Pharmacology Cardiac contractility & +Inotropes Flashcards
Cardiac CONTRACTION: Calcium entry & Calcium-Induced Calcium Release (CIRC) - 4
- Rapid depolarisation due to fast Na+ influx via Na+ channels
- Depolarisation dependent activation of L-VACCs & influx of extracellular Ca
- Ca induced activation of RyR2 on the SR & C induced C release
- Ca influx via Na –Ca exchanger via reverse mode of the Na-Ca exchanger
The Ryanodine Receptor (RyR) -4
- RyR is an intracellular calcium release channel on the SR
Three main isoforms: - RyR1 – skeletal muscles
- RyR2 – cardiac muscles
- RyR3 – brain & other tissues
Cardiac CONTRACTION: Cardiac Ryanodine Receptor (RyR2) – 5
- Contains cytoplasmic Ca binding sites: activated by low cytosolic Ca & inhibited by high cytosolic Ca
- Calstabin-2, endogenous stabiliser that keeps RyR2 channel closed;
- Calmodulin (CaM) inhibits opening of RyR2 in [Ca] independent manner
- Phosphorylation sites for PKA (sympathetic NS) & for CaMKII (enhanced with increased [Ca] in cytosol) – increased opening of RyR2
- In SR lumen: Calsequestrin-2, a low affinity, high-capacity Ca binding protein
Environment of the RyR channel in skeletal muscle - 6
- The t tubule contains tetrads of dihydropyridine receptors (DHPRs).
- A t-tubule membrane voltage change activates DHPR.
- The t-tubule signal transmitted to RyR1 channel by DHPR-RyR1 linkage.
- The t-tubule signal triggers RyR1 channel to open & release Ca stored inside SR.
- Calsequestrin (CSQ), a low-affinity high-capacity calcium buffer, found inside SR lumen near RyR1 channels.
- The SR Ca2+-ATPase (SERCA) uses the energy stored in the ATP to pump calcium back into the SR.
Environment of the RyR2 channel in cardiac muscle - 5
- The t tubule contains dihydropyridine receptors (DHPRs) & calcium extrusion mechanisms (e.g. Na/Ca exchanger)
- A t-tubule membrane voltage change activates DHPR & resulting Ca entry triggers underlying RyR2 channels to open.
- Open RyR2 channel releases Ca stored in SR, into the cytoplasm. Calsequestrin (CSQ,) buffers Ca near RyR2 channels inside SR.
- SERCA uses energy from ATP to pump Ca back into SR.
- The Na-CaX uses energy stored in Na gradient to move Ca out of the cell.
Ca++-Induced Ca++ Release (CICR) in the Cardiac Myocyte – 6
- Ca enters via a L-VACC
2.Activation of a cluster of RyRs - Local Ca release
4.Rapid summation of local events - Global raise in Ca
- CONTRACTION
Drugs which make RyR ‘leaky’: - 3
- Excess of caffeine
- Immunosuppressants
- Cardiac glycosides (e.g. Digoxin)
Genetics or acquired abnormal function (e.g. in CHF) in: - 3
- Cardiac RyR2
- Calsequestrin-2 (CASQ2)
- Calmodulin (CaM)
Cardiac RELAXATION: Calcium re-uptake & extrusion - 4
- Ca reuptake into the SR by a SR/ER Calcium ATPase (SERCA)
- Ca extrusion by Na-Ca exchanger
- Ca extrusion by Ca ATPase (Ca-Pump)
- Ca uptake into mitochondria by the mitochondrial Ca uniporter
Cardiac RELAXATION: Ca2+ re-uptake into the SR by SERCA & its regulation by Phospholamban (PLB) - 6
- SERCA increases cytosolic Ca
- Dephosphorylated PLB binds to SERCA pump & regulates its activity
- Interaction disrupted by phosphorylation of PLB or in presence of high [calcium]
- PLB is phosphorylated by:
- PKA (Protein Kinase A) (main)
- CaMKII (Ca-Calmodulin-depended Kinase II)
Cardiac RELAXATION: Ca++ extrusion by the NCX: Forward (Normal) mode - 4
- Activated by increased cytosolic Ca
- Removes 1 cytosolic Ca in exchange for 3 Na
- Reduces cytosolic [Ca]
- ELECTROGENIC: Can cause membrane depolarisation, triggering delay in depolarisation in Ca overloaded myocytes
Cardiac RELAXATION: Ca++ extrusion by the NCX: Reverse mode - 3
- Activated by increased cytosolic Na+
- Expels 3 Na in exchange for 1 cytosolic Ca
- Increases cytosolic [Ca]
Catecholamines effect on the heart
Catecholamines (via Gαs-coupled β1-adrenoceptors on cardiac myocytes) increase both force of contraction & rate of relaxation via PKA-dependent phosphorylation to maintain adequate cardiac output when the heart rate is increased.
