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106 > Pharmacology Cardiac contractility & +Inotropes > Flashcards

Pharmacology Cardiac contractility & +Inotropes Flashcards

1
Q

Cardiac CONTRACTION: Calcium entry & Calcium-Induced Calcium Release (CIRC) - 4

A
  1. Rapid depolarisation due to fast Na+ influx via Na+ channels
  2. Depolarisation dependent activation of L-VACCs & influx of extracellular Ca
  3. Ca induced activation of RyR2 on the SR & C induced C release
  4. Ca influx via Na –Ca exchanger via reverse mode of the Na-Ca exchanger
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2
Q

The Ryanodine Receptor (RyR) -4

A
  1. RyR is an intracellular calcium release channel on the SR
    Three main isoforms:
  2. RyR1 – skeletal muscles
  3. RyR2 – cardiac muscles
  4. RyR3 – brain & other tissues
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3
Q

Cardiac CONTRACTION: Cardiac Ryanodine Receptor (RyR2) – 5

A
  1. Contains cytoplasmic Ca binding sites: activated by low cytosolic Ca & inhibited by high cytosolic Ca
  2. Calstabin-2, endogenous stabiliser that keeps RyR2 channel closed;
  3. Calmodulin (CaM) inhibits opening of RyR2 in [Ca] independent manner
  4. Phosphorylation sites for PKA (sympathetic NS) & for CaMKII (enhanced with increased [Ca] in cytosol) – increased opening of RyR2
  5. In SR lumen: Calsequestrin-2, a low affinity, high-capacity Ca binding protein
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4
Q

Environment of the RyR channel in skeletal muscle - 6

A
  1. The t tubule contains tetrads of dihydropyridine receptors (DHPRs).
  2. A t-tubule membrane voltage change activates DHPR.
  3. The t-tubule signal transmitted to RyR1 channel by DHPR-RyR1 linkage.
  4. The t-tubule signal triggers RyR1 channel to open & release Ca stored inside SR.
  5. Calsequestrin (CSQ), a low-affinity high-capacity calcium buffer, found inside SR lumen near RyR1 channels.
  6. The SR Ca2+-ATPase (SERCA) uses the energy stored in the ATP to pump calcium back into the SR.
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5
Q

Environment of the RyR2 channel in cardiac muscle - 5

A
  1. The t tubule contains dihydropyridine receptors (DHPRs) & calcium extrusion mechanisms (e.g. Na/Ca exchanger)
  2. A t-tubule membrane voltage change activates DHPR & resulting Ca entry triggers underlying RyR2 channels to open.
  3. Open RyR2 channel releases Ca stored in SR, into the cytoplasm. Calsequestrin (CSQ,) buffers Ca near RyR2 channels inside SR.
  4. SERCA uses energy from ATP to pump Ca back into SR.
  5. The Na-CaX uses energy stored in Na gradient to move Ca out of the cell.
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6
Q

Ca++-Induced Ca++ Release (CICR) in the Cardiac Myocyte – 6

A
  1. Ca enters via a L-VACC
    2.Activation of a cluster of RyRs
  2. Local Ca release
    4.Rapid summation of local events
  3. Global raise in Ca
  4. CONTRACTION
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7
Q

Drugs which make RyR ‘leaky’: - 3

A
  1. Excess of caffeine
  2. Immunosuppressants
  3. Cardiac glycosides (e.g. Digoxin)
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8
Q

Genetics or acquired abnormal function (e.g. in CHF) in: - 3

A
  1. Cardiac RyR2
  2. Calsequestrin-2 (CASQ2)
  3. Calmodulin (CaM)
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9
Q

Cardiac RELAXATION: Calcium re-uptake & extrusion - 4

A
  1. Ca reuptake into the SR by a SR/ER Calcium ATPase (SERCA)
  2. Ca extrusion by Na-Ca exchanger
  3. Ca extrusion by Ca ATPase (Ca-Pump)
  4. Ca uptake into mitochondria by the mitochondrial Ca uniporter
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10
Q

Cardiac RELAXATION: Ca2+ re-uptake into the SR by SERCA & its regulation by Phospholamban (PLB) - 6

A
  1. SERCA increases cytosolic Ca
  2. Dephosphorylated PLB binds to SERCA pump & regulates its activity
  3. Interaction disrupted by phosphorylation of PLB or in presence of high [calcium]
  4. PLB is phosphorylated by:
  5. PKA (Protein Kinase A) (main)
  6. CaMKII (Ca-Calmodulin-depended Kinase II)
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11
Q

