3. cvs Flashcards
…………………………………….. is the major direct consequence of diminished cardiac output(CO)
Decreased exercise tolerance with rapid muscular fatigue
Therapeutic strategies
Removal of retained salt and water: diuretics
Reduction of after load and salt and water retention: ACEIs
Reduction of excessive sympathetic stimulation: beta blockers
Reduction of preload or after load: vasodilators
Direct augmentation of depressed cardiac contractility: cardiac glycosides
Approaches of therapy:2
non-pharmacological and pharmacological
Drugs with positive inotropic actions:
Cardiac glycosides(CGs)
Beta agonists, and
Phosphodiesterase inhibitors
Drugs without positive inotropic actions:
diuretics,
ACEIs/ARBs,
beta blockers,
vasodilators, and
aldosterone antagonists
Drugs for symptomatic relief:
CGs,
beta agonists,
PDE inhibitors,
diuretics
Drugs for slowing disease progression:
ACEIs/ARBs,
beta blockers,
aldosterone antagonists,
The hydroxyl groups and other substitutions found on the aglycone determine
The hydroxyl groups and other substitutions found on the aglycone determine its polarity
Digoxin has one additional hydroxyl group than digitoxin
mechanism of action of digoxin
Mechanism of action: Inhibition of Na+/K+-ATPase → increase in intracellular Na+→ alters the driving force for sodium-calcium exchange by the exchanger→ increase in intracellular calcium → increased contractility
digoxin effects in heart
main positive inotropic
Heart rate decreases due to improved performance of the heart and an increased vagal tone(negative chronotropy)
Hinder the conduction of excitation(negative dromotropy)
Promote the formation of heterotopic excitations(positive bathmotropy)—which can lead to ventricular extrasytoles and ventr. tachycardia
time takes digoxin to work
Binding CGs to Na+ K+ ATPase is slow
Moreover after Na+ K+ ATPase inhibition, Ca++ loading occurs gradually
Thus inotropic effect of digitalis takes hours to develop, even after i.v. administration
effect on blood vessels digoxin
a net decrease in peripheral resistance and improved venous tone
effect on kidney digoxin
diuresis secondary to improvement in circulation and renal perfusion(retained salt and water is gradually excreted)
No diuresis occurs in normal individuals or edema due to other causes
CNS effects of digoxin
CNS: higher doses cause CTZ activation resulting nausea and vomiting
Still higher doses: hyperapnea, confusion, disorientation, visual disturbances
Are also useful in atrial arrhythmias(atrial flutter and fibrillation)
digoxin
slow and large doses
Slow approach of digitalization is safe and employed when symptoms are mild
Large loading dose(divided in three or four portions given over 24-36 hours) followed by maintenance doses can be employed when more rapid effect is required
Adverse effects
GI
visual
CNS
cardiac
GI disturbances: anorexia, nausea, vomiting, diarrhea(gastric irritation & CTZ activation)
Visual disturbances: disturbed color vision
CNS effects: delirium, fatigue, confusion, dizziness, abnormal dreams
Cardiac effects: different arrhythmias
Management of toxicity: 4
Withdrawal of the glycoside for extracardiac effects may be enough
Potassium supplementation corrects tachyarrhythmias caused by chronic use of CGs( in acute CG toxicity plasma K+ is increased and contraindicated)
Use of antiarrhythmic drugs
(lidocaine for ventricular arrhythmias; propranolol supraventricular arrhythmias; atropine for AV-block and bradycardia)
Digoxin antibodies for severe toxicity(binds digoxin and digitoxin and enhances their excretion by kidney
Precautions and contraindications:
hypokalemic patients
k competetive inhibits digoxin
Elderly, renal or severe hepatic disease
Myocardial infraction
Thyrotoxicosis
Ventricular tachycardia
interactions with
diuretics
calcium
quinidine
antacids
phenobarbitone
Diuretics: cause hypokalemia(K+ supplementation may be given prophylactically)
Calcium: synergizes with digitalis and precipitates toxicity
Quinidine: displaces digoxin from plasma proteins
Antacids: decrease digoxin absorption
Phenobarbitone: enhance metabolism of digitoxin and decrease its half-life
Bipyridines
are termed as phosphodiesterase inhibitors
Representatives include inamrinone, milrinone
Increase force of contraction
Produce vasodilatation(arteries and veins)
Act by inhibiting phosphodiesterase isoenzyme III(found in heart & blood vessels)
moa of bipyridines
Phosphodiesterase is an enzyme that catalyzes the inactivation of cAMP
PDEIs result in increased concentration of cAMP
adverse effects of Bipyridines
Nausea, vomiting, arrhythmia, thrombocytopenia and liver toxicity are adverse effects( but milrinone better tolerated)
Beta agonists in HF
dobutamine and dopamine are positive inotropic agents of choice for the short-term support of circulation in advanced heart failure(in ICUs preferred to bipyridines)
Dobutamine has lesser effect on heart rate as compared to other sypmathomimetics
Dopamine improves renal perfusion additionally(advantageous in shock)
MOA of beta agonist
Activate beta receptors which activate G-proteins
Results in activation of adenylyl cyclase to generate cAMP
cAMP dependent protein kinases which phosphorylates voltage-dependent slow calcium channel
Increased calcium entry increases contractility
Diuretics
Commonly used diuretics are loop diuretics (furosemide for severe); thiazides(hydrochlorothiazide) for mild cases
ACEIs
ACEIs: captopril, enalapril, lisinopril, fosinopril,.. ↓angiotensin II and decrease degradation of bradykinin
↓ cardiac remodeling due to angiotensin II
Bradykinin exhibits vasodilator actions
Decrease aldosterone related volume retention
Have positive impact on survival of patients
Angiotensin II receptor blockers(ARBs):
list
when used
Include losartan, candesartan, valsartan,..
