Anti-Anginal therapeutics week 2 Flashcards
Major determinants of myocardial O2 demand
walls stress
interventricular pressure
wall thickness
HR
contractility
Nitroglycerin, isosorbide denitrate, isosorbide mononitrate
amyl nitrate, nitro spray
MOA
effects
toxicities
forms of adminstration
LIST the 3 uses of nitrates/nitrites
What type of drug is combined with nitrates/nitrites to combat one of the toxicities?
Explain the tolerance of these drugs
MOA: vasodilation by increasing NO in vascular smooth muscle. Activates guanylyl cyclase–>increase in cGMP–> myosin light chain (MLC) dephosphorylation–>smooth muscle relaxation
Denitrated by glutathione S-transferase to free nitrite, converted to nitric oxide (NO) which activates guanylyl cyclase
Uses: ACS (acute coronary syndrome), angina, pulmonary edema
Effects:
-Coronary dilator - ↑ coronary blood flow
-Arterial dilator – decrease afterload
-Venodilation – decrease pre-load
-Decrease platelet aggregation – NO action
Redistribution of coronary flow to ischemic regions
Toxicities:
- Reflex tachycardia caused by nitrite induced drop in BP can worsen angina (tachycardia can be blocked by ß blockers)
- hypotension, flushing, headache
-Nitrates cause methemoglobinemia – decrease O2 – Hb dissociation
“Monday disease” in ppl that work in nitroglycerin manufacturing plants: development of tolerance for the vasodilationg action during the work week and loss of tolerance on the weekend. With return to work on “Monday”, get tachycardia, dizziness, headache upon reexposure.
Tolerance-decrease in drug effect over time, sulfhydryl group depletion contributes to tolerance development.
Forms of administration:
Nitrates subject to first pass metabolism, so given SL (sublingual), IV, topically to avoid portal circulation and thus avoid first pass metabolism.
Isosorbide dinitrate: Oral formulation of nitrate, longer lasting, need higher dose because of first pass metabolism.
Amyl nitrate – inhaled gas, infrequently used
Nitro spray – used in patients who can’t hold pill under tongue
Nicorandil
MOA
NO release like nitrate
Potassium channel opener (like minoxidil)
Explain the effects of nitrates in the treatment of:
stable angina
vasospastic/Prinzmetal angina
unstable angina
Nitrates in Effort Angina
- Increase coronary flow – coronary dilator
- Decrease preload – venodilator, decreasing O2 consumption
- Reflex tachycardia (bad) – due to baroreceptor sensing BP↓ counteracts benefits of nitrates in angina.
- Increase contractility (may increase O2 Reflex tachycardia (bad) –due to baroreceptor sensing BP↓ counteracts benefits of nitrates in angina.
- Increase contractility (may increase O2 consumption) reflex effect due to ↓BP & ↑ sympathetic discharge; nitrates don’t directly affect contractility.
Nitrates in Variant Angina (vasospastic Angina)
- Coronary vasodilation
- Acute treatment, first line – IV nitro
Unstable angina (rest angina)
- ↑ coronary blood flow
- ↓ preload & afterload
- coronary vasodilator
- Avoid excessive hypotension – can make ischemia worse by decreasing blood flow to below a critical level.
- NO has some anti-platelet aggregation action.
Dihydropyridine Ca2+ channel blockers
MOA
effects
clinical uses (overall as a class)
toxicities
state the relative length of action and uses of nifedipine, amlodipine, nimodipine, isradipine, clivedipine
What are the effects of short acting agents in ischemic heart disease? What type of drug are they typically combined with?
Dihydropyridine Group
Mechanism:
- In vasculature decreases transmembrane calcium current relaxing smooth muscle.
- Selectively bind to α1 subunit on voltage dependent L-type Ca channel in smooth muscle tissue not to cardiac tissue and no binding at SA or AV node (in cardiac conducting system).
- Vasodilation (potent)
Uses (except nimodipine!): Angina, hypertension, Raynaud phenomenon
Toxicities:
- Reactive tachycardia – BP ↓ then ↑ HR (No direct effect on SA or AV node (no effect on cardiac conduction except an indirect effect through SANS activation)
- peripheral edema
- flushing
- dizziness
- constipation
- gingival hyperplasia
Short acting agents (Nifedipine immediate release) increase cardiac mortality in ischemic heart disease pts, may increase O2 consumption, reactive tachycardia – for this reason, usually combined with ß blocker.
Agents:
nifedipine – short acting unless in sustained release formulation
amlodipine – long acting
nimodipine – cerebral blood vessel affinity-prevents cerebral vasospasm in subarachnoid hemorrhage
isradipine – long acting
clevidipine: hypertensive urgency or emergency
nicardipine also in this class
Non-dihydropyridine Ca2+ channel blockers
drugs in this class and the differences in effect btwn them
MOA
effects
clinical uses (overall as a class)
toxicities
What drugs must NOT be combined with non-dihydropryidines and why?
