drugs for ischemic heart dz Flashcards
evidence based tx for ischemic heart disease
Lipid-lowering drugs Anti-platelet agents
ACEI (HOPE and PEACE trials - CAD without HF)
Beta-blockers – reduce mortality post-MI
SX control for ischemic heart disdease
Nitrates Calcium antagonists
Beta-blockers
what two things do you need to consider when tx ischemic heart dz
reducing disease process and sx control
sxs of myocardial ischemia is usually secondary to
atherosclerosis of the coronary arteries
prinzmetals variant angina
normal coronary arteries but with spasms
seen in younger women in the morning
can be seen with CAD variant
New angina at rest or an increase in angina intensity, frequency, or duration
Unstable angina:
Occurs in patients without coronary artery disease and is due to a spasm of the coronary artery resulting in decreased myocardial blood flow
Classic Prinzmetal’s variant angina or vasospastic angina:
Coronary vasospasm occurring at the site of a fixed atherosclerotic plaque
Mixed angina:
Transient change in myocardial perfusion, function, or electrical activity; can be detected on an ECG in most anginal patients; patient does not experience chest pain or other signs of angina
Silent myocardial ischemia:
<50% asthersclerotic plaques will present with what sxs
Usually asymptomatic < 50%
Symptomatic at >70% obstructed
50-70% obstructed +/- sx
most txs for ischemic heart dz work by
decreasing oxygen demand
myocardial oxygen demand is determined by
wall stress
heart rate
and contractility
which are all variants of workload
wall stress that determines work load
Intraventricular pressure = blood pressure
Wall force – ventricular volume
Wall thickness
MLCK
how does it work and what drugs act on this
myosin-LC kinase when active can promote the phosphorylation of myosin LC and when phosphorylated they combine with actin to cause contraction
dephosphorylation causes relaxation
Ca activates this phosphorylation
which is how CCB and BB work in this way as well
how do nitrates work
increase cycle cGmP and increase dephosphorylation of myosin –> vasodilation
Decreasing intracellular Ca++ -
increase dephosphorylation
cause vasodilation
if we can block calcium in the cell what effect will it have on the cell
decrease contractily
alpha 1
heart
alpha 2
all over
beta 2
increase deactivation and cause vasodilation
Nitrates cause what effect in the body
Decrease venous return to heart, and therefore decrease workload
Promote coronary vasodilation, even with atherosclerosis
nitrates contraindicated with viagra why?
sidenafil increases cGMP
through another mechanism
can’t take with nitrates b/c of unsafe drops in blood pressure
BB would cause a higer risk or orthostatic HTN with nitrates because
blocks compensatory tachy response
sxs of nitrates
Orthostatic hypotension, syncope, temporal artery pulsations, throbbing headache d/t meningeal artery pulsations, compensatory sympathetic response (tachycardia, increased cardiac contractility), compensatory renal response (Na and water retention)
Isosorbide mononitrate
metabolite of isosorbide dinitrate
Amyl nitrite
adm and onset
onset .5 mins
duration
3-5 mins
inhalent
Nitroglycerin
routes of adm
IV
sublingual
translingual
Isosorbide dinitrate
sublingual 2-5 minutes
lasts 1-2 hours
NTG
Topical Ointment
30 - 60
2 – 12 hr
Transdermal
30 - 60
up to 24h
Isosorbide mononitrate
routes of adm
PO, SR
this is what most people use
onset 30-60 minutes
duration 12-24 hrs
short acting nitrates are used to
Short acting used to abort acute anginal episodes
long-acting nitrates are used for
Long-acting formulations used as to prevent angina (maintenance therapy)
what is nitrates used for in unstable angina
