Thiazides and Related Agents

Actions

HCTZ, Chlorthalidone, Indapamide, Metolazone

-MOA: inhibits Na+/Cl- cotransporter at the luminal surface of the DCT

-Lower efficacy than loop diuretics --> 5-8% of filtered Na+ load

-slow acting (2-4 week onset of diuresis)

-Less effective in pts with renal failure due to lower GFR

-short term: decrease TBV and CO

-long term: decrease Na+ content of smooth muscles and their sensitivity to vasopressors

-Due to compensatory reaction to Thiazides they are often given with B blockers and ARBs

Thiazides and Related Agents

Adverse effects

HCTZ, Chlorthalidone, Indapamide, Metolazone

-hypokalemia -> increased sodium in collecting duct activates Na+/K+ exchanger (give with K+ sparing diuretic e.g. triamterine/HCTZ)

- salt and water depletion

- hyperuricemia -> increased reabsorption (volume depletion) or decreased excretion (compete w/ diuretics at PCT) - not for pts w gout

-progressive increase in plasma glucose (decreased K+ in Beta cells)

- hyperlipidemia (not for pts with dyslipidemia)

-erectile dysfunction, nocturia and inc. urination

Thiazides and related agents

drug interactions

quinidine - hypokalemia will increase the risk of quinidine induced polymorphic ventricular tachycardia

digoxin - can cause arrythmias through digoxin toxicity

corticosteroids - can amplify hypokalemia produced by diuretics

Thiazides and related agents

indications

HCTZ, chlorthalidone, indapamide, metolazone

HTN, edema, heart failure, DI, hypercalciuria

Diabetes insipidus - using thiazides causes a signal to the body to retain more water (opposite of what you may think)

Loop Diuretics

MOA

Furosemide, Bumetanide, Torsemide, Ethacrynic Acid

- less effective than thiazides for HTN in pts with normal renal function

- inhibit Na+/K+/2Cl- cotransporter complex in the thick ALOH

- inhibit reabsorption of 20-25% of sodium load

- has direct effect on venous capacitance -> decreases left ventricular filling

- blocks TGF causing renin release

- Short duration of action (furosemide and bumetanide) and will cause rebound Na+ retention which will offset the effectiveness

Loop diuretics

adverse effects

Furosemide, Bumetanide, Torsemide, Ethacrynic Acid

- excessive salt and water depletion

- hypomagnesemia -> predisposes arrhythmias

- hypocalcemia

- hyperuricemia

- ototoxicity w/ deafness -> common w/ furosemide

Loop diuretics

Drug Interactions

Furosemide, Bumetanide, Torsemide, Ethacrynic Acid

Aminoglycosides - synergism of ototoxicity

Anticoagulants - increased INR

Digitalis - increased arrhythmias

lithium - increases plasma levels of lithium

propranolol - increased plasma levels of propranolol

sulfonylureas - hyperglycemia

K+ sparing diuretics

MOA

Amiloride, Triamterene, Spironolactone

- 2-3% of filtered sodium load

- Spironolactone Blocks effects of aldosterone in the late DCT and collecting duct by competitive inhibition (metabolic acidosis)

- Amiloride and Triamterene block the Na channel at the lumial surface of the renal tubule

- used with thiazides and loop diuretics for positive effects on potassium

K+ sparing diuretics

adverse effects

Amiloride, Triamterene, Spironolactone

- hyperkalemia -> w/ renal disease pts, elderly, and combo therapy with ACE inhibitors

- hyponatremia -> common with thiazide/amiloride

- spironolactone -> impotence, menstrual issues

- nausea, vomiting, leg cramps

- canrenone - may reduce tubular secretion of canrenone

Osmotic Diuretics

Glycerol, Mannitol

- Increase osmotic pressure of the plasma

- used to treat cerebral edema and acute glaucoma

- glycerol -> oral  mannitol -> IV

- mannitol is filtered at the glomerulus, but not reabsorbed, so it reduces the conc. gradient of Na+ and less is reabsorbed

- mannitol improves renal function in the oliguric phase of renal failure

- primary adverse effect of mannitol is excessive plasma volume expansion

Carbonic Anhydrase Inhibitors

acetazolamide

- is a very weak diuretic and is primarily used to counteract respiratory alkilosis (altitude sickness) and for glaucoma

- CA is required for the reabsorption of Na Bicarb from the proximal tubule causes mild metabolic acidosis and increases pH in urine

- inhibition of CA in the CNS elevates the seizure threshold

non-selective B-blockers

MOA

Propranolol, Timolol, Nadolol

- block the effects of NE -> essentially slow the movement of calcium in the heart

-have equal affinity for B1 and B2

-decrease HR and Contractility

-block renin release

-increase periferal resistance initially by blocking B2, but decrease periferal resistance long term

-nadolol is long acting (HL -> 20 hrs) and does not enter the CNS as well as propranolol

