reducing preload

vasodilators therapeutic uses

• essential hypertension

• hypertensive crisis

• angina pectoris

• heart failure

• MI

• pheochromocytoma

• peripheral vascular disease

• pulmonary arterial hypertension

• production of controlled hypotemsion during surgery

adverse effects related to vasodilators

• postural hypotension (orthostatic)

  • teach pt. ab symptoms of hypotension (lighteheadedness, dizziness) advise them to sit/lie of these occur

  • avoid abruot position transitions

• reflex tachycardia

• hydrexpansion of blood volume

hydralazine / apresoline action and uses

• dilate arterioles

• unknown mechanism

• minimal postural hypotension

• therapeutic uses

  • essential hypertension

  • hypertensive crisis

  • heart failure

hydralazine / apresoline adverse effects

• reflex tachycardia

• inc. blood vol.

• systemic lupus erythematosus-like syndorme

• headache, dizziness, weakness, fatigue

hydralazine / apresoline drug interactions

other hypertensive agents

avoid excess hypotension

combined beta blocker to protect against reflex tachycardia and w diuretics to prvent sodium and water retention and expansion of blood volume

minoxidil

• dilate arterioles

• more intense than hydralazine but has more severe adverse reactions

• used for severe hypertension unresponsive to safer drugs

• adverse effects

  • relfex tachycardia

  • sodium and water retention

  • hypertrichiosis

  • pericardial effusion

  • \

sodium nitropusside

• FASTEST ACTING ANTIHYPERTENSIVE AGENT

• venous and arteriole dilation

• IV admin

• immediate onset but bp returns to crisis lvls when treatment stopped

• used for hypertensive emergencies

• adverse effects

  • excessive hypotension

  • cyandie poisoning

  • thiocynate toxicity

calcium channel blockers

• prevent calcium ions from entering cells

• greatest impacts on heart on blood vessles

• treatt hypertension, angina, dysrhythmias

• controversy: safety for pt. with hypertension + diabetes

• aka calcium antagonists and slow channel blockers

Verapamil and diltiazem calcium channel blocker

act on vascular smooth muscle and the HEART

dihydropyridines calcium channel blockers

act mainly on vascular smooth muschle (VSM)

physiologic functions and consequences of blockade

vascular smooth muscles

• calcium channels open = cpmtractile process

• calcium channels blocked = vasoconstriction

therapeutic doses

• selectivity om peripheral arterioles, arteries, arterioles of heart

• no effect on veins

heart

• myocardium - Ca entry has positive inotropic effect

• SA node and AV node

  • pacemaker activity is regulated by calcium influx

  • coupling of cardiac calcium channels to beta1-adrenergic receptors

classification of calcium channel blockers

Dihydropyridines - nifedipine

• act on arterioles (VSM)

Phenylalanine - verapamil

Benzothiazepine - diltiazem

• both act on arterioles and heart

varapamil and diltiazem

act os VSM

hemodynamic effects

• direct. effects on heart and blood vessels

• indirect (direct) effects

explain why HR doesnt inc?

• dihydropyridines dont block calcium channels they risk reflex taxhycardiam verapamil and diltiazem dont

verapamil and diltiazem - hemodynamic effects

blockade at peripheral arterioles

• reduces arterial resistance

blockade at arteries and arterioles of heart

• inc. coronary circulation

blockade at SA node

• reduces heart rate

blockade in the myocardium

• dec. or inc. force of contraction

Verapamil (calan, covera-HS, Isoptin, Verelan) - therapeutic uses

• angina pectoris (chest pain)

  • vasopastic angina (chest pain at rest)

  • angina of effort

• essential hypertension

  • first line agent

• cardiac dysrhythmias

  • atrial flutter, atrial fibrillation, paroxysmal supra-ventricular tachycardia

  • migraine

Verapamil (calan, covera-HS, Isoptin, Verelan)- adverse effects

CONSTIPATION - decreases adherence, is most common complaint

• results from blockade of calcium channels in smooth muscle of the intestine

• especially severe for the elderly

• dizziness

• facial flushing

• headache

• edema of ankles and feet’gingival hyperplasia

• heart block

Verapamil (calan, covera-HS, Isoptin, Verelan) - interactions

• drug interactions

  • beta blockers (adverse effects on AV node conduction, heart rate, contractility)

  • digoxin (inc. digoxin levels bc decreases renal clearance)

• food interactions

  • grapefruit

• toxicicty

  • severe hypotension

  • bradycardia and av blocks

  • ventricular tachydysrhtmias

what should be available for severe cardiovascular effects when using IV veraoamil

• crash cart

• oxyfen abmu cart

• emergnency medicine

• IC access

• pacing capanilites

diltiazem (cardizem, dilacor-XRm Tiazac, etc) actions and uses

• blocks calcium channels in the heart and blood vessels (similar to verapamil)