Both reduced cardiac workload and coronary artery dilation and redistribution of coronary blood flow to ischemic areas
instructions for use of NTG
Sit down
Place tablet under tongue; do not swallow; may tingle
Pain usually relieved in 3-5 minutes; if not, seek emergent medical care (call 9-1-1); may take second tablet
May repeat every 5 minutes for total of 3 doses over 15 minutes
Optimal NTG Sl dose should relieve pain and produce objective hemodynamic response seen as what bp change
Optimal NTG Sl dose should relieve pain and produce objective hemodynamic response: 10 mmHg fall SBP or 10 beat/min increase HR
MOA of NTG
NTG is broken down to NO and NO activates GMP in smooth muscle which leads to an increase in cGMP which acts to relax muscle contraction and leads to vasodilation
when should you replace NTG
befor 6 months
what might you want to consider with routes of administration for older pts
older people with tremors can have difficulty with pills
spray can be helpful
NTG IV dose
5 mcg/min, titrate by 5-10 mcg/min to effect
NTG Sl dose
0.3 – 0.6 mg/tab
Transdermal dose NTG
0.1 – 0.8 mg/hr release rate
why do you want to take nitrate breaks
only wear patch when you see most common angina attacks
need break because people build up tolerance
ADE of NTG
” Orthostatic hypotension (d/t diifulties maintaining venous tone, especially when stands up) , severe in ETCH
“ Syncope
“ Temporal artery pulsations (increase HR reflex d/t decrease vagal tone)
“ Throbbing HA, compensatory sympathetic and renal responses
“ PD5s will potentiate Nitrates hypotensive effect
SL:
- Warmth
- Flushing, lightheadedness, faint,
- Tachycardia
- HA (sot start low & slow), sublingual burn
Drug interactions with NTG
alcohol
hottub
PD5s
other uses for nitrates besides angina
Ointment used topically for anal fissures and hemorrhoids
MOA of CCB
“Binds L-type Ca channel in cardiac and smooth muscle
- ->reduction in Ca current
- -> relaxed smooth muscle (↓afterload!), ↓contractility, ↓HR (SA & AV node via T-type)
varaible effects at the heart
Areterioles > veins
which two CCB have greater cardiac effect
Diltiazem, verapamil greater decrease in HR
NTG more vein or arteriole dilation
more vein dilation
CCB more veins or arteriole dilation
arterioles
which two CCB are more selective for cerebral blood vessels
Nimodipine, nicardipine more selective for cerebral blood vessels – nimodipine not available in US
CCB are used for
HTN and angina
Raynaud’s (off label)
HA (off label)
Reduces myocardial oxygen demand
“
Raynauds
in Raynaud’s phenomenon, smaller arteries that supply blood to the skin constrict excessively in response to cold, limiting blood supply to the affected area
why do we see increased contractility in some CCB
which one do you see this with the most
reflex response
seen most common in Nifedipine
ADE of CCB
" All from vasodilating effect:
" Peripheral edema
" HA
" Dizziness
" Nausea
" Constipation (30%
w/rapper)
" Bradycardia
"
" DO NOT USE diltiazem or verapamil in CHF d/t decrease myocardial contractilitypathophys of CCB
reduces oxygen demand through peripheral vascular resistance
can reduce spasms in arteries
names of CCB
V-rapper
verapamil
Dil pickle
Diltiazem
Nimodepine
knee moped
Knee fed pine
Nifedpine
Felod pine
which CCB should you not use in HF and why?
” DO NOT USE diltiazem or verapamil in CHF d/t decrease myocardial contractility
CCB: Drug Interactions CI
Beta-adrenergic blockers: cardiac effects of both drugs may be increase
Digoxin: DIGOXIN effects may be enhanced. Increased
DIGOXIN levels and toxicity could occur. Verapamil > diltiazem.
HMG-CoA RI: Plasma concentrations of certain HMG-CoA REDUCTASE INHIBITORS may be elevated, increasing the risk of toxicity (eg, rhabdomyolysis, myositis).
