Pharmacology of HF Flashcards
What is heart failure
Reduced cardiac output to the point that there is end organ failure due to the inadequate blood supply.
What is the classification sytem for HF?
- No limitation on physical activity. Ordinary physical activity does cause undue fatigue, palpitation, dyspnoea. (pre heart failure)
- Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea.
- Marked limitation on physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation of dyspneoa.
- Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.
Symptoms of left sided heart failure
- Dyspnoea
- Orthopnoea: dyspnoea on lying down
- Paroxysmal nocturnal dyspnoea
- Pulmonary congestion and oedema (Crackles)
- Exercise intolerance
Symptoms of right sided heart failure
- Oedematous swelling of feet, ankles and legs
- Hepatomegaly: enlarged, palpable, tender liver
- Ascites: increase in abdominal fluid
- Excessive nocturnal urination
- Increase to jugular venous pressure
- Exercise intolerance
backing up from vena cava
what is the name for HF that affacets both sides of the heart
biventricular failure
vicious cycle (diagram of how injury causes increased preload and afterload)
final diagram overview of heart failure *important*
Classes of drugs used to manage heart failure
- ACE1 (-pril) (hyp)
- ARB (-sartan) (hyp)
- B blockers (-lol) (hyp)
- Diuretics
- SGLT2 inhibitors (-gliflozin)
- Nephrilysin inhibitors (-tril)
- Cardiac glycosides (ANTI-DYSRHYTHMIC)
- Ivabradine (ANGINA)
- Vasodilators (ANGINA)
- Calcium-channel blockers- mostly not for CHF (hyp)
Chronic heart failure diagnosis
Take a detailed history and perform and clinical examination.
A) Measure NT-proBNP (precursor to BNP released by both the atria and ventricles- raised in symptomatic and non-symptomatic left ventricular failure). If it is >2,000 ng/L refer urgently.
B) Perform ECG consider chest X-ray, blood tests, urinalysis, peak flow or spirometry.
3) Specialist clinical assessment including transthoracic echocardiography.
management of heart failure
1) Offer diuretics for symptoms and fluid retention – offer ACE1 and BB if symptoms continue, consider hydralazine and nitrate if intolerant of ACE1 and ARB)
2) Manage comorbidities such as hypertension, atrial fibrillation, ischaemic heart disease and diabetes
- Offer a personalised exercise-based cardiac rehabilitation
- Digoxin for heart failure with sinus rhythm
- Cardiac resynchronisation therapy
- Implantable cardioverter defibrillator
which part of the neprhon does the majority of sadium reabsorption take place in
proximal convuluted tubule
most diuretics are what
natriuretics
makes you reabsorb less and therefore excrete more sodium
where sodium goes wter follows
what part of the nephron reabsrobes the second most amount of sodium
Loop of henle
Acetazolamide
CLASS: Carbonic anhydrase inhibitor (CAI)
CHEMSITRY: Small molecule
PHARMACOLOGY: target- Carbonic anhydrases Activity- Competitive inhibitor
PHYSIOLOGY-↓ Na reabsoroption in PCT – ↑urine flow
1/3 PCT Na+ reabsorption is through Na+/H+ antiporter
Diuretic effect is mild and self-limiting
– ↓preload –↓venous congestion– sympotamtic relief
Heavy loss of HCO3- – alkaline urine/ metabolic acidosis – ↓diuresis
↑Na+ at DCT – ↑K+ loss – hypokalaemia
How does competitively inhibiting carbonic anhydrase lead to a diuretic effect
The main way that the kidney controls ECF and therefore BV is via reabsorption of Na+.
This is done in the PCT via Na+/H+ antiporters (Na+ entering tubule epithelial cells and H+ leaving into lumen).
The H+ required for this is gained from carbonic anhydrase converting carbonic acid into its ionic forms.
The only way for carbonic acid to enter tubule epithelial cells is to use CA to convert it to H2O and CO2 and then to use CA again to convert it back to carbonic acid.
