Pharmacology: Basic Cardiovascular Pharmacology (McCauley)DIURETICS:

Basic Pharmacological Effects : all diuretics increase the loss of sodium into the forming urine, which results in increased urine flow and loss of water

Drugs in this Class: - Loop Diuretics:

o Furosemide- Thiazide and Thiazide-Like Diuretics:

o Hydrochlorothiazideo Metolazoneo Chlorthalidone

- Potassium Sparing Diuretics:o Amilorideo Spirinolactone

Mechanism Based on Sites of Action: - Proximal Tubule:

o Normal Physiology: Basically all filtered organic metabolites are reabsorbed in the proximal tubule Water is passively reabsorbed and tubular fluid maintains a constant osmolarity Na Reabsorption:

Na in the lumen exchanged for intracellular H+ using the Na/H+ exchanger Once in the cell, Na pumped into interstitium/blood using the Na/K ATPase

Bicarbonate Reabsorption: Excreted H+ combines with bicarbonate in the lumen to form carbonic acid Carbonic acid is hydrolyzed by carbonic anhydrase found in the luminal membrane,

resulting in the formation of water and CO2 CO2 diffuses back into the cell where it combines again with water (using a

different CA enzyme) to form carbonic acid Intracellular carbonic acid dissociates into H+ (pumped back into lumen in

exchange for Na) and bicarbonate (reabsorbed into the blood) Cl/Base Exchanger:

Bicarbonate is reabsorbed faster/more extensively than Na, and as a result, H+ being pumped into the lumen in exchange for Na no longer buffered

Tubule fluid becomes acidic and activates this exchanger, which promotes the reabsorption of Cl- in exchange for base being pumped into lumen

Water Reabsorption: Volume of water that is reabsorbed exceeds the permeability of the cell membrane Water also passes through specialized water channels (aquaporin I)

o Drugs that Work Here: Carbonic Anhydrase Inhibitors: reduce the activity of the Na/H exchanger, leading to loss of

NaHCO3 and water; not often used in CV diseases Dorzolamide: topical CA inhibitor used locally (ie. in the eye to reduce intraocular

pressure) Osmotic Diuretics: do not permeate luminal membrane, increasing the osmolality of the

forming urine and reducing the reabsorption of water; similar to glucose in diabetics Mannitol: osmotic diuretic given by IV to avoid osmotic diarrhea

- Loop of Henle: o Normal Physiology:

Thin Loop: more water passively reabsorbed into the hypertonic interstitium Thick Ascending Loop: impermeable to water

NaK2Cl Symporter: transports Na, K and 2 Cl into the cell from the lumeno Na pumped into interstitium/blood using Na/K ATPaseo Intracellular K+ increases (coming in from lumen AND interstitium)o K+ diffuses back into lumen as a result (back diffusion of K+), resulting in a

more positive luminal potential Positive Luminal Potential: driving force for NaK2Cl symporter, as well as the

reabsorption of Ca++ and Mg++ from the tubular fluid

o Drugs that Work Here: Loop (High Ceiling) Diuretics: direct inhibitors of the NaK2Cl transporter; diuretic effect can

be severe and is primarily due to sodium loss (35% if filtered Na usually reabsorbed here) Furosemide Ethacrynic acid

- Juxtaglomerular Apparatus: o Normal Physiology:

Juxtaglomerular Apparatus: microscopic structure in kidney located between the vascular pole of the renal corpuscle and the distal convoluted tubule of the same nephron

Juxtaglomerular Cells: located in the afferent arterioles of the glomerulus; act as intra-renal pressure sensory and secrete renin*

Macula Densa: cells lining the distal convoluted tubule who sense changes in concentration of sodium chloride

Extraglomerular Mesangial Cells: communicate via gap junctions with structural mesangial cells that surround glomerular capillaries

Renin Secretion: inversely proportional to NaCl load delivered to macula densa (ie. if NaCl load is low, renin secretion increases)

o Importance in Diuretic Use: Detection of NaCl load depends on action of NaK2Cl transporter: if using a loop diuretic

(and to a lesser extent, a thiazide diuretic), the NaCl will not be able to be transported into the cells of the macula densa due to the blockage of this receptor

Macula densa will perceive it as low NaCl load and stimulate renin release As a result, these drugs are typically given along with an ACE inhibitor, to prevent

the downstream effects of renin- Distal Convoluted Tubule:

o Normal Physiology: DCT is impermeable to water NaCC (Na/Cl- Symporter): electrically neutral pump that reabsorbs Na and Cl

Na+ pumped back into interstitium/blood using Na/K ATPase Unlike in the TAL, there is no back diffusion of K+ and therefore lumen is not

positively charged (no driving force for reabsorption of cations) Ca++ Reabsorption:

Ca++ channel AND a Ca/Na exchanger Both of these under the control of PTH (receptors for it located on membrane of

tubular cells)o Drugs that Work Here:

Thiazide and Thiazide-Like Diuretics: inhibit the Na+/Cl- symporter (NaCC) of the distal convoluted tubule; diuresis not as profound as that cause by loop diuretics, and will have additive effects if used with one (can be used in combination)

Hydrochlorothiazide Metolazone Chlothalidone

- Late Distal Tubule/Collecting Duct: o Normal Physiology:

Na+ Reabsorption by Principal Cells: controlled by aldosterone* Contain an epithelial Na channel (ENaC) that allows Na to enter the cell (driven by

continuous expulsion of Na by Na/K ATPase on the basolateral side of the cell) K+ Loss via Prinicipal Cells: controlled by aldosterone (Na+ reabsorption)*

Na reabsorption creates a negative lumen potential that promotes the reabsorption of Cl- and the secretion of K+

Therefore, the more Na+ that reaches the distal tubule, the more K+ lost (ie. loop and thiazide diuretics can cause hypokalemia)

K+ loss worsened if bicarbonate also present (ie. due to CA inhibitors) because it increases negative lumen potential but cannot be reabsorbed

H+ Loss via Intercalated Cells: negative lumen potential contributes to expulsion of protons using ATP-dependent proton pump

