Drug Targets for the Treatment of Heart failure Flashcards
What is the goal of cardiac function curves and response to drug treatment?
Reduce congestion and increase Cardiac output
What type of drugs will reduce NaCl and water retention in heart failure?
Diuretic drugs increase NaCl excretion by kidney
Where do the loop diuretics act and what they target and what do they cause?
Act on the ascending loop of henle
Target Na/K/2Cl co transporter
Most efficacious diuretics
Cause loss of potassium
Where do the Thiazide diuretics act and what they target and what do they cause?
Act on the early distal tubule
Binds to the Cl- site of the Na+/Cl- cotransporter
Less efficacious than loop diuretics
Cause potassium loss
Where do the Potassium sparing diuretics act and what they target and what do they cause?
Work on th elate distal tubule and collecting tubule to inhibit aldosterone
They block the aldosterone receptor, Block ENaC- sodium channel stimulated by aldosterone
Very weak diuretics
Prevent loss of potassium stimulated by other diuretics
ADH–>INCREASE AQUAPORINS
What are sodium glucose type 2 transport inhibitors what do they do etc.?
New group of drugs introduced to treat diabetics
Inhibit glucose and sodium transport in proximal tubule-so increase sodium (and glucose excretion)
Reduce glomerular filtration rate via tubuloglomerular feedback
Lower blood glucose in diabetics
Clinical trials showed protection against cardiovasc and kidney disease:
Protection seen in non diabets patients
Application to congestive heat failure in vet medicine
Mechanism of action in congestive heart failure patient not fully understood
What do atrial natriuretic peptide do?
Produced by the atria in response to volume overload—> increase NaCl excretion by kidney
Methods of enhancing action of ANP:
Produce a drug that mimics ANPs action at receptor (recombiant human BNP)
Prevent the breakdown/clearance of ANP (Neutral endopeptidase inhibitors)
What do Vasodilator drugs work in reducing the workload of the heart?
BY:
Dilating the arterial side of the circulation to lower TPR (after load)
Reduce venous capacitance and venous return to lower cardiac filling pressure
By law of Laplace this reduces the worload for the hear pre load
What precursors are formed from ACE & ECE?
ACE: Angiotensin II
ECE: Endothelin
What inhibits ACE?
Enalapril
Why can precursors not be used for Norepinephrine?
Stored in granules, all enzymes are intracellular, after use goes back to the granules
How do non competative inhibition of vasoconstriction work do idk lol?
Vasculat smooth muscle depends on calcium entry for sustained contraction (arterial muscle particulary
Calcium enters through voltage dependent calcium channels
Blockers of L-type calcium channels in smooth muscle will be good after load reducers
What are teh physiological antagonism of vasoconstriction?
Nitric oxide activates soluble guanylate cyclase- drug examples NO donor
ANP activates guanylate cyclase membrane bound
EDHF
causes hyperpolarizastion by activating potassium channels
Adensoine/epinephrine receptors activate adenylate cyclase
If heart failure caused by poor muscle contraction could use drugs that enhance contractility:
Contactility is determined by what?
End diastolic length of the cardiac muscle fibre
Cytopalsmic calcium ion concentration in systole
Sensitivity of contractile proteins to calcium
If heart failure compenssatory mechanisms enhance contractility (norepinephrine acting on beta receptors) but excess stimulation does what?
Overloads cell with calcium
Tachycardia(toxic to heat muscle if chronic)
Adaptive changes in B-adrenceptors makes the effect on force of contaction wane
Faster the beating less volume in dyastole meaning heart pumps/beats inefficiently
What second messenger system do B-adrenoceptor couple to in the heart?
Cyclic AMP second receptors
What theraputic approches are there to increase force of contraction?
Use drugs that increase force of contraction without increasing heart rate
Use drugs that increase force of contraction without increasing intracellular calcium conc
Inhibit cardiac muscle excess stimulation by noradrenaline (use B-adrenoceptor antagonists- but reduce force of contraction
What does digoxin do and what that leads to?
Inhibits Na/K ATPase—>increase in intracellular sodium
Sodium then exchanges with Ca2+ bringing more calcium into the cell
Digoxin slows heart rate by increasing vagal stimulation of the heart
What is pimobendan?
Calcium sensitising agent increases sensitvity of troponin C to calcium
What are the advantages of Pimobendan?
Increases force of contraction without overloading cell with calcium
Efficiency of work improved no extra energy expanded getting rid of excess calcium in diastole
What do beta blockers do in heart failure?
Reduce rate of force of contaction-potential dangerous
In human heart disease-improve survival, but disease is often ischaemic
Reverse the adaptive changes to excess stimulation by norepinephrine
Resting the heart rather than stimulating it in the long term produces a better result
What could be the problem with using beta blockers in heart failure?
Concern is that sympathetic stimulation is maintaining adequate CO; inhibit and could precipitate
