Exam 2: CV Drugs 3 - VASODILATORS Flashcards

Question

Isosorbide **Mononitrate** onset & duration for each route

Answer 1

* PO * onset: 30-45 min * DOA: \>6 hrs * PO, extended release * onset: 30-45 min also * DOA: \>12-24 hrs

Answer 2

* Antihypertensive drugs –additive effects * Selective PDE-5 inhibitor drugs (avanafil, tadalafil, vardenafil, sildenafil) * Absolute contraindication * Profound potentiation * Possible life-threatening hypotension and/or hemodynamic compromise * *Accumulation of cGMP by inhibiting its breakdown* * Guanylate cyclase stimulating drugs (riociguat) – *increase the production of cGMP* * Other –see text * *Anything that causes* *↑ cGMP will be contraindicated* * **cGMP = vasodilation/relaxation**

Answer 3

* Oral nitrate forms – used for the prophylaxis of angina pectoris * Additional- heart failure in Black patients in combination with hydralazine (direct-acting vasodilator) * Orally - Well absorbed from the GI tract duration of action 6 hours * Metabolism * Dinitrate metabolized to mononitrate form (t1/2=5 hrs) – active metabolite * Mononitrate metabolized (by denitration) to isosorbide to sorbitol - inactive * Regular and extended-release forms * Need appropriate dosing intervals, to allow for nitrate-free period, to avoid tolerance * Disease concerns: similar to NTG * Avoid concomitant use with PDE5 inhibitor drugs * Toxicity similar to NTG

Answer 4

* Family of enzymes that breakdown cyclic nucleotides * Regulate intracellular levels of 2nd messengers cAMP & cGMP * 11 major subfamilies (eg., PDE-3, PDE-4, PDE-5, etc); differ in localization, potential therapeutic targets * Inhibitors – boost levels of cyclic nucleotides by preventing breakdown * Older, non-selective drugs that inhibit PDE: caffeine, theophylline Boost both cAMP and cGMP

Answer 5

* *PDE3 breaks down cAMP. So by inhibiting it you have MORE cAMP - more inotropy/chronotropy/vasodilation* * drug * amrinone * milrinone * distribution * broad * includes heart and VSMC * substrate * cAMP * cGMP * fn * cardiac contractility, plt aggregation * inhbiitor clinical use * inotrope + peripheral vasodilator * limited for acute HF * cliastazol is used for intermittent claudication

Answer 6

* drug * roflumilast * distribution * broad * includes CV, neural, immune/inflammatory * substrate - cAMP * fn * immune, inflammatory * inhibitor clinical use * COPD - decreases inflammation & remodeling

Answer 7

* *remember that PDE5 breaks down cGMP, so by inhibiting this enzyme, you have MORE cGMP* * drug * sildenafil * tadalafil * vardanafil * distribution * broad * VSMC, esp erectile tissue, retina, & lung * substrate - cGMP (relaxer!) * fn * VSMC relaxation (esp erectile tissue, lung) * inhibitor clinical use * ED * pHTN

Answer 8

* Ca++-channel activation * ↑ cytosolic Ca++ * actin-myosin-troponin interaction * **positive inotropy and chronotropy** * cAMP-dependent protein kinase * ↑ phosphorylated phospholamban * augmented Ca++ uptake by SR * **vasodilation** **PDE3 inhbitors prevent the breakdown of cAMP** "I went to cAMP when I was 3 (PDE3), no one knows why"

Answer 9

* Clinical Uses * Acute heart failure or severe chronic HF * cardiogenic shock (off-label) * heart transplant bridge or post-op (off-label) * PK * Onset (IV) 5-15 minutes * Half-life ~3-6 hrs * Parenteral only * Majority not metabolized; \>80% excreted renally unchanged * Note: amrinone another PDE3 inhibitor was withdrawn from market in US

Answer 10

* Effects * Inotropic, ↑ cardiac contractility * Vasodilation * Little chronotropic activity * Adverse effects * Arrhythmias * Hypotension

Answer 11

* ***Is an enzyme****, not named like most are named -ase* * Secreted by the JG Apparatus * Vasoconstriction and sodium retention * Goal - maintain tissue perfusion through increase extracellular fluid volume * RAAS is synergistic with SNS by increasing the release of noradrenaline from the sympathetic nerve terminals * SNS: sympathetic nervous system * ACE think -ase – enzyme that converts ANGI to ANG II

