2013-09-23 Drug Management of Angina Flashcards
What tx goals for angina?
goals:
- reduce O2 demand (wall tension, pre-load, after-load, contractility)
- improve O2 supply (dilate coronaries, improve collateral flow)
- anticipate and try to prevent complications!
What drug classes are useful in treating angina generally?
- -nitrates (trinitroglycerin)
- -beta-blockers (atenolol, metoprolol)
- -CEBs (verapamil, diltiazem)
- -antiplatlet agents (aspirin, clopidogrel)
- -Platlet Gp IIb/IIIa receptor blockersabciximab
What effects does NO have?
a.k.a. EDRF
in addition to vasodilation, inhibit platelet aggregation, phagocytosis, excitatory neurotransmission in CNS
reccently given in ICU for severe pulm HTN
What are Dr. Nierenberg’s 7 Steps to Drug Rx?
- Dx
- understand pathophy
- list whole menu of drugs that could work
- choose best one for individual pt.
- Monitor for outcomes and side effects (e.g. watch LFTs for pts on statins)
- Alliance w/ pt.
What is the “double product”?
a.k.a. rate-pressure product (RPP) or cardiovascular product
RPP = HR * SBP
determines cardiovascular risk of a pt`
Beta-blockers for angina
compare propranolol vs. atenolol vs. metoprolol
–what do they all do?
–what are differences?
all decrease O2 demand by decreasing HR, contractility (and therefore CO, BP and wall tension); also slower HR —> longer diastole —> more time for subendocardium perfusion
differences:
- -specificity: propranolol is non-specific β1 and β2 so be careful in asthmatics; (vs. atenolol and metoprolol are β1-specific)
- -t1/2: atenolol has great t1/2 but metoprolol comes XL
- -clearance: atenolol is renal; metoprolol is hepatic
What can happen w/ abrupt withdrawl of beta-blockers?
very dangerous! can lead to abrupt increase in HR, BP and contractility —> rebound angina and even MI
Nitroglycerin (TNG=trinitroglycerin/NitroStat™; also isosorbide dinitrate, very inexpensive, $4/mo)
[RANG 7.02]
- -drug class
- -PD
- -PK
- -toxicity
- -interactions
- -special considerations
- -routes of admin
• Drug class: pharmacologic class: organic nitrate; therapeutic class: antianginal, vasodilator, venodilator
• Pharmacodynamics: reacts directly with nitrate receptor on SM cell; sulfhydryl groups in receptor reduce organic nitrate (R-ONO2) to NO2 and then NO; NO crosses into SM cells, activates guanylate cyclase, leading to production of cGMP from GTP; cGMP acts to relax SM cells (probably by dephosphorylation of myosin light chains, making them less likely to react with Actin); then produces venodilation and vasodilation
• Pharmacokinetics: well absorbed po, but very high first pass effect; prompt onset (1-2 min) when taken as SL tablet or spray; also can be given transdermally or iv
• Toxicity: excessive hypotension, esp if patient is volume depleted; throbbing headache; flushing
• Interactions: excessive hypotension with other vasodilators; severe hypotension if taken with ViagraTM (sildenafil)[why is that???]
• Special considerations: remove transdermal patch before defibrillation; use only fresh TNG tablets; tolerance can develop quickly (give 8 h holiday each night)
• Indications and dose/route: For angina, 0.15-0.3-0.4-0.6 mg SL tablets, take one
tablet every 5 minutes up to three; also available as transdermal paste, IV
Which CEBs are safest? By what mechanism do they work?
verapamil and diltiazem have been widely used for exertional angina, though UpToDate recommends starting w/ nitrate + beta-blocker and then adding amlodipine rather than verapamil vs. diltiazem
Mechanisms seems to be similar to that of beta-blockers (reduce HR, BP, contractility, wall tension, etc.)
What drug classes are useful in treating vasospastic angina in particular?
nitrates are key tx
–CEBs can also be useful b/c of their direct vasodilating effect
–BETA-BLOCKERS Contraindicated b/c then you have unopposed α1 agonism by catecholamines worsening vasoconstriction
What drug classes are especially useful in treating unstable angina in particular?