Water Reabsorption: ADH stimulates the expression AQP2 on apical membrane to increase water reabsorption (Lithium dramatically reduces this effect polyruria, polydipsia)

o Drugs that Work Here: potassium sparing diuretics (all may cause HYPERkalemia) Amiloride: specific inhibitor of ENaC with mild diuretic action; used more commonly to blunt

hypokalemic side effects produced by diuretics (however, can also be managed by oral KCl supplements)

Spironolactone: competitive antagonists of aldosterone with mild diuretic action

Loop Diuretics (High Ceiling): - Drugs in this Class:

o Furosemide*o Bumetanideo Ethacyrnic Acido Torsemide

- Clinical Use/Effects:o Edema associated with:

Heart failure Liver disease (cirrhosis) Renal disease (nephrotic syndrome, chronic and acute renal insufficiency)

o Increases RBFo Appears to have direct effects that relieve pulmonary congestion and left ventricular pressure in heart

failure (ie. these effects occur prior to diuresis)*o Acute hypercalcemia (in combination with saline)o Mild hyperkalemiao Elimination of bromide, fluoride, and iodine ions in toxic OD (halogens reabsorbed in ascending limb)o Acute renal failure (increase urine flow and K+ excretion, may help flush intratubular casts)

- Pharmacokinetics:o Well absorbed orally o Eliminated by tubular secretion and filtration (by the kidneys)o Half life depends on renal function (usually 1.5 hours)

Short half life is the reason why these agents are typically not good for tx of HTN- Adverse Effects:

o Hypokalemia (increased Na+ to collecting duct causes K+ secretion)o Alkalosis (increased Na+ to collecting duct causes H+ secretion)

Both managed with administration of potassium sparing diuretics or KClo Hypomagnesia (controlled with Mg supplementation)o Dehydration (+/- hypercalcemia)o Hyperuricemia and gouty attacks (hypovolemia-enhanced reabsorption of uric acid in the proximal

tubule)o Dose related hearing loss and allergic reactions (rare)

- Drug Interactions:o NSAIDs decrease diuretic effects

Thiazide and Thiazide-Like Diuretics: - Drugs in this Class:

o Hydrochlorothiazide*o Chlorthalidone*o Metolazone*o Quinethazoneo Indapamide

- Clinical Use/Effects:o Edema associated with cardiac, hepatic and renal conditions o Hypertension (most important CV application)

Use of low doses recommended (increasing can lead to unwanted SEs and extreme diuresis) Lower peripheral resistance without significant effect on either HR or CO

Indirect action on smooth muscle cells by depletion of Na, which leads to reduction in intracellular Ca (Na/Ca exchanger brings in Na), making SMCs refractory to contractile stimuli

Marginally decrease plasma volume and RBF

Increase plasma renin activity Equally effective in African and European-American populations (Asians may be more

sensitive) o Chronic heart failure (often in combination with ACE inhibitors or loop diuretics)o Idiopathic hypercalcuria with kidney stones

Inhibit NCC and lower Na+ reabsorption in DCT, leading to increased activity of basal Na/Ca exchanger that moves Na into cells and Ca into interstitium

Also leads to reabsorption of Ca++ from tubule through apical channelo Nephrogenic diabetes inisipidus (ie. caused by lithium)

Results in paradoxical decreased urine flow that has not be explained (MOA unclear) Need to monitor Li levels because it may reduce Li clearance

- Pharmacokinetics:o Well absorbed orally o Excreted in the urine via organic acid secretory system in the proximal tubuleo Half life varies (majority of them are long enough for once daily dosing)

- Adverse Effects:o Hypercalcemia (not by itself, but can unmask subclinical hypercalcemic conditions)

Hyperparathyroidism Sarcoidosis Paraneoplastic syndromes

o Hypokalemia (same mechanism as loop diuretics)o Alkalosis (same mechanism as loop diuretics)

Both reversed by potassium sparing diuretics or KCl supplementso Hyperuricemia (competes with uric acid for secretion by the organic acid secretory system in the

proximal tubule)o Induce hyperglycemia (use with caution in patients with diabetes)

Impaired pancreatic release of insulin and reduced peripheral utilization of glucoseo Alter lipid profile (use with caution in patients with dyslipidemia)

5-15% increase in total cholesterol and LDLo Hypnatremia (severe but rare side effect that only occurs in predisposed individuals; can be fatal)

- Drug Interactions:o NSAIDs reduce diuretic effects

Spironolactone: - Clinical Use/Effects:

o Severe (late) congestive heart failure Reduces morbidity and mortality Appears to be due to antagonism of aldosterone, which facilitates myocardial fibrosis

o In conjunction with thiazide and loop diuretics to prevent K losso Primary and secondary aldosteronismo Edema (particularly due to hepatic cirrhosis)

- Adverse Effects:o Hyperkalemiao Endocrine like effects (gynecomastia, impotence, peptic ulcers)

Epleranone: more specific antagonist and causes less of these effects

AGENTS THAT INTERFERE WITH ANGIOTENSIN II: Pharmacological Effects of Angiotensin II:

- Structure and Production : octapeptide produced by serial proteolytic cleavage of angiotensinogeno Angiotensinogen (Renin) Angiotensin I (ACE) Angiotensin II

Renin: cleaves the amino terminal decapeptide from the plasma protein angiotensinogen to give angiotensin I (highly dependent on the concentration of angiotensinogen, which is produced in and secreted by the liver)

Factors Affecting Production/Secretion of Angiotensinogen: o Corticosteroidso Estrogens (oral contraceptives)o Thyroid hormones

Angiotensin Converting Enzyme (ACE): cleaves two C-terminal residues from angiotensin I to produce angiotensin II (located in the vascular endothelium of most organs- esp. lungs and kidney)

Also catalyzes the degradation of bradykinin- Control of Secretion of Renin:

o NaCl Load (Macula Densa): release of renin INVERSELY proportional to NaCl load that is detected by the macula densa; NaCl is transported into the macula densa to be detected using NaK2Cl symporter (TAL) and the NaCC symporter (DCT)

o Changes in Renal BP (Juxtaglomerular Cells): changes in renal BP detected by these cells in the afferent arterioles of the glomeruli; increased pressure inhibits the release of PGs and stimulates renin secretion