Answer 12

* Regulates tissue perfusion, blood pressure, electrolytes & fluid * Remember the B1 action of renin in the kidney!! SO metop would block this * *Remember that ACE = kininase II !* * *Also breaks down bradykinin, which causes vasodilation* * *Prevents vasodilation* *→ increases vasoconstriction* * *ACE located in membrane of endothelial cells*

Answer 13

* Renin * formed/secreted from JG cells * rel stimulated by decrease BP or Na+, B1 rec activation * protease - cleaves angiotensinogen to form... * Angiotensin I * inert * ACE (kininase II) * broad protease action - forms ANG II from ANG I * metabolism of BKN to inactive form * located in the membrane of EC cells (??) * ANG II * vasoconstriction (AT1 receptor) * aldosterone secretion (AT1 receptor) * other: increases ADH, increases proximal tubule Na+ reabsorption * Aldosterone * steroid; adrenal cortex * regulates gene expression, increases Na+ reabsorption * H2O retention, K+ excreted (??? what)

Answer 14

* GPCR * subtypes: AT1 R, AT2 R * Current antagonist drugs block AT1 R * AT1R * reg of BP * reg of body fluid balance * vasoconstriction * inflammation * plt aggregation/adhesion * ROS production * proliferative * hypertrophy * fibrosis * AT2R * natriuresis * neuronal activity * vasodilation * anti-inflammation * pro-apoptotic * antioxidative * anti-hypertrophic * anti-fibrotic

Answer 15

* B1AR antagonists (metop) * block SNS stimulation at renal JGC * Renin inhibitor * prevent Renin from converting Angiotensinogen to ANG I * ACE inhibitor (enalapril, lisinopril ...) * prevents ACE from converting ANG I to ANG II * ANG II Receptor Antagonists (ARB) (Losartan, valsartan) * prevents ANG II from binding to AT1 subtype of ANG II receptor * Aldosterone Antagonists (spironolactone, eplerenone) * prevents increase in aldosterone * AT1 can be blocked by ARBs also!

Answer 16

* MOA * prevents ACE from converting ANG I to ANG II * prevents ACE from converting bradykinin (BKN) to its inactive form * Effects * decrease in ANG II * vasodilation * ↓ remodeling * ↓ aldosterone (↓ Na/H2O retention, ↑ K+ retention) * ↓ SNS output * ↑ natriuresis * increase in bradykinin * vasodilation * cough * angioedema * *The blocking of BKN breakdown is what contributes to the bad SEs of ACE inhibitors* * d/c the drug if they have angioedema/cough

Answer 17

* Endogenous peptide * T1/2 = 17 sec * Constitutive actions: * Stimulates NO & prostacyclin formation * Vasodilation (heart, kidney, microvascular beds) * Inflammatory actions: * capillary permeability

Answer 18

* generic name (Brand) * Captopril (Capoten) * Benazepril (Lotensin) * Enalapril (Vasotec) * Fosinopril (Monopril) * Lisinopril (Zestril, Prinivil) * Moexipril (Univasc) * Perindopril (Aceon) * Quinapril (Accupril) * Ramipril (Altace) * Trandorapril (Mavik)

Answer 19

* Mechanism of Action * Block the conversion of Angiotensin I to Angiotensin II * Prevent vasoconstriction * Prevent aldosterone secretion, decreasing sodium and water retention * First-line therapy * HTN * CHF * Mitral Regurgitation * More effective in diabetes mellitus pts * Delay progression of renal disease

Answer 20

* Clinical effects * ¯ BP, peripheral vascular resistance * ¯ preload, afterload * ¯ cardiac workload * Do not result in reflex tachycardia (compared to the direct vasodilators * improves/prevents LV hypertrophy, remodeling * improves morbidity/mortality HF * diabetic nephropathy-delays progression (improves renal hemodynamics) * Common Clinical Uses * \*HTN - *most commonly used for* * Post MI * \*HF (systolic dysfxn) * Diabetic nephropathy

