Anti-hypertensives Flashcards
Angiotensin Converting Enzyme (ACE) Inhibitors
Use
- 1st line therapy: HTN, CHF (Post-MI to reduce CHF progression), Mitral Regurgitation
- Delay progression of renal disease → More effective in diabetics
Ang II normal physiology effects
-
Ang II is potent vasoconstrictor: arterial smooth muscle constriction
- Main action mediated via AT-1 G-protein coupled receptor
- Signaling = ↑ Ca2+ release from SR
- Main action mediated via AT-1 G-protein coupled receptor
-
AT-1 receptor effects
- Generalized vasoconstriction (esp afferent arterioles of renal glomeruli)
- ↑ NE release
- Proximal tubular Na+ reabsorption
- Secrete aldosterone from adrenal cortex
ACE Inhibitors
MOA
-
MOA: Block conversion of ang I to ang II in vascular endothelium
- Via interaction w/ zinc ion of ACE (peptidyl-dipeptidase)
- ↓ arterial pressure
- ↓ cardiac work load
ACE Inhibitors
Side Effects
- Highly potent & minimal side effects → good pt compliance
-
Side Effects:
- Prolonged hypotension intra-op (do NOT take AM of surgery!)
- Granulocytopenia
- Hyperkalemia (esp CRI)
- Angioedema
- Persistent cough
ACE Inhibitors
Drug Interactions
- NSAIDs antagonize effects
- Other anti-hypertensives additive effect
ACE Inhibitors
Contraindications
- Pregnancy
- Renal artery stenosis pts may develop renal failure d/t impaired afferent arteriole constriction
Angiotensin II Receptor Blockers (ARBs)
MOA
- Angiotensin II (AT1) receptor antagonists
- MOA: Competitive binding to inhibit action of ang II at its receptor
- Blocks vasoconstrictive actions of ang II w/out effecting ACE activity = ↓ peripheral vasoconstriction
Angiotensin II Receptor Blockers (ARBs)
Side Effects
- Similar to ACEI’s but no significant bradykinin accumulation = no cough side effect
Angiotensin II Receptor Blockers (ARBs)
Contraindications
Pregnancy, Renal artery stenosis
Hydralazine
MOA/Dose
- Vasodilation through activation of guanylate cyclase (interferes w/ action of IP3 mediated Ca++ release from SR) and hyperpolarization
- Produces direct relaxant effect on vascular smooth muscle & ↓SVR
- arteries > veins
- Alter Ca2+ transport in vascular smooth muscles
- Dose 2.5-10 mg IV
Hydralazine
Clinical Uses
- In combo w/ BB and diuretic
- Also, used in CHF (combo w/ isosorbide mononitrate)
- Limits increased SNS activity
Hydralazine
Pk
- Extensive hepatic first pass metabolism
- After IV < 15% appears unchanged in kidney
- Onset: 15 min, give slowly
- Peak: 10-20 min
- DOA: up to 6 hrs
- E½t = 3 hrs
Hydralazine
Side Effects
- Angina w/ EKG changes
- DBP reduced >SBP
- Reflex ↑HR, SV, CO
- Tolerance & Tachyphylaxis
- Na+ & H2O retention
- Lupus-like syndrome
Minoxidil
MOA
- KATP channel opener → hyperpolarization (↓VG-Ca2+ channel activity) & vasodilation
- Directly relaxes arteriolar smooth muscle; little effect on venous capacitance
Minoxidil
Clinical Use
- In combo w/ BB (offset reflex tachycardia) & diuretic (offset Na+ & H2O retention)
- Treat most severe forms of HTN d/t: renovascular dz, renal failure, transplant rejection
- Topically used to treat baldness (side effect hirsutism)
Minoxidil
Pk
- Orally active
- Very potent; activity via active sulfate metabolite
- 90% oral dose absorbed from GI tract
- 10% of drug recovered unchanged in urine
- Peak levels = 1 hr
- E½t = 4 hrs
Minoxidil
Side Effects
- Marked ↑ in HR & CO
- ↑ plasma concentration of NE and Renin
- Compensatory retention of Na+ & H2O
- Weight gain, Edema
- Pulmonary HTN, Pericardial effusion or tamponade
- Compensatory retention of Na+ & H2O
- Hypertrichosis
- Abnormal EKG: Flat or inverted T wave, ↑ voltage of QRS complex
Sodium Nitroprusside (SNP)
MOA
- Direct acting, nonselective peripheral vasodilator
- Relaxation of arterial & venous vascular smooth muscle
- Lacks significant effects on non-vascular smooth muscle and cardiac muscle
- MOA:
- SNP interacts with oxyhemoglobin
- dissociates immediately to form
- Methemoglobin
- Releasing Nitric Oxide (NO) and cyanide
- dissociates immediately to form
- NO activates guanylate cyclase (in the vascular muscle) = ↑ cGMP
- cGMP inhibits Ca++ entry into vascular smooth muscle & increases uptake of Ca++ into smooth ER → Results in vasodilation via NO
- SNP interacts with oxyhemoglobin
Sodium Nitroprusside (SNP)
Effects
-
CV:
- Direct venous & arterial vasodilation, ↑ venous capacitance d/t ↓VR
- ↓SBP, SVR, PVR
- Baroreceptor reflex = ↑HR
- ↑contractility
- Intracoronary steal in MI- damanged areas
- CNS: ↑CBF, ICP
- Pulmonary: Attenuate hypoxic vasoconstriction
- Blood: ↑intracellular GMP→ inhibit platelet aggregation = ↑bleed time
Sodium Nitroprusside (SNP)
Metabolism
- Transfer of electron from Iron (Fe) of oxyhemoglobin to SNP yields
- methgb and an unstable SNP radical where all 5 cyanide ions are released.