NSAIDs and other inhibitors of PG synthesis DECREASE renin secretiono Activation of Beta-1 Adrenergic Receptors: by SS postganglionic stimuli (powerful force for renin

secretion)- Effects of Angiotensin II:

o General Effects: all mediated by AT1 receptor and involve many mechanisms of signal transduction Increased arterial pressure Na and fluid retention (directly and indirectly- induce release of aldosterone) Vascular and cardiac remodeling

o Effects on Peripheral Resistance: Direct Effects: acts directly on arteriolar smooth muscle cells to cause constriction and

increase in vascular resistance (more potent than NE) Most pronounced in kidney Least pronounced in skeletal muscle beds

Indirect Effects: also act to increase BP Enhances release of NE from SS nerves and EPI from the adrenal glands Reduces neuronal NE uptake Increases vascular sensitivity to NE Acts on areas of CNS that are not protected by BBB to increase sympathetic tone

(ie. area postrema)o Effects on Renal Function:

Increased Na retention: Stimulated Na/H exchange in proximal tubule Enhances aldosterone secretion Decreased renal blood flow (AT1 mediated contraction of renal smooth muscle and

enhance SS tone) Decreased GFR

Constricts mesangial cells in glomerulus Constricts both afferent and efferent arterioles of glomerulus (exert opposing

effects on GFR)o Effects on Cardiovascular Structure:

Direct Effects: contribute to increased wall-to-lumen ratio in vessels and the concentric cardiac hypertrophy seen in HTN

Increases migration, proliferation and hypertrophy of smooth muscle cells Hypertrophy of cardiac myocytes Increases ECM synthesis by both cardiac and vascular fibroblasts

Indirect Effects: involved in cardiac hypertrophy and remodeling Increased cardiac preload (volume expansion) Increased afterload (greater peripheral resistance) Increased aldosterone causes myocardial fibrosis

Angiotensin Converting Enzyme (ACE) Inhibitors: - General Pharmacological Effects:

o Decrease peripheral resistance without increasing HRo Reduce cardiac and vascular remodelingo Promote naturiesis

- Drugs in this Class:o Enalapril*

o Lisinopril*o Captoprilo Fosinoprilo Peridoprilo Quinaprilo Ramipril

- Clinical Uses/Effects:o Hypertension

Effective in both high and low renin HTNs Most mild to moderate HTNs (independent of plasma renin levels) can be controlled with

ACE inhibitors +/- diuretic o Heart failure (all stages)

Reduced preload (venodilation and improved renal hemodynamics) Reduced afterload (decreased peripheral resistance and increased arterial compliance)

Both of these effects lead to increased CO and SV Reduced cardiac and vascular remodeling

o Decrease effects of high renin levels caused by loop (and possibly thiazide) diureticso Ventricular dysfunction after infarctiono Diabetic nephropathy (and other chronic renal diseases)

Decrease resistance in glomerular efferent arteriole and reduced intraglomerular pressure (with decreased GFR)

Above effects + improved renal blood flow leads to reduced proteinuria and improve renal function (naturiesis)

- Pharmacokinetics:o Enalapril and lisinopril are PRODRUGs that are activated by cleavage of an ester bond in the liver

Half lives around 12 hourso Most ACE inhibitors are subject to first pass metabolism

- Adverse Effects:o Hypotension possibly causing LOC (after first dose in patients with high plasma renin activity)o Persistent dry cough (most common; due to increased bradykinin and lung PGs; most severe in African

Americans)o Hyperkalemia (in patients with renal insufficiency or those treated with potassium sparing diuretics , K

supplements or beta-blockers) ACE inhibitors are K sparing themselves due to reduction in aldosterone secretion Used clinically to minimize the ability of diuretics to cause hypokalemia (often combined with

thiazide diuretics in one formulaton)o May be less effective in African-Americans and elderly patients

- Drug Interactions:o NSAIDs:

Decrease Na excretion and may cause hyperkalemia Antagonize antihypertensive effect of ACE inhibitors

- Contraindications:o Pregnancy: teratogenico Bilateral renal artery stenosis: acute renal failure may occur in these patients since renal perfusion is

maintained by angiotensin II

Renin Inhibitor (Aliskiren):- MOA: inhibits renin competitively and consequently reduces angiotensin II synthesis- Formulations: first drug of this class approved in the US; also formulated in combination with HCZ- Adverse Effects: cough and GI disturbances - Drug Interactions:

o Decreases serum concentration of fureosemideo Cyclosporine increases aliskiren blood levels dramatically

- Contraindications: pregnancy (teratogen)

AT1 Antagonists (Angiotensin Receptor Blockers/ARBs): - General Pharmacological Effects: similar effects to ACE inhibitors with similar pharmacological efficacy

o Especially useful in patients who develop ACE-inhibitor-mediated cough - Drugs in this Class:

o Losartan*o Valsartan*o Candesartano Irbesartan

- Adverse Effects: same as ACE inhibitors (except for the cough); also reports of hepatic dysfunctiono Also possibly less effective in African Americans

- Drug Interactions:o NSAIDs: decrease antihypertensive effects

- Contraindications: pregnancy (teratogen)

SYMPATHOLYTIC AGENTS: Beta Blockers:

- General Uses in CV Medicine:o HTNo Cardiac arrhythmiaso Anginao Acute MIo Heart failure

- Effects of Beta Blockade:o Reduced heart rate

Important to minimize myocardial O2 consumption in patients with angina and heart failureo Decreased conduction velocity through the AV node and increased refractory period

Reduce reentry (involved in pathogenesis of different arrhythmias) Prevent the propagation of atrial arrhythmias to the ventricles

o Suppresses ventricular ectopic beats Especially important in the acute phase of MI

o Reduction of cardiac contractility (decreased work and reduced O2 consumption) Reduction of cardiac work during exertion (also due to decreased HR) prevents occurrence of

angina episodes and improves exercise toleranceo Decreased peripheral resistance and slowing of ventricular ejection

Improves SV in obstructive cardiomyopathy o Decreased rate of development of systolic pressure

Beneficial in dissecting aortic aneurismo Produces a slower, regular, more efficient heart beat with decreased peripheral resistance (after MI) o Reduce NE mediated cardiac hypertrophy in heart failureo Control cardiac effects of thyrotoxicosis (decrease chronotropism and inotropism)o Suppression of renin release due to sympathetic stimulation of the juxtaglomerular apparatus

