Pharmacology of heart Failure (c) Flashcards
What are the different NTHA functional classifications of heart failure?
1 - no limitation of physical activity, norm activity does not cause undue fatigue, palpitation, dyspnoea
2 - Slight limitation of physical activity. Comfortable at rest. Oridinay physical activity results in f, p, d.
3 - Marked limitation of physical activity. comfortable at rest, less than ordinary activity causes f,p,d.
4 - Unable to carry out any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.
What are the different terms used for heart failure?
Chronic Heart Failure
Congestive Heart Failure.
What are the symptoms of left heart failure?
Dysponoea
Otrhopneoea - dyspnoea when lying down
Paroxysmal noctural dyspnoea (awakenes patient and relieved when sitting up)
Pulmonary congestion and oedema (crackles)
Exercise intolerance
Pulmonary odema
These symptoms occur due to congestion of blood into the lungs
What are the symptoms of right heart failure?
Odematous swelling of feet, ankles and legs
Hepatomegaly: enlarged palpate, tender, nutmeg liver.
Ascities
Excessive nocturnal urination
Increased Jugular venous pressure
Exercise intolerance
Occurs due to congestion of blood into systemic circulation.
What term is used for when left and right ventricular heart failure co-exist>
Bi-ventricular failure
Explain the pathophysiological process underpinning heart failure.
Injury to the heart
Results in heart failure and reduced cardiac output
This activates normal physiological mechanisms to try to compromise.
Acute - baroreceptors response to low BP, Frank Starling to in contractility from inc EDV.
1. Decreased renal perfusion - RAAS and vasoconstriction
2. Also Increased SANS inc renin and vasoconstriction
This results in increased blood volume causing venous congestion causing release of naturetic peptides.
These acute and chronic methods of compromise lead to increased afterload and preload, and can cause pulmonary congestion.
The heart is working harder to cope with increased fluid demand - results in higher energy consumption and cardiac remodelling can worsen pump failure.
Ventricular dysfunction occurs.
What are the different types of drugs given in heart failure?
ACEi
ARB
Beta blockers
Duirectics
SGLT2 inhibitors
Neprilysin inhibitors
Cardiac glycosides
Ivabradine
Vasodilators
Calcium channel blockers (very rare)
What naming indicates an SGLT2 inhibitor?
-gliflozin suffix
What naming indicatoes a neprilysin inhibitor?
-tril suffix
What is the NICE diagnostic pathway for heart failure?
IN suspected heart failure take a detailed history and clinical examination
Measure NT-proBNP
If NT-proBNP is below 400ng/l heart failure not confirmed consider other cause
Is 400-2000ng/l refer to be seen within 6 weeks by specialised
Is above 2000ng/L refer very urgently to be seen within 2 weeks by specialist
Specialist will perform a clinical assessment including a transthoracic echocardiogram
Heart failure can be ruled or or confirmed
If confirmed further investigation for aetiology (if correctable) and assess severity.
What are the NICE treatment guidelines for initial treatment of patients with chronic heart failure?
Offer diuretics for congestive symtpoms and fluid retentions
If ejection fraction reserved manage co-morbidities and symptoms.
If ejection fraction reduced offer ACEi (or ARB if intolerant or hydralazine and nitrate if intolerant of ARB) and BB or then a MRA is symptoms continue.
Both groups of patients should be offered a exercise based cardiac rehabilitation programme unless unstable condition.
What should be used as second line treatment for heart failure?
Requires specialist re-assessment are four potential options
1)Replaced ACEi with sacubitril valsartan Ej<35%
2) Add ivabradine EJ,35% must has sinus rhythm and heart rate
3) Add hydralazine and nitrates
4) Digoxin
Some patients may also be referred for cardiac resynchronization therapy or an ICD.
What are the main diuretics used in heart failure?
Thiazide
Loop diuretics
Potassium sparing (not in isolation)
May also use SGLT2 inhibitors.