Therefore, if you antagonise CA, you stop carbonic acid entering the epithelial cells and also block its conversion into H+ for Na+ transport.
Na+/K+ -ATPase “sodium pump” on the apical side allows for Na+ to be transported out of tubular epithelial cells to the basolateral side.
Na+/HCO3- co-transporter allows Na+ to also be transported to the basolateral side
name 2 pumps that transfer Na from within tubule epithelial cells to the basolateral side
Na+/K+ -ATPase “sodium pump”
Na+/HCO3- co-transporter
what are the 3 ways that CO2 is transported in the blood
10% dissolved in plasma
20% bound to Hb
79% converted to H2CO3
Hydrochlorothiazide
CLASS: Thiazide diuretic
CHEMISTRY: Small molecule
PHARMACOLOGY: Target- NCC = Na+ Cl- symporter Activity- Inhibition
PHYSIOLOGY:
↓Na+ reabsorption in DCT – ↑urine flow
Mild diuretic action
Some loss of HCO3- – metabolic alkalosis
↑K+ loss – hypokalaemia
Secreted by OAT (organic anionic transporter) uricaemia ↑risk of gout
CLINICAL: Hypertension; oedema
Furosemide
CLASS: Loop (“high ceiling”) diuretic
CHEMISTRY: small molecule
PHARMACOLOGY: target: NKCC2= Na+-K+-Cl- symporter on the apical side Activity: Inhibitor
PHYSIOLOGY:
- ↓Na+ reabsorption in thick ascending loop of Henle – ↑ urine flow
- Potent diuretic action (up to 15% of filtered load)
- ↑ K+ loss – hypokalaemia (and metabolic acidosis)
- Secreted by OATs in PCT – ↑ concentration in tubules
- ↓ uric acid secretion (competes for OATs) – uricaemia – ↑ risk of gout
spironolactone
CLASS: K+ sparing diuretic or MRA (mineralocorticoid receptor antagonist)
CHEMISTRY: small molecule- steroid so acts intracellularly
PHARMACOLOGY: Target- Mineralocorticoid receptor Activity: Competitive antagonist
PHYSIOLOGY:
- Antagonises action of aldosterone in late DCT/CD
- ↓ expression of ENaCs and Na+/K+ -ATPase
- Weak diuretic effect (most Na+ is already absorbed at this point)
- causes K+ retention- hypertension
why is spirinalactone often used in conjunction with thiazide?
offsets the loss of K+
Amiloride
CLASS: k+ sparing diuretic
CHEMISTRY: small molecule
PHARMACOLOGY: target: epithelial Na Channel (ENaCs) activity: channel blocker
PHYSIOLOGY:
- ↓Na+ entry from lumen of DCT into cell
- Rate-limiting step of Na+ reabsorption
- Weak diuretic effect (most Na+ already reabsorbed by this point)
- K+ retention – hyperkalaemia
CLINICAL: used with thiazide (balances K+) for odeema and heart failure
what is a ROMK
renal outer medullary K channel
k+ leaves via channel to balance charge when Na+ enters
Mannitol
CLASS: Osmotic diuretic
CHEMISTRY: Small molecule- natural sugar
PHARMACOLOGY: Target- NONE Activity- NONE
PHYSIOLOGY:
- Does not cross membranes
- Raises osmotic pressure – draws water towards itself
- Response directly proportional to concentration ←the effect does not saturate
CLINICAL:
- Used ACUTELY rapid loss of fluid e.g., cerebral oedema
- NOT used in chronic hypertension or congestive heart failure
- Very potent diuretic
- Substantial K+ loss
- Also: laxative, mucolytic
what is an osmotic diuretic
Osmotic diuretic- inhibits the reabsorption of water by increasing the osmolarity of blood and renal filtrate
Dapagliflozin