Major role in the control HTN (inhibit B1 receptors) Potassium sparing (like ACE inhibitors) due to the reduction in aldosterone secretion

(secondary to decreased renin) Usually combined with a diuretic (often a thiazide) to control HTN, although they are

effective alone- Adverse Effects:

o Due to excessive beta blockade: Bradycardia Heart failure Hypotesion Bronchospasm (B2 block in bronchioles)

o CNS Effects: Depression Fatigue Insomnia Hallucinations Impotence

o Hypoglycemia: can occur in diabetics due to block of beta2 receptors which are normally stimulated to enhance glycogenolysis; can also mask hypoglycemia sensations (hunger, palpitations, tremor- NOT sweating)

o Negative effects on lipid profiles: raise triglycerides, lower HDL and HDL/LDL ratio Beta blockers with intrinsic sympathomimetic effects may have less of these effects (ie.

pindolol and labetalol)o Hypertensive crisis and acute coronary events upon withdrawal: due to up-regulation of post synaptic

receptors induced by long-term beta blocker treatmento Racial differences: may be less effective in African Americans

- Contraindications:o Asthmaticso Caution with diabetics (hypoglycemia)

- Drug Interactions:o NSAIDs: reduce antihypertensive effects

- Various Beta Blockers:o Propanolol: non-selective

Extensive first pass hepatic metabolism Blood levels show remarkable variation

o Metoprolol: beta1 selective (prototype) Extensive first pass hepatic metabolism Can be used with caution in some forms of COPD (ie. emphysema), but still contraindicated in

asthmatics because their specificity is not absolute Sustained release form used against chronic heart failure (reduces mortality and

hospitalization)o Atenolol: beta1 selective

Does NOT undergo first pass metabolism Specificity not good enough to allow use in asthmatics

o Pindolol: non-selective with some beta1 agonist activity Less cardiodepressant effects Less effects on serum lipids

o Labetalol: alpha1 and non-selective beta blockers PLUS some beta sympathomimetic activity Reduces peripheral resistance with less effect on HR and CO Does not affect serum lipids May be EQUALLY as effective in African-Americans as in other groups May cause orthostatic hypotension Used to manage hypertension in pregnant patients

o Carvediol: alpha1 and beta non-selective blocker (beta effects more prominent) Also inhibits oxygen radical mediated lipid peroxidation Reduces vascular smooth muscle mitogenesis Both of the above properties contribute to use in heart failure Metabolized by CYP2D6 (quinidine and fluoxetine compete)

o Esmolol: ultra-short acting beta1 selective blocker Half life of only 10 minutes Administered by IV to control supraventricular arrhythmias, HTN and MI in acutely ill

individualso Sotalol: non-selective PLUS a K+ channel blockero Nebivolol: beta1 selective antagonist metabolized to a beta2 agonist

Acts on peripheral beta2 receptors to increase NO and lower peripheral resistance 3rd generation beta blocker (secondary antihypotensive effects)

Other 3rd Generation Beta Blockers: celiprolol and betaxolol Other Sympatholytic Agents:

- Methyldopa: o MOA: overall, dampens central adrenergics to reduce vasomotor tone (does NT suppress peripheral

adrenergic activity Brain: Actively transported into the brain and metabolized in neurons to form methylNE,

which is released and acts on presynaptic alpha2 receptors Especially in nucleus of tractus solitarius of the medulla oblongata Results in INHIBITION of further NE release

Periphery: stored in secretory vesicles in place of NE and causes same potent vasoconstrictor effects as NE

o Effects: lowers peripheral resistance without significant effects on HR, CO, RBF, plasma volume or renin secretion

o Adverse Effects: CNS Effects:

Sedation Dry mouth Reduced libido Parkinsonian signs Hyperprolactinemia (may lead to galactorrhea)

Hepatotoxicity (rare) Hemolytic anemia (~20% develop + Coombs test due to presence of anti-Rh Abs; 1-%

develops actual hemolytic anemia)o Use:

Effective antihypertensive (especially when combined with a diuretic; SEs limit use) Tx of HTN in pregnancy

- Clonidine: o MOA: selective alpha2 receptor agonist that inhibits central release of NE, causing reduction of

adrenergic outflow from solitary tract in medulla oblongata At high concentrations, may also act as an agonist at alpha2 R on vascular smooth muscle

cells and cause vasoconstriction Some hypotensive effects also mediated by activation of imidazoline R in rostroventrolateral

medullao Effects: same as methyldopao Use:

Antihypertensive (effects potentiated by diuretic) Transdermal patch can blunt reflex sympathetic activity caused by vasodilators

o Adverse Effects: Sedation Dry mouth Postural hypotension Impotence Symptomatic bradycardia (or even sinus arrest) in patients with dysfunction of sinus node AV block in patients with AV node dysfunction (or taking drugs that depress AV conduction)

o Contraindications: Do not give to depressed patients (withdraw if depression develops)

o Withdrawal: Associated with increased SS tone (headache, tremors, tachycardia and rebound HTN) For this reason, patches should not be given to poorly compliant patients

o Drug Interactions: TCAs may reduce antihypertensive effects (surprisingly, this is NOT seen with methyldopa)*

- Guanethidine: o MOA: taken up by postganglionic SS fibers and accumulates in synaptic vesicles, where it replaces NE

(gradual depletion of NE stores); also stabilizes the neuronal membrane (acts like a LA) and inhibits NE release

NO action in the CNS (too polar to pass BBB)o Effects: reduction in peripheral resistance (antihypertensive effects)o Guanethidine-Induced Sympathectomy: results in relative PS predominance and reduces clinical use

Reduction of HR and CO Orthostatic hypotension Diarrhea Impaired ejaculation

- Reserpine : o MOA: blocks the ability of neuronal vesicles to take up and store SS amines (NE, DA, 5HT) in both the

CNS and PNS (postganglionic adrenergic neurons and adrenal medulla)o Effects: antihypertensive effects due to reduced peripheral resistance AND reduced COo Adverse Effects:

At effective doses, sympathetic reflexes are basically intact and postural hypotension is mild Depletion of central amine stores can cause sedation, depression and Parkinson sx

o Use: Mild to moderate HTN (in combination with a diuretic)