What is meant by a natriuretic?
Lowers plasma sodium
Hence lowers plasma water retention
Osmotic forces keep water out of the blood and in the lumen filtrate in the kidney
Increased volume of more dilute lumen
Most diuretics and natriuretics.
What is the clinical use of acetazolamide?
Used to reduced intraocular pressure in glucoma.
Treatment of glaucoma
Treatment of epilepsy
What is the mechanism of action of acetazolamide?
Class - carbonic anhydrase inhibitor
Chem - small molecule derived from sulphonadie antibiotics
Pharmacology - competitive inhibitor at carbonic anhydrase enzymes
Physiology - reduces Na+ reabsorption in the PCT mainly through action at Na+/H+ antiporter - increase urine flow
This decreases pre-load, venous congestion providing symptomatic relief.
This effect is mild and self-limiting.
Why does acetazolamide (CAI) have a self limiting effect?
Decrease absoprtion of Na+ through Na+ H+ antiporter in PCT
However increase Na+ delivery to DCT - increase ENaC channel activity - compensatory effects - some sodium reabsorbed here
Also has a consequence of hypokalemia.
Similarly inhibiting CA decreases HCO3- and H+ production, can cause metabolic acidosis and increase activity of Na+ H+ antiporter and Na+ HCO3- transporter - reducing diuretic effect.
Draw a diagram to represent the role of carbonic anhydrase in tubule epithelial cells in the PCT?
Links to acetazolamide function
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What is the role of the carbonic anhydrase enzyme?
Catalyses the reversible reaction of converting H20 and Co2 to HCO3- and H+ via a carbonic acid intermediate.
What is the clinical use of hydrochlorothiazide?
In treatment of hypertension and odema in combination with other treatments.
Has mild diuertic action
What is the mechanism of action of hydrochlorothiazide?
Is a small molecule dervide from CAIs.
Class - thiazide diuretic
Pharmacology: inhibits the Na+ Cl- symporter in the DCT, found on the apical membrane. Drug is thought to bind to the Cl- binding site.
Physiology: decreases Na+ reabsoprtion in the DCT
What are the potential side effects of thiazide diuretics?
1) Have limited glomerular filtration so reach target site via secretion into PCT via OAT transporters - this competitively reduces the amount of uric acid secreted - can uraemia and increased risk of gout.
2) Encourages K+ loss causing hypokalemia, causes H+ loss resulting in metabolic alkalosis.
Draw a diagram to show how thiazide diuretics carry out their effects at the DCT
Ans
What is the clinical use of furosemide?
Resistant Hypertension
(Resistant) Odema
Heart failure
What is the mechanism of action of furosemide?
Is a loop diuretic
Small molecule derived from thiazide
Pharmacology : targets and inhibits NKCC2 symporter in thick ascending limb of the loop of Henle.
Physiology:
Reduces Na+ reabsoprtion has a strong diuretic effect increase urine output - by 15-25% of filtered load
What are the potential side effects of furosemide use?
- Has a low filtration at the glomerulus, so is secreted into tubule in PCT by OAT transporter, competes with uric acid, decreased uric acid secretion - uricaemia - gout
- Increase K+ loss, increase H+ loss - metabolic alkalosis.
Draw a diagram to show how loop diuretics affect the renal tubule?
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What is the function of the Na+/Cl- transporter?
Function in kideny
Reabsoprtion of Na+ and Cl-
1;1 ratio
What is the function of the NKCC2 channel?
Kidney specific
Electroneutral reabsoprtion of Na+, K+ and Cl-
1;1;2.
What is the clinical use of spironolactone?
Often used in combination with thiazide/loop to offset K+ loss
Hypertension, oedema and heart failure.
What is the mechanism of action of spironolactone?