Answer 21

* Metabolism & Elimination * Many are pro-drugs → Enalapril & ramipril – ester prodrugs (plasma conversion) * Usually renal * Oral dosage forms * Exception: enalaprilat (IV) * Lots of combo (+ diuretic, etc.) * Drug Interactions * K+ sparing diuretic * K+ supplements

Answer 22

* CV * Hypotensive sx’s, syncope * “1^st dose effect” possible – *more significant hypotensive effect initially* * Electrolyte * • HYPERkalemia * Caution with K+ sparing diuretics & K+ supplements * Renal * ¯ GFR, BUN & serum Cr, renal dysfxn * Contraindicated – bilateral renal artery stenosis (they have↑ ANGII to promote BF, so if you block that it might be bad) * Inflammatory * Dry cough (~5-20%), reversible if d/c’d; BKN-related * Not self-limiting * Angioedema (~1%); BKN-related – they would be taken off this if this happened * Ex of pt who had stopped ACE inhibitor before surgery, and got the angioedema when they restarted it * In surgery/anesthesia--can result in prolonged hypotension * Neutropenia/agranulocytosis (captopril) * Proteinuria

Answer 23

* **Fetal malformations - teratogenic** * **Contraindicated in pregnancy** * Seen effects in 1^st trimester, but more profound effects during 2^nd and 3^rd trimester * **Any drug that works on the RAAS system – ACE inhibitor, ARB** * Neonatal * Skull hypoplasia * Anuria * Hypotension, death

Answer 24

* renal artery stenosis * Renal artery stenosis patients may develop renal failure due to efferent arteriole constriction

Answer 25

* C A P T O P R I L * Cough/C1 esterase deficiency (contraindication) * Angioedema/Agranulocytosis * Proteinuria/Potassium excess (hyperK+) * Taste change * Ortho hypoTN * Pregnancy (contraindication – fetal renal damage) * Renal artery stenosis (contraindication) * Increases Renin * Leukopenia/Liver toxicity

Answer 26

* generic name (Brand) * Azilsartan (Edarbi) * Candesartan (Atacand) * Eprosartan (Teveten) * Irbesartan (Avapro) * Losartan (Cozaar) * Olmesartan (Benicar) * Telmisartan (Micardis) * Valsartan (Diovan, Prexxatran)

Answer 27

Again, have extensive T1/2 * Mechanism * Competitive antagonist @ AT1 rec * Blocks effects of Ang II mediated by AT1 rec * Does not block breakdown of BKN – thus BKN does not accumulate * Clinical Effects & Uses • Similar to ACEi * PK * Varies with various agents * Metabolism - CYP 450 enzymes * CYP2C9 - losartan, irbesartan

Answer 28

* Adverse effects * similar to ACEi (see ACEi list) * Less frequent … * Cough (~30% rate of ACEi) * Angioedema (rare) * Interactions * K+ sparing diuretics * K+ supplements * Contraindication * renal artery stenosis * pregnancy

Answer 29

* Efficacy in HTN - No differences * Total mortality * CV morbidity, mortality (cardiac, stroke) * ARBs slightly more tolerable, less likely to be discontinued * Main reason: ¯ dry cough (~1% vs 4%) * ACEi – higher quality of data * ARBs no comparison vs placebo (ARBs compared to ACE inhibitors, but never really against the placebo)

Answer 30

* Mechanism * Competitive antagonist at mineralocorticoid rec (kidney, but also heart, blood vessels, brain) * Prevent nuclear translocation of rec * Blocks transcription of genes coding for Na+ channels * Spironolactone -- Off-target effects include androgen, progesterone rec blocking * Often combined with non-K-sparing drugs to offset the K+ excretion * Effects * Na+ , H20 excretion, mild diuresis * K+ reabsorption * Uses * HTN, HF * K+ sparing diuresis * 1° hyperaldosteronism * Spironolactone, off-label * Acne, hirsutism, PCOS