Above effects and introduction of new drugs has lowered use Low cost still makes it a sensible option (esp. in the elderly and in poor countries)

- Phentolamine and Phenoxybenzamine: o MOA: nonselective alpha receptor blockerso Use: clinical treatment and diagnosis of pheochromocytoma and impotence

- Prazosin :o MOA: selective alpha1 receptor antagonistso Effects: antihypertensive action due to decreased arteriolar resistance and increased venous

capacitanceo Adverse Effects:

Initially in the course of treatment, patients experience a sudden drop in peripheral resistance, increased HR and CO, and increased renin secretion (over long term, these effects normalize)

Orthostatic hypotension is the most common (depends on plasma volume; hypervolemia reduces incidence)

o Use: Tx of HTN (not for monotherapy; combined with diuretics or beta blockers) Tx of urinary symptoms associated with BPH (inhibit contraction of prostate smooth muscle)

o Others in the Class: Doxazosin (associated with increased risk of developing heart failure) Tamsulosin (tx of urinary symptoms associated with BPH) Terazosin

CALCIUM CHANNEL BLOCKERS: Pharmacological Effects:

- Voltage-Gated Calcium Channels: multi-subunit proteins involved in excitation-contraction coupling; principle type in cardiac and vascular tissues is L-type (slow channel)

o Mediates entry of Ca++ into smooth muscle cells and cardiomyocytes of atria/ventricleso Also carries Ca++ currents to cells forming SA and AV nodes

- MOA: binding of drug reduces the frequency of VGCC opening and subsequently markedly reduces the transmembrane Ca++ current

o Smooth Muscle: roughly half Ca required for maximal contraction comes from SER and other half from extracellular space (through VGCCs); inhibition of these channels results in reduction of arteriolar smooth muscle tone and peripheral resistance

Very prominent with nifedipine (and other DHPs), less with non-DHPs (verapamil>diltiazem) No CCBs have significant effects on venous beds (ie. no effect on cardiac preload)

o Cardiac Contraction: Ca influx through VGCC necessary for cardiac contraction; inhibition results in reduced cardiac inotropism

Effect minimal for nifedipine and other DHPs (trigger sudden peripheral vasodilation that causes baroreflex-mediated SS tone overcomes any negative inotropic effect)

Significant for diltiazem and marked for verapamil (non-DHPs)o SA Node Automatism and AV Node Conduction: depend on both Ca currents and the rate of recovery

of slow Ca channels Nifedipine and other DHPs slow inward current of Ca without affecting recovery of channels,

resulting in minimal effects on SA node automatism and no effect on AV conduction Diltiazem and verapamil (non-DHPs) reduce both Ca influx and rate of channel recovery,

resulting in marked effects on SA node automatism and AV conduction (reduce HR and AV conduction velocity)

Dihydropyridines: - Drugs in this Class:

o Nifedipine* (short half life of 3 hours, but also available in time released formulation)

o Amlodipine* (half life of 40 hours allowing for once daily dosing with minimal cardiac effects; can be safely administered in patients with heart failure- only DHP that reduces mortality in patients with LV dysfunction)

o Clevidipine (management of emergency HTN; much shorter half live than nicardipine) o Nicardipine (management of emergency HTN)o Felodopineo Israpineo Nitrendipineo Nimodipine (affects cerebral vessels more prominently than other DHPs; reduction of morbidity in

patients with subarachnoid hemorrhagic stroke)o Nisoldipine

- Effects: all DHPs tend to effect vascular VGCCs more than cardiac VGCCs (use as antihypertensives)- Pharmacokinetics:

o Oral Administration: but bioavailabilty reduced by first pass hepatic metabolismo Metabolism: extensively in the livero Plasma Protein Binding: extensive

- Adverse Effects:o Short-acting agents (ie. nifedipine) cause sudden vasodilation leading to powerful baroreceptor

mediated reflex (increased HR and inotropism, leading to possible development of heart attacks due to increased oxygen demand)

o Flushingo Peripheral edema (pitting in the ankles)o Dizziness

- Drug Interactions:o NSAIDs: do NOT mitigate antihypertensive effects of CCBso Increased metabolism: rifampin, phenytoino Decreased metabolism: azole antifungals

Non-Dihydropyridines: - Drugs in this Class:

o Diltiazemo Verapamil

- MOA: act at different sites in the VGCC than DHPs (more cardioselective)o Verapamil: also has alpha1 blocking properties that contribute to anti-hypertensive effects

- Use:o Treatment of supraventricular tachycardiaso Prevention of ventricular arrhythmias in patients with atrial fibrillation

- Adverse Effects:o Bradycardia and heart failure (due to depression of cardiac contractility)o Cardiac block (due to depression of AV conduction)o Hypotension

- Contraindications:o Patients with cardiac block or systolic dysfunctiono Patients being treated with beta blockers (similar pharmacological actions)o Flushing, pitting edema, dizziness (more common with DHPs)

- Drug Interactions:o Verapamil:

Severe hypotension may occur if used with quinidine (also an alpha blocker) Decreases renal clearance of digoxin (need to lower dose)

NITRATES: Nitroglycerin and Isosorbide Dinitrate:

- MOA: powerful smooth muscle relaxantso Increase NO in SMCs activations guanlyl cyclase to catalyze synthesis of cGMP dephosphorylation

of MLCs and smooth muscle relaxationo Sensitivity is veins>arteries>arterioles>precapillary sphincters

- Effects:

o Increased venous capacitance leads to decreased venous return and resulting decrease in ventricular filling pressure

o Reduce peripheral resistance (action on arteries) leading to reduction in afterload AND redistribultion of coronary flow from epicardium to endocardium (dilation of coronary vessels)

o Also cause relaxation of intestinal, hepatic and renal SMCs (transitory and not used clinically)- Uses:

o Classic Angina: atheromatous obstruction of larger coronary vessels Benefit: reduction of myocardial oxygen consumption

Venous dilation results in decreased venous return to the heart and reduction of intraventricular pressure and ventricle radius

Reduction in end diastolic ventricular pressure results in reduction in coronary flow resistance (improves cardiac perfusion)