What are their basic mechanisms?
tx must include suppression of platelet adhesion and aggregation
- -ASA (permanently blocks COX 1&2 which stops TXA2 production)
- -clopidogrel (ADP receptor blocker on platelets)
- -abciximab (GP IIb/IIIa inhibitor)
Why does low-dose aspirin only really affect platelets and not endothelial cells?
platelets have no nuclei so they cannot continue producing new COX enzymes (which ASA permanently inhibit)
Abciximab/ReoPro™ (also tirobifan/Aggrastat™, eptifibatide/Integrilin™) [RANG Ch. 10] --drug class --PD --PK --toxicity --interactions --special considerations --routes of admin
- Drug class: pharmacologic class–Fab fragment chimeric monoclonal antibody; therapeutic class: adjunct to PCI to prevent ischemic complications; treatment of MI
- Pharmacodynamics:noncompetitive inhibitor of the GP IIb/IIIa receptor, prevents binding of fibrinogen, vWF, and other adhesive ligands to the receptor on activated platelets. Need to block >80% of these receptors to maximially inhibit platelet
- Pharmacokinetics: IV bolus followed by IV infusion; half-life about 30 min. Bleeding time declines to <12 min within 12 h of stopping infusion
- Toxicity: contraindicated in presence of aneurysm, AV malformation, bleeding, coagulopathy, GI bleed, intracranial mass, retinal bleeding, stroke, surgery, low platelets, trauma, vasculitis
- Interactions: Additive effects with aspirin, clopidogrel, heparin, low dose t-PA
- Special considerations: Exact role is still being defined, and evolves over time; cost is a big factor
- Indications and dose: when PCI is planned to treat ACS, 0.25 mg/kg bolus (e.g. 20 mg) followed by 10 mcg/min for 18-24 h
Clopidogrel (Plavix™) [RANG Ch. 10] --drug class --PD --PK --toxicity --interactions --special considerations --routes of admin
- Drug Class: pharmacologic; therapeutic class–platelet aggregation inhibitor
- Pharmacodynamics: Blocks ADP receptors, which then helps prevent aggregation mediated by ADP released by an activated platelet from recruiting other platelets; useful in primary or secondary prevention of TIA, stroke, angina, MI, angioplasty, stent placement, ACS, etc
- Pharmacokinetics: well absorbed, onset 1-2 h after oral dose, hepatic metabolism, half-life ~8h
- Toxicity: hemorrhage at virtually any site;
- Interactions: may inhibit CYP 3A4
- Special considerations: Careful risk/benefit assessment in each patient, AND it’s quite expensive
- Indications and dose: for ACS, LD 300 mg up front, then 75 mg once daily (in conjunction with ASA 81-325 mg daily)
Aspirin [RANG Ch. 10] --drug class --PD --PK --toxicity --interactions --special considerations --routes of admin
- DRUG CLASS: Pharm class–salicylate; therapeutic class–analgesic, anti-inflammatory, antiplatelet, antipyretic, prevention of MI
- PHARMACODYNAMICS: at low doses (<325 mg/day), tends to irreversibly inhibit COX (1) in platelets, leading to decreased formation of TBX A2 (vasocontrictor, platelet aggregator), and transiently inhibit COX(2) in endothelium, leading to transient decreased formation of prostacyclin (PGI2) (vasodilator, inhibitor of platelet aggregation)
- PHARMACOKINETICS: F~60%, Tmax variable (e.g. AlkaSeltzer), metabolized to salicylate, half-life 3-4 h, duration 4-24+ h, 90% excreted as salicylate metabolites in urine
- TOXICITY: especially at high doses can cause ulceration of GI tract, bleeding disorders, tinnitus
- INTERACTIONS: inhibit tubular secretion of methotrexate, potentiate bleeding from warfarin
- SPECIAL CONSIDERATIONS: avoid in patients with nasal polyps and asthma; regular, buffered, enteric coated
- INDICATIONS AND DOSE: for antiplatelet effects, 81-325 mg per day; for arthritis, 2.4-3.6 g/day in divided doses