CLASS: SGLT2 inhibitor (-gliflozin)
CHEMISTRY: small molecule- modified sugar
PHARMACOLOGY: Target- SGLT2 (sodium/ glucose transporter 2) Activity- Competitive inhibitor
PHYSIOLOGY:
↓ glucose reabsorption in PCT - glycosuria -osmotic diuresis
↓ Na+ reabsorption in PCT - natriuresis
↓ blood glucose
CLINICAL: diabetes mellitus (mostly type 1) ,Congestive heart failure
SGLT2 receptors
- Na+ / glucose co-transporter
- Expressed in early PCT
- 1 Na+ in: 1 glucose in
- 1* function in kidney
- = reabsorption of glucose (~90%)
- Low affinity/ high capacity
SGLT1 co-transporter
Na+/ glucose co-transporter
Expressed in late PCT
In intestine + kidney – glucose absorption
2Na+: 1 glucose in
Also in kidney = reabsorption of glucose (~10 %)
High affinity/ low capacity
sacubitril
CLASS: Nephrilysin inhibitor (-tril)
CHEMISTRY: prodrug: active metabolite= sacubitrilat
PHARMACOLOGY: Target- Nephrilysin (enzyme)- neutral endopeptidase Activity- Competitive inhibitor
PHYSIOLOGY:
- Nephrilysin cleaves/ degrades ANP and BNP (also enkephalins, AT-1 and AT-II)
- Hence, sacubitril ↑ ANP/BNP levels
CLINICAL: used in combination with valsartan (ARB) = ARNI
Congestive heart failure
ANP and BNP
CLASS: Natriuretic peptides
CHEMISTRY: Endogenous peptides produced when the atria (ANP) and ventricles (BNP) are distended (Hypertension of CHF)
PHARMACOLOGY: Target- Natriuretic Peptide Receptor 1= NPR1 (also NPR2 and NPR3) Enzyme- Transmembrane guanlyl cyclase Activity: agonist
PHYSIOLOGY:
- NPR1 widely expressed, including kidney
- Guanylyl cyclase converts GTP - cGMP - ↑PKG activity
- -inhibition of ENaC and Na+/K+-ATPase in collecting duct
- ↑ GFR ↓ renin release - ↓ ECF
- Oppose action of AT-II and aldosterone (e.g., decrease expression of eNaCS)
CLINICAL: Sacubitril effectively ↑ activity of ANP/BNP
Digoxin
Low priotiry????
CLASS: cardiac glycoside
CHEMISTRY: natural molecule
PHARMACOLOGY: Target- Na+/ K+-ATPase (sodium pump) transporter Activity: Competitive inhibitor (K+ bonding sites)
PHYSIOLOGY:
- Na+/ Ca2+ exchanger (NCX) removes Ca2+ from cytoplasm during diastole
- ↑ [Na+]I ↑ driving force for Ca2+ extrusion ↑[Ca2+]I ↑force of contraction +ve inotropic effect
- ↓oedema
- TOXIC- low therapeutic index
CLINICAL:
- Atrial fibrillation: ↓ AVN conduction
- Formerly congestive HF
Ivabradine
CLASS: xxx
CHEMSITRY: small molecule, structurally similar to vermapril
PHARMACOLOGY: Target- HCN channels (“funny” current)
PHYSIOLOGY: Inhibiting If (funny) current ↓HR ↓ cardiac work
CLINICAL: Angina, congestive heart failure (last ditch)
Hydralazine
CLASS: vasodilator
CHEMISTRY: small molecule
PHARMACOLOGY: not well understood
PHYSIOLOGY: Vasodilator
May block IP3-dependant Ca2+ release from SR
CLINICAL: anti-hypertensive, congestive heart failure (used with nitrates)
nitrovsodilators
- Sodium nitroprusside
- Isosorbide dinitrate
- Isosorbide mononitrate
- Glyerceryl trinitrate
Pharmacology of nitrates:
Varying pharmokinetics: duration of action, route of admission etc…
Each compound break down/ is metabolised to release nitric oxide
NO activates NO sensitive soluble guanylyl cyclase (ANP an BNP)
↑cGMP ↑PKG vasodilation and other responses…