Answer 31

* PK - Metabolism (both hepatic, just different enzymes) * Spironolactone * Hepatic * active metabolites-canrenone & 7- alpha-spironolactone (t1/2 : 12-20 hrs) * P-gp inhibitor * Eplerenone • CYP3A4 * AEs include… * Hyperkalemia * Spironolactone—broad; includes hepatic, renal, serious derm (S-J, TEN, etc), GI, gynecomastia, menstrual irregularities, tumorigenic in animals * Blocking androgen and progesterone * Drug Interactions * Other K+ sparing (e.g., ACEi, ARBs, etc.) * K+ supplements * NSAID ( renal risks) * Eplerenone - CYP3A4 inhibitors

Answer 32

* Mechanism of action * Release of NO from endothelial cells * Inhibition of Ca release from SR? * Effects * Vasodilates arterioles * Minimal venous effect * Decreased SVR * DBP reduced \>SBP * Increase HR, SV, CO * PK * Extensive first-pass * Bioavailability ~25% * Half-life 1.5 – 3 hours

Answer 33

* Clinical uses * Hypertension * Usually in combination with beta blocker & diuretic (to limit SNS effects) * HF – reduced ejection fraction (off-label) * Adverse effects * Headache, nausea, palpitations, sweating, flushing * Reflex tachycardia, tolerance/tachyphylaxis * Sodium and H20 retention * Angina with EKG changes – *r/t reflex responses in response to vasodilation* * Lupus erythematosus (reversible) * Rash, arthralgias/myalgias, fever – reversible * Used in combo with _______ isosorbide? * Particularly effective in Black patients * Not a lot of orthostatic hypotension * Contraindication * CAD, mitral valve RH disease

Answer 34

* Mechanism of action * Directly relaxes the arteriolar smooth muscle little effect on venous capacitance * increases the efflux of potassium from vascular smooth muscle resulting in hyperpolarization and vasodilation * Effects * Dilates arterioles, not veins * Use in hypertension (limited to later-line therapy due to risk-benefit profile) * PK * 90% oral dose absorbed from the GI tract * Peak effects 2-3 hours * Half-life ~ 4 hours * 10% of drug is recovered unchanged in the urine

Answer 35

* Clinical uses * Hypertension—later line therapy * Usually in combination with beta blocker & diuretic (to limit SNS effects) * Adverse effects * Tachycardia, increased myocardial workload * Palpitations, angina * Sodium/fluid retention, edema * Weight gain * hypertrichosis = excessive hair growth , vasodilation/stimulation of resting hair follicles * Warnings * Fluid retention * Pericardial effusion/tamponade * Rapid BP response * Sinus tachycardia * Elderly

Answer 36

* Direct acting , nonselective peripheral vasodilator * Relaxation of arterial and venous vascular smooth muscle * Lacks significant effects on nonvascular smooth muscle and cardiac muscle * Mechanism of action * SNP interacts with oxyhemoglobin * dissociates immediately to form * Methemoglobin * Releasing Nitric Oxide (NO) and cyanide * Nitric Oxide activates guanylate cyclase (in the vascular muscle) thus increasing cGMP * cGMP inhibits calcium entry into vascular smooth muscle but increases uptake of Ca into the smooth Endoplasmic Recticulum. * Results in vasodilation via NO * Metabolism * Transfer of an electron from the Iron (Fe) of oxyhemoglobin to SNP yields → metHGb and an unstable SNP radical * Unstable SNP radical breaks down → all 5 cyanide ions are released. * One of these cyanide ions reacts with metHGb to form cyanomethemoglobin (nontoxic) * Remainder are metabolized in the liver and kidney → converted to thiocyanate

Answer 37

* Toxicity: occurs due to the effects of high plasma concentrations of thiocyanate * Cyanide Toxicity * Can occur at rates \>2ug/kg/min for long periods * Suspect when the pt starts demonstrating resistance to hypotensive effects or a previous responsive patient who is unresponsive (tachyphylaxis) at rates \>2-10 ug/kg/min * May precipitate tissue anoxia, anaerobic metabolism, and lactic acidosis * Treatment of Cyanide Toxicity * Immediate discontinuation of SNP * 100% 02 administration despite normal oxygen saturation * Sodium bicarbonate to correct metabolic acidosis * Sodium thiosulfate 150mg/kg over 15 minutes * Sodium thiosulfate Acts as a sulfur donor to convert cyanide to thiocyanate * Sodium nitrate 5mg/kg if severe toxicity * Converts hemoglobin to metHgb which coverts cyanide to cyanometHemoglobin * Thiocyanate Toxicity * Rare as thiocyanate is cleared by the kidney in 3-7 days * Less toxic than cyanide * Symptoms include: * N/V, tinnutis, fatigue, CNS hyperreflexia, confusion, psychosis, miosis seizure and coma * Methemoglobinemia * Rare * Should be considered as a differential diagnosis in patients with impaired oxygenation despite adequate cardiac output and arterial oxygenation * Phototoxicity * SNP should be mixed with 5% glucose in water and be protected from exposure to light. * With continuous exposure to light SNP is converted to aquapentacyanoferrate in the presence of light and the release of hydrogen cyanide * Wrap the solution and tubing in foil or dark plastic bag.