Class - K+ sparing diuretic (an MRA)
Chem - small molecule, as a steroid it acts intracellularly
Pharmacology - competitive antagonist at mineralocorticoid receptors
Physiology - antagonises the action of aldosterone in the late DCT/CD.
Leads to decreased expression of ENaCs and Na+/K+ ATPase
This has a weak diuretic effect as most Na+ is already reabsorbed.
What are some potential side effects of spironolactone and amiloride?
Can cause mild K+ retention - hyperkaelamia
This is not normally very common as used in combination with thiazide and loop diuretics which increase K+ excretion.
What is the clinical indication of amiloride?
Use in combination with thiazide/loop diuretics to offest K+ loss
Hypertension, odedma and heart failure - not often CHF.
What is the mechanism of action of amiloride?
Is a K+ sparing diuretic (NOT an MRA)
Chem - small molecule
Pharmacology - channel blocker at ENaCs in DCT
Physiology - reduced Na+ entry from lumen of DCT into cels, this inhibits the rate limiting step of Na+ reabsoprtion in the DCT
this has weak diuretic effect as most Na+ already absorbed.
Why do all diuretics (not potassium sparing) increase risk of hypokalemia?
Increase Na+ delivery to DCT
Increase activity of ENaC hence Na+ K+ pump and ROMK channel
ROMK channel balances K+ secretion with Na+ reabsoprtion to balance charge.
What is the function of the mineralcorticoid receptor in the DCT?
Activated by aldosterone
Increase ENaC and Na+ K+ ATPase expression.
What is the clinical use of mannitol?
Give by IV injection in acute situations to cause rapid fluid loss
For example given in cerebral odema or raised intraocular pressure
Is NOT given in chronic hypertension or CHD.
What is the mechanism of action of mannitol?
Is an osmotic diuretic
Chem - small molcule
No pharmacology
Physiology - is filtered into renal lumen, does not cross membranes so is not reabsorbed
Has a high osmotic force, increases osmotic pressure drawing water inwards down an osmotic gradient.
The response is dependent on the concentration used - does nat saturate
Very potent
Causes substantial K+ loss.
What is a potential side effects of mannitol use?
Causes severe K+ loss.
What is the origin of SGLT2 inhibitors?
Structural origins include phlorizin and phloretin (components of phlorizin)
Phlorizin does not inhibit GLUTs, phloretin dose.
These were found to inhibits SGLT1/2 - used in diabets research as bring about diabetic effects
Found naturally in will bark and bark of apple tree.
What is the moa of dapagliflozin?
Is an SGLT2 inhibitor (-gliflozin)
Chem - is a small molecule derived from phlorizin
Pharmacology - is a competitive inhibitor of target SGLT2
Physiology - decrease glucose reabsoprtion in PCT - glycosuria - results in osmotic diuresis and decreased blood glucose
Also decreases Na+ reabsoprtion in PCT - natriuresis.
What are the clinical indication of SGLT2 inhibitor dapagliflozin?
Diabetes mellitus mainly type 2
Congestive heart failure with reduced ejection fraction
Also CHF with preserved/mildly reduced ejection fraction
Compare the featues of SGLT1 and SGLT2 in the PCT of the nephron.
SGLT2 - expressed in early PCT only, absorbed glucose and Na+ in a one to one ratio, reabsorbes most glucose in PCT, has a low affinity but high capacity for glucose
SGLT1 - expressed in late PCT - reabsorbs 10% of PCT glucose in a 2Na+ to 1 glucose ratio, has a high affinity but low capacity. Is also expressed in intestine for glucose reabsoprtion.
What are the NICE recommendations around the use of SGLT2 inhibitors in CHF?
Recommended for symptomatic relief if primary treatment fails
Recommend dapagliflozin or empagliflozin
Can be used for a preserved or midley reduced ejection fraction.
Must be used in combination of other drugs not in isolation.
Where in the kidney do different diuretics act?