Inotropic effect (medication changes to contractility of the heart) - 4
- Increased force of contraction (positive inotropic effect) is enabled by more rapid increase in [Ca++]cyt due to enhanced activity of:
- L-VACCs (greater Ca influx),
- RyR2 (more Ca is released from the SR),
- Increased Ca-sensitivity of the tropomyosin complex via phosphorylation of regulatory Troponin I
Lusitropic effect (rate of myocardial relaxation) - 3
- Increased rate of relaxation (positive lusitropic effect) via accelerated reuptake of cytosolic Ca++ into the SR due enhanced activity:
- SERCA results of increased phosphorylation of phospholamban (PLB).
- Enables a stronger force of contraction at increased HR.
Define Heart failure & give symptoms
Heart failure: Complex syndrome of symptoms & signs caused by impairment of the heart’s action as a pump supporting the circulation. Caused by structural or functional abnormalities of the heart.
Symptoms: breathlessness (exertional dyspnoea, orthopnoea & paroxysmal nocturnal dyspnoea), fatigue, & oedema)
Pathogenesis as a cause of signs & symptoms in CHF - 6
- Impaired cardiac function reduces cardiac contractility & reduces CO
- Leads to:
A) reduced tissue perfusion (symptoms: fatigue symptoms & exercise intolerance);
B) reduced Renal Blood Flow, leading to activation of RAAS (vaso- & venoconstriction),
C) an increase in Central Venous Pressure (CVP) due to fluid & salt retention because of reduced CO & overactive RAAS (leading to various oedema or congestions). - Reduced CO activates sympathetic NS (via central & carotid baroreceptors) increasing circulating catecholamine levels.
- All increase systemic peripheral resistance & in central venous pressure
- Positive feedback loop where physiological compensatory mechanisms progressively weaken the heart.
- Called congestive HF (CHF) or HF with reduced ejection fraction (HFrEF) due to reduced CO due to left ventricular dysfunction & fluid retention.
CHF Pathogenesis as the basis for current therapies - 5
- Positive inotropes: To enhance CO
- Beta-Blockers: To decrease cardiotoxicity of catecholamines
- ACEIs/ARBs/MRAs: To reduce activation of the RAAS
- Diuretics: To reduce oedema
- Vasodilators: To decrease TPR & CVP
Pharmacological therapy of CHF -3
- 1st LINE THERAPY: ACEI/ARB + beta-Blocker + Diuretic + SGLT2 inhibitor
- Drugs that can be added or used instead if CHF symptoms not improved:
A) MRA (Mineralocorticoid receptor antagonist: e.g. Spironolactone)
B) add/or Hydralazine + Nitrate vasodilators (Effective in patients of African-Caribbean origin)
c) Sacubitril/Valsartan (ARNI) - If HF associated with angina: CCB (give Amlodipine)
BENEFITS BETA-BLOCKERS IN TREATMENT OF HF - 8
- Examples: Bisoprolol (b1), Nebivolol (b1), Carvedilol (b/a1)
- Beta-blockers are negative inotropes, but have benefits
- B1-blockers thought to reduce sympathetic drive to the heart, leading to increase of density of B-adrenoceptors
- This reduces hypertrophic cardiomyopathy.
- Inhibition of cardiotoxicity of catecholamines
- Increase of the density of β-adrenoceptors on cardiac myocytes
- Anti-hypertensive, antianginal & anti-arrhythmic effects
- Antioxidant & anti-proliferative effects (Carvedilol, Nebivolol)
BENEFECIAL EFFECT OF POSITIVE INOTROPIC AGENTS IN CHF - 3
- In CHF CO considerably drops below normal range
- Positive inotropes can raise CO closer to normal CO
- Reduces symptoms
POSITIVE INOTROPIC AGENTS AND THEIR USES IN CHF: Catecholamines - 4
- Noradrenaline
- Adrenaline
- Isoprenaline (non-selective β-agonist)
- DOBUTAMINE (β1 agonist) (in specialised cases & acute decompensated HF)
POSITIVE INOTROPIC AGENTS AND THEIR USES IN CHF: Phosphodiesterase type-3 inhibitors – 2 & Cardiac glycosides:
- MILRINONE (short-term treatment of acute severe decompensated HF)
- ENOXIMONE (in congestive HF with reduced output & increased filling pressure)
Cardiac glycosides:
DIGOXIN; Digitoxin; Ouabain (in worsening or severe HF with normal sinus rhythm, in HF patients with AF)
MoA of Catecholamines, (e.g. Dobutamine) - 4
- Catecholamines act by binding to specific adrenergic receptors on target cells, primarily alpha & beta subtypes.