Answer 38

* 0.3ug/kg/min - 10ug/kg/min IV * Max dose: should not be infused for greater that 10 minutes * Immediate onset * Short duration of action * Requires continuous IV administration to maintain therapeutic effect * Extremely potent: use A-line

Answer 39

* CV: * Direct venous and arterial vasodilation, decreased venous capacitance due to venous return Baroreceptor mediated reflex responses increased HR * ↓ SBP, ↓ SVR,↓ PVR, contractility, causes an intracoronary steal in areas of damage associated with MI; decreased diastolic BPàdecrease coronary perfusion * CNS: * ↑ CBF, and ICP with modest decrease in MAP or with greater decrease in MAP can reduce cerebral blood flow (caution with carotid disease) * Pulmonary: * Attenuation of hypoxic vasoconstriction. * Blood: Increases in intracellular GMP → inhibit platelet aggregation and increase bleeding time

Answer 40

* Controlled hypotension: 0.3-0.5ug/kg/min not to exceed 2 ug/kg/min * Hypertensive crises: infusion 1-2ug/kg IV can be given as bolus * Cardiac disease: * decreases LV afterload, benefits management of MR or AR, CHF, and heart failure. * Consider coronary steal

Answer 41

NO BB therapy reduces perioperative MI

Answer 42

NO Benefits outweigh risks, UNLESS severe LV dysfn -no good evidence one way or the other

Answer 43

YES Withholding for 1 dosing interval (best if they don’t take the night before) Dr. Walker: *Give them back their RAAS! They need some compensatory mechanism*

Answer 44

NO risk for rebound HTN if you hold it

Answer 45

Ca-channel blockers – reduced inotropy Inhalational agents will cause myocardial depression Potential that it can improve outcomes? **Prolongs paralytics**

Answer 46

* Indications: Minimize blood loss, fluid replacement and electrolyte disturbances * Think of surgery that has high expected blood loss, and someone who you don’t want to/can’t transfuse * Antibodies * Jehovah’s witness * Pre-transplant * Severe CAD – avoid losing blood * Pt Refuses * Not used as much today * Stroke * POVL * Keep them within 20% of their b/l range * Still use – jaw/dental surgery on young pts (16-21 yo) – their SNS system works! * Reduce MAP to pre-determined level * 50-60 mm Hg; may need higher MAP * Maintain cerebral and renal blood flow and autoregulation * Arterial line is REQUIRED * Ways to do it * Increase inhalational agent * SNP

Answer 47

* Sodium Nitroprusside: 0.3-0.5mcg/kg/min not to exceed 2 mcg/kg/min (really high dose, usually ≅ 1 mcg/kg/min – and that’s for a carotid case) * More Arterial * Hypertensive crises: infusion 1-2mcg/kg IV can be given as bolus * Nitroglycerin: 125-500 mcg/Kg/min * More venous * Nicardipine: 5mcg/kg/min * Dexmedetomidine: 0.2-0.7mcg/kg/hr * Decreases release of NE * No amnesia * Propofol infusion – vasodilation * Labetalol/B-blockers IVP * Alpha and beta * 15-1 hr? Will get you thru the surgery, but be careful bc it will stick around * Will often see asthma in young ppl – bronchoconstriction B2 blockade * Esmolol – higher doses = non-selective, and **so short acting that you’ll have to keep re-dosing it** * \<10 minutes

Exam 2: CV Drugs 3 - VASODILATORS Flashcards

(72 cards)