Diltazem and verapamil
Mechanism
- Bind α1 subunit on voltage gated L-type Ca channel
- Act on smooth muscle Ca channels, SA node & AV node & myocardial cell Ca channels (↓ contractility)
Uses: Hypertension, angina, atrial fibrillation/flutter
- Stable angina without ß blockers
- Can worsen heart failure – negative inotropic
- Acute or chronic treatment SVT (I_V & oral preparations_)
- Used to slow AFlutter/AFibrillation reducing the ventricular response to rapid atrial activity by blocking AV Node conduction
- Ca++ mediated ventricular arrhythmias
- EAD – early after depolarization
- DAD – delayed after depolarization
Toxicities: Cardiac depression, AV block, peripheral edema, flushing, dizziness, hyperprolactinemia (verapimil), constipation, gingival hyperplasia
Verapamil – strong effect on SA, AV node & negatively inotropic, used for SVT(AV block), slows ventricular response in AFibrillation (see arrhythmia lecture)
Diltiazem – more vasodilator than verapamil, but strong SA & AV node block
Diltiazem and Verapamil: do not combined with a ß blocker to avoid bradycardia and severe AV block.
Rank the efficacies of the dihydropyridine and non-dihydropyridine Ca2+ channel blockers as it pertains to actions on vascular smooth muscle and the heart.
Vascular smooth muscle:
amlodipine=nefidipine> diltiazem> verapamil
Heart:
verapamil> diltiazem> amlodipine = nifedipine
Verapamil=Ventricle
Explain how B-blockers effect contractility and coronary flow and how these effects can worsen angina.
Explain the clinical benefits of B-blockers in stable, unstable, and vasospastic/Prinzmetal angina.
ß blockers
- Slow HR ↓ O2 consumption-decreases work of the heart
- ↓ contractility (can increase preload & worsen angina-decreased contractility means increased EDV and therefore increased SV for the next systolic contraction)
- ↓ coronary flow – worsen variant angina (blocks β SANS mediated coronary vasodilator, leaving alpha unopposed causing constriction)
Clinical benefits of ß blockers
- effort angina – reduces frequency & severity
- unstable angina (may worsen vasospasm) and thus give with nitrate)
- reduces mortality post MI
- reduces mortality in heart failure
- may worsen vasospastic (variant) angina – leaves alpha unopposed leading to coronary constriction
What is the mechanism of action and clinical use of the following drugs?
ranolazine
ivabradine
Ranolazine – late sodium channel blocker, shortens the plateau phase of active potential, decreasing the time for Ca++ entry, decreasing Ca+ intracellularly, reducing contractility, may also decrease fatty acid oxidation (change myocardial metabolic substrate), decreasing O2 consumption.
- Used as a second line adjunctive therapy for effort angina (not vasospastic).
Ivabradine – bradycardiac drug, IF sodium channel blocker (funny channel) inhibiting the hyperpolarization activated Na channel in SA and AV nodes, slows HR by decreasing automaticity.
- No effect on coronary flow or myocardial contractility.
Explain the following procedures and in what clinical situations they are used:
angioplasty plus stenting
surgical revascularization
intra-aortic balloon counterpulsation
- Angioplasty plus stenting (pushing the plaque aside and then inserting a metal scaffold to prevent medial hyperplasia to cause re-occlusion).
- Surgical revascularization – coronary artert bypass graft (CABG), artery or vein conduit to “bypass” the obstruction in coronary blood flow. Conduit from aorta to area distal to coronary obstruction.
- Intra-aortic balloon counterpulsation for unstable angina used acutely, balloon inserted in descending aorta and it inflates in diastole increasing coronary flow.
MOA and uses of the following drug:
pentoxifylline
Peripheral Arterial Disease & Intermittent Claudication
Pentoxifylline – xanthine derivative
Mechanism of action:
- Red cells more pliable
- Blood viscosity reduced
- Vasodilation
Actions combine to increase blood flow in arterial system to extremities.
Cilostazole, dipyrimadole
Mechanism
clinical use
toxicities
MOA: phosphodiesterase III inhibitor. Increases cAMP in platelets, resulting in inhibition of platelet aggregation; vasodilators.
Clinical use: Intermittent claudication, coronary vasodilation, prevention of stroke or TIAs (combined with aspirin), angina prophylaxis
Toxicity: nausea, headache, facial flushing, hypotension, abdominal pain
MOA and use of sildenafil, tadalfil, vardenafil
What drug must not be taken with these drugs?
What is alprostadil? What is it used for?
Erectile Dysfunction
- Erection requires relaxation of the corpora cavernosa in the penis.
- Parasympathetic nerves release NO, relaxes the smooth muscle of the cavernosa, blood rushes in and penis becomes erect.
- Sildenafil (also tadalafil & vardenafil)– increase cGMP by inhibiting phosphodiesterase isoform 5 (PDE-5) inhibitors. This leads to increase in relaxation of the corpova cavenosa.
- PDE-5 inhibitors potentiate action of nitrates on the vasculature resulting in hypotension (six hour nitrate free interval required before using a PDE-5 inhibitor) or risk severe hypotension
- PDE-5 inhibitors used in pulmonary hypertension
- Alprostadil – PGE1 analog, injected into cavernosa or urethal suppository & works when PDE-5 inhibitors don’t for erectile dysfunction.