- When catecholamines bind to β1 receptors (Gs-protein coupled), they activate adenylyl cyclase, increasing cAMP production.
- cAMP activates protein kinase A (PKA), which increases heart rate (chronotropy), the force of contraction (inotropy).
- Resulting in enhanced CO & increased heart rate.
PDE-3 inhibitor method of action – 4
- PDE3 inhibitors bind to PDE3, changing the shape of the active site, inhibiting its effect.
- By inhibiting PDE3, PDE3 inhibitors prevent breakdown of cAMP, leading to increased cAMP.
- Elevated cAMP levels activate protein kinase A (PKA), which increases heart rate (chronotropy), the force of contraction (inotropy).
- Resulting in enhanced CO & increased heart rate.
POSPHODIESTERASE TYPE 3 INHIBITORS: Benefits 3 vs adverse 3
Beneficial systemic effects:
- Increased CO
- Reduction in right atrial pressure (less risk of pulmonary oedema)
- Reduced TPR & reduced cardiac preload (due to peripheral arterial & venous dilatation)
Adverse reactions: - Lethal arrhythmias with a prolonged use of MILRINONE
- Hypotension
- Headache
Mechanism of digoxin as positive inotrope - 4
- Inhibition of Na-K ATPase leads to cellular sodium build-up
- Activates the reverse mode of the NCX
- Increases intracellular Ca & hence more stored in SR & available for release upon next stimuli via the CICR mechanism
- Force of contraction is increased
Mechanism for digoxin cardiac toxicity & Delayed-After-Dpolarisation (DAD): - 5
- Digoxin overdose can lead to build up of Ca in the cytoplasm;
- Stimulates the forward mode of the NCX: removing the excess of cytosolic Ca outside the cell in exchange for Na+.
- The NCX is electrogenic (exchanges 3Na for 1 Ca, i.e. generates +ion flux in direction of net Na movement)
- Forward mode moves Na in creating inward movement of + charges into the cell (reduced electronegativity)
- Causes membrane depolarisation & triggers a DAD that can lead to arrhythmias
Glycosides, Dygoxin: Therapeutic use - 3
- In worsening or severe HF in patients with normal sinus rhythm
- Increase in force of cardiac contraction due to: + inotropic action, reduction in fluid volume, preload due to diuretic action increases CO & improve dynamic of blood flow.
- Reduces sympathetic activity & lessen detrimental effects in CHF patients
Glycosides, Dygoxin: Benefits in CHF - 4
- Anti-arrhythmic helps control stroke risk
- Positive cardiac inotrope
- Mild diuretic effect in CHF patients
- Reduces sympathetic activity (due to improved CO, fluid loss &, improved haemodynamic)
CARDIAC GLYCOSIDES: Adverse Effects of DIGOXIN - 4
- Dose-dependent toxicity
- Cardiac tachyarrhythmias (due to DADs from cardiac calcium overload)
- GI (gastric irritations, diarrhoea, nausea, vomiting)
- CNS: Dizziness, headache, Bradycardia
CARDIAC GLYCOSIDES: Factors that may affect plasma levels & toxicity of DIGOXIN - 6
- Most of digoxin excreted by transporter called P-glycoprotein in the kidneys in the PCT
- Drugs that inhibit this protein can cause variable degrees of digoxin retention.
- In practice digoxin is most commonly used with amiodarone or verapamil in patients with resistant atrial fibrillation (hence careful monitoring required).
- Clinical effectiveness of digoxin treatment influenced by thyroid status of the patient.
- Untreated hyperthyroidism require higher doses of digoxin, compared to patient with normal thyroid function.
- Hypothyroidism require lower doses.