-Timolol Ophthalmic is used to treat glaucoma

Non-selective B-blockers

adverse effects

propranolol, timolol, nadolol

- bronchospasm in asthmatics

- bradycardia

- hypoglycemic episodes (blocks gluconeogenesis in liver-> B2 mediated) 

- increased triglycerides

- CNS -> sleep disturbance, vivid dreams, hallucinations

Selective B-Blockers

MOA

metoprolol, atenolol, bisoprolol, betaxolol

-have greater affinity for B1 than B2 receptors (cardioselective) -> produce less bronchoconstriction and other B2 effects

-selectivity for B1 is dose dependent

-dec. HR, lower contractile force, and block renin release

-may cause withdrawal w/ abrubt discontinuation

-lipid solubility - propranolol + betaxolol > metoprolol > atenolol

-betaxolol -> ophthalmic (better than timolol for asthma pts)

B-blockers with intrisic sympathomimetic activity

Acebutolol, penbutolol, pindolol

-ISA- drug is an agonist at B receptors, but this effect blocks the effects of catecholamines

- will produce smaller reductions in HR and BP

- pindolol - oral nonselective with ISA.  ISA is greater for B2 than B1

- acebutolol - oral cardioselective w/ mild ISA for B1 -> less likely to cause braycardia and cold extremities

- penbutolol - nonselect B-blocker w/ ISA for B2 and high lipid solubility

Combined a- and B-blockers

Carvedilol, Labetolol

B - decreases HR and CO 

a - decreases peripheral vascular resistance

- labetalol - nonselective B-blocker with partial agonist activity and selective a1-blocker

has 2 optical centers -> 4 diasteriomers

- Carvedilol - nonselective B-blocker and selective a1 blocker (1:10 - a:B).. antioxidant and antiproliferative effects (benefial for CHF + MI)

nebivolol

B1 selective at 5mg but loses this at >10mg

less B-blocker side effects

ACE inhibitors

Sulfhydryl-containing

ACE inhibitors

phosphonate-containing

ACE inhibitors

dicarboxylate-containing

Enalapril(at), benazepril, lisinopril, quinapril

ACE inhibitors

MOA

- block formation of AT2 and inhibit breakdown of bradykinin (vasodilator)

- decrease both arterial and venous pressure

- inhibits angiotensin stimulated aldosterone secretion -> prevents compensatory Na retention

- K+ retention is increased

-Drug of choice for diabetics (have renoprotective effect) and pts w renal disease and left ventricular hypertrophy

-decrease afterload and increase CO-> reduces risk of death in pts with heart failure

ACE inhibitors

Adverse effects

-cause fetal and neonatal morbitity -> pregnancy

-renal failure in pts w bilateral renal artery stenosis (stiffness of artery that supplies the kidney)

-most common-> dry nonproductive cough (20%) due to increased bradykinin

-rash occurs in up to 10% (higher with captopril to to SH group -> also abnormal taste)

-angioedema, painful swelling of the lips, face and throat

ACE inhibitors

drug interactions

-may cause hyperkalemia with K-sparing diuretics and K supplements

-lithium- increases lithium levels -> cause toxicity

-NSAIDs- can reduce effects of ACE inhibitors

ARBs

-sartan's

-selectively (10,000 fold) block AT1 receptors

-allow for activation of AT2 receptors -> mediate vascular development

-will not increase levels of ACE substrates i.e. bradykinin-> no cough (primary benefit)

-takes 3-6 weeks for effect

-block aldosterone secretion (hyperkalemia)

aliskiren

-blocks the first, rate-limiting step of renin-angiotensin-aldosterone system (conversion of Agiotensinogen to AT1)

-lowers levels of AT1 and AT2, while ACEi will cause increased AT1 and ARBs will cause increased AT2

Ca channel blockers

non-dihydropyridines

verapamil, diltiazem

Indications: HTN, angina, diabetic nephropathy, atrial flutter, a-fib, migraine specific to NDHP's

- block L-type Ca channels -> slows contraction

-have 1:1 effect on vascular SM:cardiac tissue

-slow rate of firing of the SA node and slow conduction through the AV node -> causes bradycardia and heart block

-verapamil- causes reduced cardiac contractility (negative inotropic effect) -> can precipitate heart failure in patients with poor LV function

alters gut motility-> constipation

Ca Channel Blockers

dihydropyridines

dipine's

- block L-type Ca channels -> slows contraction

-much greater effect in vasculature (10-1000x)

-cause tachycardia and palpitations -> lower vascular resistance and BP which causes response

-arterial dilation causes headaches, flushing, dizziness, ankle edema

-nifedipine- AE - nausea and heartburn

-have little effect on venous beds -> don't significantly effect cardiac preload

vasodilator

-direct arterial dilation- unknown mechanism

- dilation is associated with powerful stimulation of sympathetic NS

-does not dilate epicardial coronary arteries or relax venous smooth muscle -> postural hypotension is uncommon