Reduction in peripheral resistance results in decreased afterload (less O2 consumption)

o Variant Angina: transient spasm of coronary vessels Benefit: mainly due to dilation of epidural arteries

Redistribution of coronary flow from epicardium to endocardium Prevention of arterial spasm

o Unstable Angina: increased coronary artery tone or non-occlusive platelet clots near AS plaques Benefit:

Decreased O2 demand and coronary artery dilation NO decreases platelet aggregation (important in pathogenesis)

o Heart Failure: Benefit: decrease in preload and afterload

Improves CO and decreases pulmonary congestion (preload)- Adverse Effects:

o Orthostatic hypotension (tends to subside)o Reflex tachycardia (can be treated with beta blockers)o Throbbing headache (meningeal artery pulsations; tends to subside)

- Administration:o Acute Angina: sublingually (avoid first pass metabolism)o Prevention of Angina: orally (increase dose)

- Pharmacokinetics:o Half Lives: isosrbide has a longer half life AND tow active mononitro catabolites (longer duration of

action)o Formulations: nitroglycerin also available as a transdermal patch or ointment o Tachyphylaxis: some patients develop a certain degree of tolerance to nitrates (mechanism unclear)

- Contraindications:o PDE-5 Inhibitors (Viagra): potentiate actions of nitrates and can cause profound hypotension or MI

Newly Approved Agents for Angina: - General: approved for the treatment of classic angina in patients who are still symptomatic after tx with a

combination of more conventional agentso MOA: metabolic modulators that partially inhibit enzyme required for oxidation of free fatty acids in

the myocardium (results in a switch of myocardial metabolism from FFA to glucose oxidation, with reduction of myocardial O2 consumption- FFA oxidation requires more O2 per ATP produced)

- Ranolazine: o Additional MOA: thought to inhibit a late Na current that normally facilitates inward Ca current

(results in reduction of intracellular Ca)o Use: recommended for use in association with nitrates, beta blockers and/or CCBs (only modestly

increases exercise duration alone)o Adverse Effects: most serious is prolonged QT intervalo Metabolism: CYP3A4 in the liver (watch DDIs) o Contraindications: quinidine, sotalol and ziprasidone (all prolong QT interval)o Drug Interactions: potential interaction with digoxin (increased effect of digoxin)

- Trimetazidine

VASODILATORS: General :

- MOA: act directly on arteriolar smooth muscle to produce vasodilation and reduce peripheral resistance- Use: not used alone (cause reflex mediated increase in HR, CO, renin secretion and plasma volume); usually

administered with a beta blocker to reduce these effectso Classic Angina: not great against this because it is an ARTERIOLAR dilator (no effects on coronary

arteries) Coronary Steal: arterioles below AS plaque of obstructed vessel are already maximally

dilated and therefore only mildly responsive to arterial vasodilators while other arterioles downstream from normal coronary vessels are powerfully dilated (result is diversion of blood from ischemic areas angina attacks or MI)

Hydralazine :- MOA: unknown (but relaxes smooth muscle)- Use:

o Complicated HTN (triple combination of hydralazine + beta blocker + diuretic) Rare due to development of lupus-like syndrome or other immune related diseases that are

reversible upon withdrawalo Heart failure (combined with nitrates)

Combination reduces mortality in patients intolerant to ACE inhibitors or ARBs Beneficial effects due to reduction of afterload (improve CO)

Minoxidil :- MOA: induces the activation of ATP-modulated K channel of smooth muscle resulting in K influx,

hyperpolarization and relaxation of arteriolar smooth muscle cells o Leads to enhanced flow from arterial to venous bed and increases venous return (no direct effects on

venous system), leading to improved CO This occurs EVEN when coadministered with beta-blockers and diuretics

- Use: always in triple combination with beta-blockers and diureticso Severe hypertension that is poorly responsive to other agents (esp. those associated with renal

insufficiency secondary to hypertension- usually improves renal function, due to dilation of renal arteries)

- Contraindications: hypertensive patients with left ventricular hypertrophy (increased venous return and poor ventricular compliance can cause increased filling pressure, pulmonary hypotension and possibly heart failure)

- Adverse Effects:o Hypertrichosis (if on the drug for extended periods of time)- exploited for the topical treatment of

male baldness (Rogaine) Diazoxide :

- Use:o No longer used for routine management of HTN (long-term uses causes hyperglycemia due to

inhibition of insulin secretion)o Management of hypertensive crises (rarely)

Needs to be administered by IV bolus or continuous IV infusion Recommended to combine with a beta blocker (enhances hypotensive action and minimizes

reflex tachycardia and increased CO) Sodium Nitroprusside:

- MOA: generates NO via both enzymatic and nonenzymatic pathways (activation GC, increase cGMP, dilation of arterioles and venules)

- Effects:o Reduction of peripheral resistance and afterload (arterioles)o Reduction of preload (venules)o CO Effects:

Reduction of cardiac output in patients with HTN but preserved cardiac function Enhanced CO in patients with severe LV dysfunction

Associated with modest increase in HR and overall reduction in myocardial O2 consumption rate

- Uses:o Hypertensive emergencies (sometimes)o Acute aortic dissection (with a beta-blocker to prevent increase in HR)o Cardiogenic shock secondary to massive acute MI or rupture of papillary muscle

o Induction of controlled hyptension in normotensive patients under surgical anesthesia- PK:

o Decomposes in light (cover solutions with opaque wrapping)o Fast acting (effects disappear within 3 minutes)o High doses/long term treatment can result in cyanide or thiocyanate poisoning (metabolism by SMC)

- Cyanide Accumulation:o CN Thiocynate in the liver, which is eliminated by the urineo CN accumulation more likely to occur in people with impaired renal functiono Can cause severe lactic acidosiso Can be prevented with administration of sodium thiosulfate

AGENTS THAT INCREASE CARDIAC CONTRACTILITY: Digoxin :

- MOA: inhibitor of the Na/K ATPase, causing the accumulation of Na in the cytoplasmo Na removed by the Na/Ca exchanger, causing an increase in cytoplasmic Ca which enters the SERo Increase in release of Ca from SER results in improved efficiency of contractions of the heart without

increasing cardiac work or O2 consumption (positive inotropic effect)o Also directly affects electrical activity of the heart