CARDIAC GLYCOSIDES: Factors that may affect plasma levels & toxicity of DIGOXIN: Hypokalaemia
Hypokalaemia (e.g. caused by diuretics or hyperaldosteronism)
(Increased binding to the Na-Pump in the heart: more CV effects)
CARDIAC GLYCOSIDES: Factors that may affect plasma levels & toxicity of DIGOXIN: Hyperkalaemia
Hyperkalaemia (e.g. caused by aldosterone antagonists, ACEIs/ARBs) (Increased plasma levels: more CNS & GI effects)
CARDIAC GLYCOSIDES: Factors that may affect plasma levels & toxicity of DIGOXIN: Hyperthyroidism
Hyperthyroidism
(If untreated, needs high doses than when treated)
CARDIAC GLYCOSIDES: Factors that may affect plasma levels & toxicity of DIGOXIN: Impaired kidney function
Impaired kidney function
(less excretion, increased plasma levels)
CARDIAC GLYCOSIDES: Factors that may affect plasma levels & toxicity of DIGOXIN: Drugs affecting renal excretion
Drugs affecting renal excretion
(P-gp substrates or inhibitors (e.g. Amiodarone, Spironolactone, CCBs e.g. Verapamil, Nifedipine)
CARDIAC GLYCOSIDES: Factors that may affect plasma levels & toxicity of DIGOXIN -
- Cytotoxic agents &/or radiotherapy can damage the intestine lining, reduces absorption of digoxin tablets
- Non-renal (biliary) excretion of digoxin small, but absorption from gut can be influenced by diseases/chronic inflammation of GIT.
- Increased plasma K+ displace digoxin > clearance
- Untreated hyperthyroid patients require higher doses of digoxin
- Untreated hypothyroid patients require lower doses. Evidence that GFR is changed by thyroid status & this could account for these observations
CARDIAC GLYCOSIDES: Treatment and prevention of DIGOXIN toxicity - 6
- If with CCBs: lower dose (renal & non-renal increase in plasma levels)
- If hypokalaemia – Oral K+ supplements, increase plasma K+, increase plasma digoxin
- If hyperkalaemia – use of digoxin-specific immunoglobulin fragments, Fab – a digoxin-immune fragment binds digoxin more potently than Na/K ATPase, increasing Cl
- Tachyarrhythmia: Anti-arrhythmic propranolol (a beta-blocker)
- Bradycardia management: atropine.
- Steroid-binding resins: Cholestyramine bind to digoxin in GIT, reducing its BA.
ARNI: DUAL ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITORS: Targets - 2
- RAAS
- Natriuretic Peptide (NP) systems
Expression of Nartiuretic peptides - 4
- Tissue expression of Natriuretic Peptides, proteolytic activation processing from pre-prohormones to mature & biologically active peptides.
- Tubular cells in the kidney release the NP, urodilatin, acts locally in the kidney & excreted via kidney.
- BNP & NT-proBNP are more stable in plasma compared to ANP/NT-proANP, due to being less sensitive to breakdown by neutral endopeptidase.
- Pre-pro-BNP is transcriptionally regulated & synthetised when ventricles are stretched by excess of blood & then released as proBNP.
Natriuretic peptide Types - 3
- Atrial NP (ANP) - Atria/Ventricles
- Brain NP (BNP) - Ventricles/Atria
- C-type NP (CNP) - wider sources
Processing of Natriuretic peptides - 5
- Produced as pre-pro-NPs, processed, then released as pro-NPs.
- Pro-ANP is stored in vesicles in atrial myocytes – quickly released.
- Pro-NPs then converted by surface proteases to active hormones & inactive NT-pro-NPs segments
- Raised BNP & NT-proBNP correlate with degree of left ventricular dysfunction in HF.
- BNP & NT-proBNP are important biomarkers in diagnosis of HF.
Key points on NP system - 4
- NPs act via membrane-bound NP receptors:
NPRA (ANP=BNP)
NPRB (CNP) - NRPA/NRPB are guanylyl cyclase-coupled receptors (increase in cGMP/PKG)
- NPRC (no GC-domain)- Involved in Clearance of
ANP = CNP>BNP - Degradation by NEP (neprilysin or neutral endopeptidase)
INTERACTIONS WITH THE RAAS & BRADYKININ & THERAPEUTIC POTENTIAL OF NEP INHIBITORS - 5
- Renin to angiotensin to Ang I converted by ACE to Ang II
- Ang II causes ANP & BNP produce NPR-A.
- Ang II converted by ACE to AT1R.
- Each system counteracts each other’s effect on the organs.
- Bradykinin also effects blood vessels e.g. vasoconstriction
THE NP SYSTEM: MoA of LCZ696 (Sacubitril/Valsartan - 8
- ProBNP processed into NT-ProBNP & BNP
- BNP acts (e.g. vasodilation) & undergoes degradation into breakdown products.
- RAAS system: Angiotensin (liver) acted on by renin (kidneys)
- Produces Angiotensin I, ACE (lungs) produces Angiotensin II, which acts on its receptor.
- LCZ 696 metabolised into AHU 377, then LBQ 657, acting as Neprilysin inhibitor.
- ProBNP & NT-proBNP are not substrates of neprilysin, & ergo, can still be used as markers of HF severity in patients who are taking LCZ 696.
- LCZ 696 also metabolised into Valsartan, an ARB.
- NEP inhibitor blocked both NP system & RAAS system.