Quinidine: Hypotension, bradycardia, ventricular tachycardia and AV block may occur (verapamil > diltiazem)
Carbamazepine: Serum
CARBAMAZEPINE levels may be increased, resulting in an increase in pharmacologic and toxic effects
Rifampin: Loss of clinical effectiveness of oral VERAPAMIL or DILTIAZEM; due to increased first-pass hepatic metabolism
drug interactions with verapmil
Calcium products: pharmacologic antagonism; Clinical effects and toxicities of VERAPAMIL may be reversed by CALCIUM
Ethanol: Increased and prolonged CNS effects of ETHANOL affecting coordination and judgment. Possibly due to inhibition of ethanol metabolism
Diltiazem CI
Aminophylline: The pharmacologic and toxic effects of THEOPHYLLINES may be increased.
Nifedipine, felodipine CI
Barbiturates: decreased serum NIFEDIPINE and FELODIPINE concentrations, possibly reducing efficacy. Enhanced metabolic clearance caused by enzyme induction.
Cimetidine: the effects of NIFEDIPINE and FELODIPINE may be increased. hepatic metabolism of NIFEDIPINE may be decreased.
Melatonin: may interfere with the antihypertensive effect of NIFEDIPINE.
Felodipine
CI
Grapefruit juice: Serum FELODIPINE concentrations may be elevated, producing an increase in both pharmacologic and adverse effects.
Erythromycin: The pharmacologic and adverse effects of FELODIPINE may be increased.
HYDANTOINS: The pharmacologic effects of FELODIPINE may be decreased. The metabolism of FELODIPINE may be increased because of induction of mixed-function oxidases by HYDANTOINS, causing an increase in first-pass metabolism and decreased bioavailability.
MOA of BB
Competitively inhibit beta adrenergic receptor
three main CV effects of BB
Lower BP; negative inotropic and chronotropic effects resulting in reduced cardiac output ( heart primarily beta 1 receptors, 10-40% beta 2 receptors)
Vascular effects: Oppose beta 2-mediated vasodilation
Antagonize release of renin
(neurohormonal)
Respiratory BB effects
blockade of beta2 receptors may increase airway resistance
eye effects of bb
beta receptor blockade reduces IOP by decreasing aqueous humor production
Metabolic effects of BB
Inhibit sympathetic nervous system stimulation of lipolysis
Glycogenolysis in liver partially inhibited; may impair recovery from hypoglycemia
Lipids: increased TG and decreased HDL; less with ISA
BB problem with hypoglycemia
will block feelings of hypoglycemia
how do BB help with angina ?
Reduced cardiac workload and oxygen demand
Slowing and regularization of heart rate may contribute – improved coronary artery filling during diastole
Timolol, propranolol and metoprolol prolong survival following myocardial infarction
which three BB prolong survival following MI
Timolol, propranolol and metoprolol
what tx should you use first for long term tx of angina
bb Generally should be used before nitrates and CCB for long-term tx
____ more effective at lowering incidence of anginal episodes
BB more effective at lowering incidence of anginal episodes
____ most effective at preventing silent ischemia
BB most effective at preventing silent ischemia
___lower mortality in HTN, HF, post-MI
BB lower mortality in HTN, HF, post-MI
What BB have been indicated for angina
atenolol, metoprolol, nadolol, propranolol
What BB have been indicated for HTN
all except sotolol and esmolol
BB for SVT, sinus tachycardias, intraoperative HTN/tachycardia:
SVT, sinus tachycardias, intraoperative HTN/tachycardia: esmolol (IV), others PO
BB for Ventricular arrhythmias
sotolol
bb for SVT and ventricular arrhythmias:
propranolol
BB for Migraine prophylaxis
: propranolol, timolol (also atenolol, metoprolol, nadolol)
BB Post-MI
: atenolol, metoprolol, propranolol, timolol