-no longer first line therapy due to AEs

-may cause symptoms associated with systemic lupis erythematosis -> fever, malaise, joint pains, myalgias, fatigue, and temporary loss of cognitive abilities

vasodilator - for severe HTN

-prodrug converted to minoxidil sulfate

-activates Katp channel-> opens K+ channels in SM causing hyperpolarization and relaxation of SM

-causes reflex increase of contractility + CO -> given with B-blocker

-causes increased proximal tubular reabsorption of Na and water -> given with diuretic

-causes hair growth (rogaine)

vasodilator

-nitrovasodilator that releases NO -> mimics production of NO by vascular endothelial cells

-NO activates guanylyl cyclase

-must be given in continuous IV to be effective

-mostly used for hypertensive crisis

-also used in other situations to reduce short term cardiac preload and/or afterload

-causes thiocyanate accumulation -> tachycardia, sweating, hyperventilation, metabolic acidosis

Centrally acting a2-agonists

MOA

methyldopa (DOC in pregnancy), clonidine, guanabenz, guanfacine

-act at presynaptic a2 autoreceptors in the CNS

-reduce central sympathetic outflow and increase vagal parasympathic outflow

-reduces venous + arterial pressure, HR, and BV (net increase in BV -> compensatory)

-Methyldopa - prodrug metabolized to methylNE

-clonidine, guanabenz, and guanfacine also activate peripheral postsynaptic a2 causing vasoconstriction (net effect is vasodilation)

-clonidine used to diagnose pheochromocytoma - adrenal tumor- if levels of catecholamines doesn't lower -> cancer cells are producing them

Centrally acting a2-agonists

adverse effects

methyldopa, clonidine, guanabenz guanfacine

-sympathetic block -> failure of ejaculation, postural hypotension (less w/ clonidine), fluid retention

-unopposed parasympathetic-> diarrhea

-dry mouth-> sympathetic wins?

-sudden withdrawal of clonidine and guanabenz can produce severe rebound hypertension

-methyldopa induces autoimmune hemolytic anemia, hepatitis, and lupis-like syndrome

Adrenergic Neuron Blockers

MOA

guanadrel, guanethidine

-inhibits function of peripheral postganglionic adrenergic neurons

-taken up into neuron by uptake 1 -> responsible for reuptake of NE

-replace and deplete NE in secratory vesicles

-when given initially, will increase BP because displaced NE is not broken down fast enough which can cause hypertensive crisis

adrenergic neuron blockers

adverse effects

guanedrel, guanethidine

-hypotension upon need for O2 -> lack of sympathetic compensation

-fatigue, weakness, impotence, diarrhea

-CHF due to fluid retention

-pheochromocytoma -> contraindicated because they release excess catecholamines

adrenergic neuron blockers

drug interactions

guanadrel, guanethidine

-levodopa and alcohol -> additive hypotension

-MAOi's -> contraindicated

-oral contraceptives, sympathomimetics -> decrease hypotensive activity

-TCA's - block uptake of TCA's and stop their action

interferes with sympathetic neuronal function

-inhibits enzyme that starts rate limiting step of catecholamine biosynthesis -> tyrosine hydroxylase (catalyzes converstion of tyrosine to DOPA)

- main use -> Pheochromocytoma

-may cause orthostatic hypotension, sedation, diarrhea, anxiety

interferes with sympathetic neuronal function

-binds tightly to storage vesicles and prevents storage of NE, dopamine, serotonin -> destroyed by MAO in cytoplasm

-recovery of sympathetic function takes 3days-weeks -> must synthesize new storage vesicles

-first drug found that interferes with sympathetic nervous function -> currently cheaper than other anti-HTN drugs and used in developing nations

a1-blockers

MOA

prazosin, terazosin, doxazosin

-bind to postsynaptic a1 receptor -> inhibits direct vasoconstriction by catecholamines in both arteries and veins (postural hypotension)

-must be initially given in small bedtime doses to avoid orthostatic hypotension

-will cause lethargy, headache, dizziness, compensatory palpitation, nausea, impotence, and diarrhea

-alcohol and sildenafil - interaction -> additive hypotension

-sympathomimetics - interaction -> decrease effectiveness of a1 blockers

non-selective a-blockers

phenoxybenamine (long acting reversible) phentolamine (short acting competitive)

-cause decreased BP and PVR, while increasing cardiac stimulation and reflexes due to a2 stimulation

treprostinil

(Remodulin)

prostacyclin analogue

indicated for pulmonary HTN -> causes lower lung blood perfusion due to increased pressure.  

Will cause: dizziness, fainting, SOB, angina, edema, and fatigue

administered via continuous SC or IV infusion

longer HL than eproprostenol

Tadalafil

cialis

PDE inhibitor

increases concentrations of cGMP in corpus cavernosum

indicated for ED and pulmonary HTN