• lowers bp by arteriolar dilation (TREATS HEART)

diltiazem (cardizem, dilacor-XRm Tiazac, etc) therapeutic uses

• angina pectoris

• hypertension

• cardiac dysrhythmias

  • atrial flutter, atrial fibrillation, paroxysmal tachycardia

diltiazem (cardizem, dilacor-XRm Tiazac, etc) - adverse effects

similar to verapamil except less constipation

dizziness

flushing

headache

edema ankles and feet

exacerbates bradycardia, sick sinus syndrome, HF, second or third degree heart block

diltiazem (cardizem, dilacor-XRm Tiazac, etc) drug interactions

antifungals

cimetidine

digitoxin

dihydropyridines

acts on VSM, not for heart, cant give for tachydysrythmia

• nifedipine (adalat, nifedical, nifediac, procardia)

blocks calcium channels in blood vessels

doesnt block calcium channels in heart

Nifedipine effects

direct effects

• limits blockade of Ca channels in VSM

• no direct suppressant effects on:

  • automaticity

  • AV conduction

  • contractile force

indirect effects

• lowered bp, activates baroreceptor reflex

• primarily with fast acting vs sustained release

Nifedipine - therapeutic uses

• angina pectoris

• hypertension

• investigational basis to relive migraine headache and to suppress preterm labor

Nifedipine - adverse effects

flushing

dizziness

headache

peripheral edema

gingival hyperplasia

chronic eczematous rash in older pt.

reflex tachycardia (complications = fainting, cardiac arrest, heart failure)

• can be combined w a beta blocker to prevent reflex tachycardia

• beta blockers dec adverse effects of nifedipine but intensify adv. effects of verapamil and diltiazem

rapid-acting nifedipine effects

• inc. mortality in pt. with MI and unstable angina

• no cause and effect relationship established

• use w great caution

nimopedine `

is a dihydropyridines approved for patients having vasospams following subarachnoid hemorrhage

beta blockers action

with careful control of dosage can improve pt. status

protect from excessive sympathetic stimulation

protect against dysrhythmias

beta blockers adverse effects

fluid retention or worsening HF

fatigue

hypotension

bradycardia/ heart block

digoxin and cardiac glycosides

• use lots of caution w/ beta blockers and diabetes and asthma

• they have positive inotropic actions

  • inc. myocardial contractile force

  • alter electrical activity of heart

  • favorably effect neurohormonal systems

• are second line agents

cardiac (digitalis) glycosides

• digoxin aka lanoxin, lanoxicaps, digitek

• naturally occurring compound

• profound effects on mechanical and electrical properties of heart

• inc. myocardial contractility

• inc. CO

• can cause severe dysrhythmias

digoxin / lanoxin effects

Positive inotroic action on heart

• inc, force of ventricular contraction

• inc. mypcardial contractility

• watch K+ levels

hemodynamic benefits

• dec. sympathetic tone

• inc. urine production

• dec. renin release

neurohormonal benefits

• modulates activity of neurohormonal system

• suppresses renin release in kidney

• dec. sympathetic outflow from CNS

• inc. sensitivity of cardiac baroreceptors

electrical effects

• inc. firing rate of vagal fibers

• inc. responsiveness of SA now to acetylcholine ***

digoxin / lanoxin adverse effects

• dysrhythmias

  • predisposing factors

    • hypokalemia

    • elevated digoxin lvl ( has narrow therapeutic range .5-.8)

    • heart disease

• noncardiac adverse effects

  • anorexia, nausea, vomiting, fatigue

• reduce effects w education

  • take meds exactly as prescribed

  • if taking potassium supplement or K+ sparing diuretic take exactly as prescribed

diagnosing and managing digoxin induced dysrhythmias

diagnosis is hard

• lab data required

• based on experience and clinical judgment

managing

• withdraw digoxin and potassium wasting diuretics

• monitor potassium, if low give K+ bc displaces digoxin from Na/K pump therefore reverses toxicity

• antidysrhythmic drugs - phenytoin and lidocaine, dont use quinidine bc rises digoxin lvls

• give atropine to pt. that get bradycardia or AV block

• if overdose is severe, give Fab antibody fragments (DIgifav), fragments binds digoxin and prevents it from acting

digoxin / lanoxin drug interations and pharmacokinetics

• diuretics

• ACE inhibitord and ARBs

• sympathomimetics

• Quinidine

• Verapamil

Pharmacokinetics

• absorption

• distributed widely and crosses placenta

• eliminated primarily by renal excretion

• half-life is 1.5 days (long, if you don’t pee enough one day, can become toxic quick)

inotropic agents - dopamine

sympathomimetics (dopamine, dobutamine) (inc. contractility and heart rate)

dopamine (inotropin)

• catecholamine

• activates beta1-adrenergic receptors in heart, kidney, and blood vessels

• inc. HR

• dilates renal blood vessels

• activates alpha1 receptors

inotropic agents - Dobutamine

• synthetic catecholamine

• selective activation of beta1-adrenergic receptors

• sympathomimetics

inotropic agents - phosphodiesterase inhibitors

Milrinone (Primacor)

• indofilator

  • inc. myocardial contractility and promotes vasodilation

• reserved for pt. with severe reduction in CO resulting in dec. organ perfusion because can cause arrhythmias and myocardial ischemia

Ivabradine (Corlanor)

• for use in patients with stable, symptomatic heart failure WITH

  • LVEF (left ventricular ejection fraction) <35%

  • sinus rhythm

  • HR > 70 bpm

**** CAN BE USED FOR PT. WHO HAVE A CONTRAINDICATION TO BETA BLOCKER USE or have diabetes/asthma