Systolic HF BB
metoprolol, carvedilol, bisoprolol
Others:
ISA
intrinsic sympathomimetic activity
partial agonist
but antagonist
which BB reduces late Na current that facilitates Ca entry via Na-Ca exchanger and has nitric oxide-induced vasodilatory properties
Nebivolol
BB w/ alpha-1 adrenergic blocking effect
Carvedilol**
this BB can be titrated quickly to manage bp due to quick half life and RBC esterase metabolism
Esmolol
ADE of BB
Bradycardia, will worsen HF if we don't go low and slow Bronchospasm Impaired peripheral circulation " ↓exercise tolerance " Worsening angina if abrupt D/C "
Worsening HF if dosed incorrect
” Well tolerated
“ HA, nausea, bradycardia
would caution use of BB in DM pt on
sulfonaurias or insulin
BB di
Cimetidine, quinidine, diphenhydramine, food
NSAID’s
Clonidine
Agents that induce hepatic enzymes (rifampin, barbiturates):
Verapamil, diltiazem: heart block
Sympathomimetics, ergot derivativeS
Sympathomimetics, ergot derivatives DI with BB
: unopposed alpha adrenergic-mediated or ergot-mediated vasoconstriction
Agents that induce hepatic enzymes (rifampin, barbiturates) are CID w/ BB b/c
decrease efficacy of hepatically metabolized
beta blockers
clonidine is CI w/ BB b/c
additive bradycardia; beta-blocker inhibition of beta2 receptor mediated vasodilation leaves peripheral alpha receptor mediated vasoconstriction unopposed during clonidine withdrawal. Management:Closely monitor blood pressure after initiation or discontinuation of clonidine or a beta-blocker when they are given concurrently. Discontinue either agent gradually; preferably, discontinue the beta-blocker first.
why is NSAID CI with BB
additive bradycardia; beta-blocker inhibition of beta2 receptor mediated vasodilation leaves peripheral alpha receptor mediated vasoconstriction unopposed during clonidine withdrawal. Management:Closely monitor blood pressure after initiation or discontinuation of clonidine or a beta-blocker when they are given concurrently. Discontinue either agent gradually; preferably, discontinue the beta-blocker first.
why is Cimetidine, quinidine, diphenhydramine, food CI w/ BB
: increase efficacy of hepatically metabolized -blockers (CyP2D6)
“Third generation” cardioselective beta-blocker
Nebivolol (Bystolic)
Ranolazine Extended-Release Tablets (Ranexa) indication
Chronic angina – often used for cases where other antianginals have been inadequate
MOA of Ranolazine Extended-Release Tablets (Ranexa)
reduces late sodium current that facilitates calcium entry via Na-Ca exchanger –> reduces diastolic tension, cardiac contractility, and work
CI of Ranolazine Extended-Release Tablets (Ranexa)
Existing QT prolongation; Concurrent use of QT prolonging drugs Potent and moderate CYP450 3A inhibitors Liver impairment (Child-Pugh A, B, C)
ADE of ranolozine
Dizziness, headache, constipation, nausea, asthenia, syncope, palpitations
Tinnitus, vertigo
Abdominal pain, vomiting, dry mouth
Peripheral edema, dyspnea
Bradycardia, hypotension, tremor, blurry vision, hypoesthesia, hematuria
Transient eosinophilia, decreased hematocrit
Ivabradine MOA
” I-funny inhibition
Ivabradine indications
Reduces HR
Recently approved for chronic heart failure; studied for angina
ADR of ivabradine
atrial fibrillation(8%), bradyarrhythmia (10%)
DI in ivabradine
Drugs that prolong QT: fluoroquinolones, dronedarone, ziprasidone, mesoridazine
CyP3A4 inhibitors: nelfinavir, ritonavir, nefazodone, conivaptan
1st line in Variant angina
CCB often used first-line (antispasmodic effect, low ADE); may add on nitrate; BB may cause vasoconstriction
tx of acute unstable
BB and nitrates acutely
CCB if poor response
anti-plt (chewable ASA)