- One of these cyanide ions reacts with methgb to form cyano-methemoglobin (nontoxic)
- Remainder metabolized in liver and kidney; converted to thiocyanate
Sodium Nitroprusside (SNP)
Dosage
- 0.3 mcg/kg/min – 10 mcg/kg/min IV
- > 2.0 mcg/kg/min ↑risk toxicity
- Do not infuse max dose >10 min
- Onset: Immediate
- DOA: Short
- Need continuous IV admin to maintain therapeutic effect
- Extremely potent: use A-line
Sodium Nitroprusside (SNP)
Dosing for different clinical uses
- Controlled hypotension: 0.3-0.5 mcg/kg/min not to exceed 2 mcg/kg/min
- HTN crises:
- Infusion 1-2 mcg/kg IV can be given as bolus
- Infusion not to exceed 10 mcg/kg/min
- Cardiac disease:
- ↓ LV afterload, useful for MR, AR, heart failure
- Consider coronary steal
Sodium Nitroprusside (SNP)
Cyanide Toxicity
- Cyanide Toxicity: toxicity occurs due to effects of high plasma concentrations of thiocyanate
- At rates >2 mcg/kg/min for long periods
- Suspect when pt starts demonstrating resistance to hypotensive effects or a previous responsive patient who is unresponsive (tachyphylaxis) at rates >2-10 mcg/kg/min
- May precipitate tissue anoxia, anaerobic metabolism, and lactic acidosis
- Caution in pregnancy
Treatment of SNP-Related Cyanide Toxicity
- Immediately d/c SNP
- 100% O2 despite normal O2 sat
- Sodium bicarbonate to correct metabolic acidosis
-
Sodium thiosulfate 150 mg/kg over 15 min
- Acts as sulfur donor to convert cyanide to thiocyanate
-
Sodium nitrate 5 mg/kg if severe toxicity
- Converts hgb → metHgb, which coverts cyanide to cyanometHgb
SNP: Other Toxicity
- Thiocyanate Toxicityz; Rare → thiocyanate cleared by kidney in 3-7 days
- Less toxic than cyanide
- Symptoms: N/V, tinnutis, fatigue, CNS hyperreflexia, confusion, psychosis, miosis, seizure, coma
- Methemoglobinemia: Rare
- Consider as differential diagnosis in pts w/ impaired oxygenation despite adequate CO and arterial oxygenation
- Phototoxicity
- SNP should be mixed w/ 5% glucose in water and protected from exposure to light.
- SNP is converted to aquapentacyanoferrate in presence of light and release of hydrogen cyanide occurs
- Wrap solution/tubing in foil or dark plastic bag
Nitroglycerin (NTG)
MOA
- Organic Nitrate
- Acts on venous capacitance vessels and large coronary arteries
- Administered IV, SL, PO, transdermal ointment
- MOA:
- Similar to SNP
- Generates NO through a glutathione-dependent pathway which involves glutathione S-transferase
- Requires presence of thio-containing compound to generate NO
- Generation of NO then stimulates cGMP to cause peripheral vasodilation.
- E½t = 1.5 min
- Methemoglobinemia
- Nitrite metabolite oxidizes ferrous ion in Hgb to ferric form which leads to formation of methgb.
- Caution w/ high doses
- Treat w/ methylene blue 1-2 mg/kg IV over 5 min to reconvert methgb to hgb
- Similar to SNP