Duration of ventricular AP shortens (increased K conductance in response to higher Ca++ levels in the cytoplasm)

- Effects:o Increase in CO, reducing stimulus for increased SS tone (reduced HR and vascular tone)o Decreased filling pressure and increased systolic ejection fraction decrease heart size and O2 demando Improved RBF and GFR reduces edema

- Use:o Reduces hospitalization, symptoms and death from progressive heart failure in patients that can be

treated with 1ng or less of digoxin per mL of plasma (higher levels toxic)- Toxicity:

o Fairly selective for cardiac Na/K ATPase (4 isoforms of alpha subunit, which it binds), but first sign of toxicity is the result of inhibition of Na/K ATPase in GI tract and CTZ (N/V/D, anorexia)

CNS effects may also occur (ie. aberrations in color vision)o High doses of digoxin cause membrane potential to become more positive, resulting in the appearance

of DADs (delayed after potentials) Caused by very high Ca load in SER and oscillating Ca levels in the cytoplasm DADs initiate a second contraction (bigeminy) Can eventually initiatie afterpotentials that cause ventricular fibrillation Treated by reducing the level of digoxin using anti-digoxin Fab fragment

o Electrolyte levels determine digoxins effects: Potassium (esp. important)

Hyperkalemia reduces effects (K inhibits binding to Na/K ATPase) Hypokalemia increases cardiac pacemaker rate, AP duration and arrhythmogenesis

o Especially pronounced in ECTOPIC pacemakerso Can occur secondary to diuresis, vomiting, diarrhea

Calcium (hypercalcemia increases risk of arrhythmias) Magnesium (hypomagnesium increases risk of arrhythmias)

- PK:o Safety: very narrow therapeutic window and prone to PK interactionso Absorption: well absorbed orally; some patients require higher doses due to reduced bioavailability as

a result of their GI flora (toxicity may result in these patients if they take Abx- reduce flora) o Distribution: well distributed (including to CNS)o Excretion: largely unchanged in the urine

Quinidine reduces renal elimination (causes toxicity)o Half Life: ~40 hours

Bipyridines :- Drugs in this Class:

o Inamrinoneo Milrinone

- MOA: inhibitors of the isoform of cAMP phosphodiesterase that is found in cardiac and smooth muscleso Increases intracellular cAMP which amplifies cardiac and vascular effects of catecholamines (normally

stimulate activation of AC cAMP)o Results in increased myocardial contraction and vasodilation

- Toxicity: serious toxicities include arrhythmias, marrow and hepatic toxicities - Use: only available as IV agents used exclusively for acute heart failure and temporary management of severe

chronic heart failure Adrenergic Agonists:

- Dobutamine :o MOA: racemic mixture with the predominant effect as an agonist at beta1 and 2 R (mostly beta1)

Isomer action at alpa1 receptors are opposing o Effects: most important pharmacological effect is enhancement of CO (systolic pressure) with little

increase in HR and diastolic pressure (therefore, overall O2 consumption is only moderately increased) Only induces a moderate increase in HR (unclear why) with important increase in cardiac

contractility improved CO Systolic pressure is increased but diastolic pressure is unchanged (no effect on peripheral

resistance)o Use:

Short-term treatment of acute cardiac decompensation after heart surgery Acute heart failure or MI Diagnosis of the presence of coronary obstruction (infusion during ECG useful to induce

segmental alterations of cardiac contraction in people with CAD) o Cautions:

Use in MI may increase size of infarct (increase myocardial O2 demand) Patients with atrial fibrillation (infusion may increase the ventricular response rate- facilitates

AV conduction) - Dopamine :

o Effects: synthesized in epithelium of proximal tubule and seems to exert local diuretic and natriuretic effects

Low Doses: interacts mainly with vascular D1 receptors resulting in smooth muscle vasodilation of renal, mesenteric and coronary beds

Improves renal function (enhances GFR, RBF, and sodium excretion) Medium Doses: interacts with Beta1 receptors (increase HR, contractility and systolic

pressure with no effect on diastolic pressure- no change in peripheral resistance) High Doses: interacts with alpha1 receptors, causing substantial increase in peripheral

resistanceo Use:

Low doses for short-term treatment of severe congestive heart failure associated with compromised renal function

Medium or high doses for the treatment of cardiogenic or septic shock- Isoproterenol :

o MOA: potent non-selective beta R agonist with low affinity for alpha receptorso Use:

Promptly enhances HR and AV conduction in patients with bradycardia or AV blocks while they are prepared to be implanted with an artificial pacemaker

Chronotropic effects also useful in patients with torsades de pointes (facilitate restoration of sinus rhythm)

No longer used for the treatment of asthma and shock (replaced by other sympathomimetic drugs)

DRUGS FOR CARDIAC ARRHYTHMIAS: Cardiac Arrhythmias:

- Cardiac Action Potentials: o SA node: electrical impulses originate here

AP typical of automatic tissue (same for AV node): Depolarization (phase 0) caused by inward Ca current Repolarization (phase 3) due to outward K current (delayed rectifier)

Diastolic potential (phase 4) is unstable resulting in gradual diastolic depolarization (inward Na current partially mitigated by outward rectifying K current)

Diastolic depolarization eventually reaches threshold and accounts for automaticity of SA node

o Ventricular muscle/Atrial muscle/Purkinje Fibers: AP is not automatic (usually- note that all cardiac tissue has the potential to become automatic)

Depolarization (phase 0) caused by inward Na current which inactivate rapidly and depolarizing current is limited by rectifying K channels

Plateau phase maintained by inward Ca current (L-type and some T-type) and outward K current)

Repolarization (phase 3) due to outward K current Diastole (phase 4) is more stable than nodal tissue (balance of inward Na and Ca against

outward K; effects of Na/K ATPase and Na/Ca exchanger also present)o EKG:

P Wave: atrial depolarization QRS Complex: ventricular depolarization (also masks atrial repolarization) T Wave: ventricular repolarization PR Interval: time period between atrial and ventricular depolarizations (AV conduction time) ST Segment: reflects the plateau of the ventricular AP QT Period: period from ventricular depolarization until repolarization

- Mechanisms of Cardiac Arrhythmia: o Altered automaticity:

Abnormal electrical activity can occur if SA nodal rate is pathologically low (ie. after MI) and a latent pacemaker generates escape rhythm

Ectopic rhythms develop when latent pacemakers arise that have faster intrinsic rates than the SA node (due to ischemia, electrolyte imbalance or high SS activity)

o Triggered activity: General: normal action potentials trigger afterdepolarizations Early After Depolarizations: occur when QT interval (ventricular depolarization) is prolonged

and exceeds the refractor period, so that an AP can occur before ventricular repolarization Can lead to torsades de pointes (very dangerous arrhythmia)

Delayed Afterdepolarizations (DADs): occur after ventricular depolarizations (mechanism not well understood)

In the case of cardiac glycoside toxicity (digoxin), related to increased intracellular Ca++

Reflected in the EKG as bigeminyo Defects in conduction:

Re-entry: pathological self-sustaining electrical circuit that stimulates a region of the myocardium repeatedly and rapidly

Must be a barrier to conduction (a region of damaged tissue that will not support normal conduction but will allow retrograde conduction at a slower than normal velocity)

Conduction will flow around the damaged area, and if retrograde flow is slow enough (ie. that the refractory period of normal tissue is past), the returing current can depolarize the tissue (“circus rhythm)

o Conduction block: Action potential fails to propagate because of unexcitable myocardium (drugs, trauma,

scarring, ischemia) Tissue beyond the block is then able to generate escape rhythms

o Accessory pathways: Bypass the AV node Wolf-White-Parkinson Syndome: Bundle of Kent (short circuit between atria and ventricles

that competes with normal pathway) Predisposes the individual to re-entry and tachyarrhythmias

Antiarrhythmic Drugs: - Class I Agents (Na Channel Blockers):

o MOA: blockage of Na channels (not highly selective for Na channels- affect others) Decreases automaticity by reducing the phase 4 slope in the SA node

Increases threshold in the myocardium by decreasing the phase 0 upstrokeo State Dependent: most channel blockers bind to the open and/or inactivated states (dissociate from

resting channels) Therefore, the blockers bind better when firing rate is high (ie. more open and inactivated

channels) Also dissociate more slowly from ischemic tissues (longer depolarization)

o Class IA: Procainamide:

MOA: blocks Na channels (in open state)o Increases threshold of myocardiumo Decreases conduction velocity in myocardium o Prolongs AP (non-specific blockade of K channels) and therefore prolongs

QRS duration Use: usually drug of 2nd choice; should be started in the hospital (as should all class

I drugs)o Atrial and ventricular arrhythmias o Sustained ventricular arrhythmias after MI

Cardiac Toxicity:o Excessive slowing of conductiono Excessive AP prolongationo Prolonged QT interval and induction of torsades de pointes

Other Toxicity:o Long term therapy can cause lupus like disease with anti-nuclear Abs

Quinidine Disopyramide

o Class IB: Lidocaine Mexiletine

o Class IC: Flecainide Propafenone Moricizine

- Class II Agents (Beta Blockers):o Effects:

Reduce HR Increase AV conduction time and PR interval Inhibit afterdepolarization-mediated automaticity

o Use: Prevent ventricular tachycardia due to atrial flutter or fibrillation Prevent recurrences of paroxysmal supraventricular tachycardias

o Agents Used: Esmolol: short half life and can be used by IV for immediate control of atrial tachycardia Sotalol: nonspecific beta blocker that also has K channel blocking properties

Use: for both atrial and ventricular tachyarrhythmias SE: torsades de pointes (due to increased QT interval) Contraindications: Wolf-White-Parkinson Syndrome

- Class III Agents:o MOA: inhibit repolarization of the myocardium by blocking outward K channels

Prolongation of AP (longer QT interval) increases refractoriness and decreases reentry However, also increases EADs and possibly torsades de pointes Treatment should be initiated in the hospital

o Drugs in this Class: Dofetilide (specific K channel inhibitor) Ibutilide (specific K channel inhibitor) Sotalol (also a class II agent) Amiodarone:

MOA: inhibits Na (inactivate state), K and Ca channels; also a powerful alpha and beta blocker (considered class III but has powerful class I and significant class II and class IV properties)

Effects:o Prolongs refractorinesso Increases AV conduction timeo Causes bradycardia

Uses:o Restoring sinus rhythm in atrial tachycardia (oral)o Treating recurrent ventricular tachycardias and fibrillation (oral)

Effects on EKG:o PR, QRS and QT intervals are all prolonged (however, torsades de pointes

is uncommon) Adverse Effects:

o Cardiac: bradycardia, decreased contraction and heart blocko Non-Cardiac:

Pneumonitis leading to pulmonary fibrosis Hyper and hypothyroidism (analog of thyroxin) CNS symptoms

Metabolism: in the liver by CYP3A4 Drug Interactions:

o Inhibits the metabolism of digoxin, warfarin, benzos and other drugso Levels decreased by rifampin (and other inducers of CYP)o Levels increased by cimetidine (and other inhibitors of CYP)

- Class IV Agents (Calcium Channel Blockers):o Verapamil and Diltiazem: block L-type channels in cardiac cells more readily than DHPs

Verapamil: blocks both open and inactivated channels (favors actively firing tissues) Effects:

o Reduces phase 0 of SA and AV nodal APs causing bradycardia and prolonged AV node conduction velocity and refractoriness

o Also suppresses EADs and DADs Uses:

o Reentrant supraventricular tachycardiaso Reduce the risk of ventricular tachycardia due to atrial flutter or

fibrillation Diltiazem: has similar effects Contraindications of Both: Wolf-White-Parkinson syndrome Adverse Effects:

Bradycardia Hypotension Decreased contraction

Drug Interactions: common Beta blockers Raise drug levels of digoxin

- Miscellaneous Agents:o Adenosine:

MOA: binds to P1 purinergic receptors that open G-protein regulated K channels Administration: given rapidly as a bolus (half life of 6 seconds) Effects: inhibits SA nodal, atrial and AV nodal conduction Use: terminate many supraventricular arrhythmias

o Magnesium Sulfate: Use: given by IV

Treat digoxin related arrhythmias (mechanism unclear) Drug induced torsades de pointes (mechanism unclear) Arrhythmias due to hypomagnesia