Osmotic - PCT to thin descending loop of henle
CA inhibitors and SGLT2 inhibitors - PCT
Loop - Thick ascneding loop of henle
Thiazides - DCT
K+ sparing - DCT and CD.
What is the use of sulfanilamides?
For example sulfamethoxadole
Are structural analogues of PABa, a components that is incorporated into DHF acid.
Compete with PABA
Competitive inhibitor of bacterial enzyme - dihydropteroate synthesis
This inhibits bacterial folate synthesis
Clinical - anti-bacterial in syphilis.
Sulfanilamide is also a carbonic anhydrase inhibitor.
What is the link between syphilis drugs and CHF drugs?
Syphilis antibacterials have origins in organomercurials such as mersalyl acid.
Sulphonamides - no longer contain mercury but are affective antibacterial, used as a structural basis for acetazolamide which was the first modern diuretic not containing mercury.
What are the potential problems with acetazolamide? (carbonic anhydrase inhibitor)
Loss of HCO3- in urine
Alkaline urine
Metabolic acidosis
What is the order of development of diuretics?
Carbonic anhydrase inhibitors
Thiazide diuretics
Loop diuretics
What are the clinical uses of sacubitril?
Clinical - congestive heart failure
Always used with an ARB to counter for increased AT-II.
Never be used with an ACEi to avoid increased bradykinin - which would have a risk of angioedema.
What is the mechanism of action of sacubitril?
Is a neprilysin inhibitor (-tril)
Chem- small molecule, pro-drug. Is converted to atvie metabolite sacubitrlat
Pharmacology -is a competitive inhibitor of target enzyme neprilysen
Neprilysen is a endopeptidase
Physiology: neprilysen cleaves ANP/BNP and AT-II, hence drug increases levels of ANP/BNP - dilation of afferent arteriole increase GFR and help decrease water retention.
What are the potential side effects of sacubitril?
Is a neprilysin inhibitor
Prevents the cleavage of Bradykinin, enkephalins and AT-II
Must be used with ARB to prevent AT-II from increasing blood volume
Inc bradykinin may cause angioodema and a cough.
What are natriuretic peptides?
When are they released?
Endogenous peptides
ANP - released from atrial mycots in response to stretch
BNP - Secreted by ventricles in response to increased myocardial stress, NT-proBNP is an inactive protein cleaved from pro-BNP to release BNP, has a longer half life so tends to be used in diagnostic tests.
What are the clinical uses of ANP and BNP?
Have an indirect use through sacubitril (neprilysin inhibitor)
There increased levels due to drug effects is beneficial in congestive heart failure when used alongside ARB.
What is the mechanism of action and ANP?BNP in helping treat CHF?
Is an agonist at NRP1 receptors
These receptors are transmembrane guanylyl cyclase
Increases cGMP and PKG activity
This inhibis ENaCs and Na+/K+ ATPase in the collecting duct.
This increases GFR and decreases renin release - decreasing ECF
Oppose the actions of AT-II and aldosterone
Decreases blood volume
What biomakers is looked for in the diagnosis of CHF?
NT-proBNP
proBNP –> BNP (active) and NT-proBNP
What is the clinical use of digoxin?
Acts on cardiac myocytes
Used to decrease AV node conduction in Atrial fibrillation
Previously used in CHF - may still be used now in extreme cases.
What is the mechanism of action of digoxin?
Is a cardiac glycoside
Is a natural small molecule originating from foxglove
Pharmacology: targets Na+ K+ ATPase in cardiac myocyte, acts as a competitive inhibitor
Physiology:
Reduces Sodium Potassium Pump Activity, inc cytoplasmic Na+, decreases conc gradient for Na+ influx via Na+ Ca2+ co-transporter
Therefore also inhibits Ca2+ efflux
Higher intracellular Ca2+ conc - increased contractility of myocyte, reducing odema.
Draw a diagram to represent the mechanism of action of cardiac glycoside digoxin at the cardiac myocyte.