Have similar effects
Used as a substitute for ACEIs for patients who can not tolerate the latter(dry cough, angioedema)
Direct vasodilators:
Nitrates(e.g. nitroglycerin) reduce preload→ reduces size of ventricles→ improved pumping efficiency
Hydralazine reduces afterload→ pumping improves by even weaker contraction
Combination of both has positive impact on survival of patients
aldosterone antagonist
Spironolactone
Beta blockers:
plus caution
Metoprolol, carvedilol, bisoprolol
attenuation of the adverse effects of high conc. of catecholamines (cardiac remodeling, apoptosis)
decreased heart rate
can precipitate acute decompensation of cardiac function
But most patients in stable severe heart failure respond favorably
…….. and ……….provide symptomatic relief but lack mortality benefit
CG
diuretics
………….. ,…………… ,…………………., nitrates plus hydralazine demonstrated mortality benefit
acei
b blockers
spironolactones
Drugs for acute HF
Loop diuretics e.g. furosemide
Beta agonists/bipyridines
Direct vasodilators
Anti-anginal drugs
Nitrates: nitroglycerine(GTN), isosorbide dinitrate, isosorbide mononitrate
Beta blockers: propranolol, metoprolol, atenolol, etc
Calcium channel blockers: verapamil, diltiazem, nifedipine, amlodipine, nimodipine, etc
Others: nicorandil, ranolazine
Angina pectoris(AP)
plus types
: atherosclerotic disease of the coronary arteries
Known as coronary artery disease or ischemic heart disease
AP is a characteristic sudden, severe, pressing chest pain radiating to neck, jaw, back, & arms
Results from an imbalance in the myocardial oxygen supply-demand relationship
Types of angina: 3 principal forms
Classical, typical, effort-induced, stable angina advanced atherosclerosis of the coronary vessels→ inadequate coronary perfusion
Symptoms occur during physical activity, emotional excitement and other cause
Unstable angina: chest pain occurs with increased frequency, duration, and intensity
Episodes occur for more than 20 minutes with less effort or even at rest
Results from rupture of atheromatous plaques attracting platelet deposition and clot formation
Prinzmetal’s, variant, vasospastic, or rest angina
results from coronary artery spasm(less common) → decreased blood flow to the heart muscle often in patients with coronary atherosclerosis
Anginal attacks unrelated to physical activity(occur at rest)
Responds promptly to vasodilators
Therapeutic strategies:
Goals of therapy:
Therapeutic strategies:
Increasing blood flow(oxygen supply)
Decreasing work load of the heart(decreasing oxygen demand)
Goals of therapy:
Relieve symptoms
Prevent occurrence of episodes
Slow disease progression
nitrates
type moa se
Mechanism of action: nitrates are changed in the body into reactive free radical nitric oxide(NO) by –SH containing enzymes mainly gluthathione reductase
Nitric oxide stimulates guanylyl cyclase which catalyzes the conversion of GTP into cGMP
Increased cGMP activates protein kinase which causes dephosphorylation of myosin light chain kinase—-relaxation of smooth muscle of vessels
↑cGMP also decreases calcium entry
Tolerance develops to high doses or long acting preparations due to:
- Exhaustion of –SH stores
- Systemic compensation via sympathetic discharge and sodium and water retention
Cross-tolerance also occurs, tolerance disappears after about 8-12 hours
Monday morning sickness in persons working in explosives industry describes tolerance
At very high doses: methemoglobinemia (met-Hgb) → tissue hypoxia and death
Low met-Hgb can be used for treatment of cyanide poisoning
Met-Hgb + CN-=cyanmet-Hgb+ sodium thiosulfate→ SCN-(readily excreted)
Excessive met-Hgb can be treated by methylene blue
Beta adren.antagonists
plus caution
Important in the prophylaxis of angina(propranolol, metoprolol, atenolol,..)
By virtue of their negative inotropic , negative chronotropic effects and reduced BP: reduce myocardial oxygen consumption
Lower heart rate is associated with increased diastolic perfusion time(advantageous)
Nonselective blockers avoided in variant angina because of the increased risk of vasospasm due to unopposed action of circulating catecholamines on alpha adrenergic receptors
Sudden withdrawal of beta blockers may exacerbate angina
Calcium channel blockers
Are substances of different chemical classes
Phenylalkylamines: Verapamil
Benzothiazepines: Diltiazem
Dihydropyridines: Nifedipine, nicardipine, amlodipine, felodipine , nimodipine,….
Block voltage-gated L-type calcium channels found predominantly on non dihydro the heart and dihydro smooth muscle (vascular smooth muscle most sensitive)
Newer anti-anginal drugs
Ranolazine acts by reducing a late sodium current that facilitates calcium entry via the sodium calcium exchanger
Decreased intracellular calcium→ reduced cardiac contractility and work
Nicorandil is potassium channel activator and stimulant of guanylyl cyclase to increase cGMP
Causes smooth muscle relaxation (hyperpolarization)