Cardiac RELAXATION: Ca++ extrusion by the NCX: Forward (Normal) mode - 4

A
  1. Activated by increased cytosolic Ca
  2. Removes 1 cytosolic Ca in exchange for 3 Na
  3. Reduces cytosolic [Ca]
  4. ELECTROGENIC: Can cause membrane depolarisation, triggering delay in depolarisation in Ca overloaded myocytes
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12
Q

Cardiac RELAXATION: Ca++ extrusion by the NCX: Reverse mode - 3

A
  1. Activated by increased cytosolic Na+
  2. Expels 3 Na in exchange for 1 cytosolic Ca
  3. Increases cytosolic [Ca]
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13
Q

Catecholamines effect on the heart

A

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.

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14
Q

Inotropic effect (medication changes to contractility of the heart) - 4

A
  1. Increased force of contraction (positive inotropic effect) is enabled by more rapid increase in [Ca++]cyt due to enhanced activity of:
  2. L-VACCs (greater Ca influx),
  3. RyR2 (more Ca is released from the SR),
  4. Increased Ca-sensitivity of the tropomyosin complex via phosphorylation of regulatory Troponin I
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15
Q

Lusitropic effect (rate of myocardial relaxation) - 3

A
  1. Increased rate of relaxation (positive lusitropic effect) via accelerated reuptake of cytosolic Ca++ into the SR due enhanced activity:
  2. SERCA results of increased phosphorylation of phospholamban (PLB).
  3. Enables a stronger force of contraction at increased HR.
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16
Q

Define Heart failure & give symptoms

A

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)

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17
Q

Pathogenesis as a cause of signs & symptoms in CHF - 6

A
  1. Impaired cardiac function reduces cardiac contractility & reduces CO
  2. 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).
  3. Reduced CO activates sympathetic NS (via central & carotid baroreceptors) increasing circulating catecholamine levels.
  4. All increase systemic peripheral resistance & in central venous pressure
  5. Positive feedback loop where physiological compensatory mechanisms progressively weaken the heart.
  6. Called congestive HF (CHF) or HF with reduced ejection fraction (HFrEF) due to reduced CO due to left ventricular dysfunction & fluid retention.
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18
Q

CHF Pathogenesis as the basis for current therapies - 5

A
  1. Positive inotropes: To enhance CO
  2. Beta-Blockers: To decrease cardiotoxicity of catecholamines
  3. ACEIs/ARBs/MRAs: To reduce activation of the RAAS
  4. Diuretics: To reduce oedema
  5. Vasodilators: To decrease TPR & CVP
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19
Q

Pharmacological therapy of CHF -3

A
  1. 1st LINE THERAPY: ACEI/ARB + beta-Blocker + Diuretic + SGLT2 inhibitor
  2. 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)
  3. If HF associated with angina: CCB (give Amlodipine)
20
Q

BENEFITS BETA-BLOCKERS IN TREATMENT OF HF - 8

A
  1. Examples: Bisoprolol (b1), Nebivolol (b1), Carvedilol (b/a1)
  2. Beta-blockers are negative inotropes, but have benefits
  3. B1-blockers thought to reduce sympathetic drive to the heart, leading to increase of density of B-adrenoceptors
  4. This reduces hypertrophic cardiomyopathy.
  5. Inhibition of cardiotoxicity of catecholamines
  6. Increase of the density of β-adrenoceptors on cardiac myocytes
  7. Anti-hypertensive, antianginal & anti-arrhythmic effects
  8. Antioxidant & anti-proliferative effects (Carvedilol, Nebivolol)
21
Q

BENEFECIAL EFFECT OF POSITIVE INOTROPIC AGENTS IN CHF - 3

A
  1. In CHF CO considerably drops below normal range
  2. Positive inotropes can raise CO closer to normal CO
  3. Reduces symptoms
22
Q

POSITIVE INOTROPIC AGENTS AND THEIR USES IN CHF: Catecholamines - 4

A
  1. Noradrenaline
  2. Adrenaline
  3. Isoprenaline (non-selective β-agonist)
  4. DOBUTAMINE (β1 agonist) (in specialised cases & acute decompensated HF)
23
Q

POSITIVE INOTROPIC AGENTS AND THEIR USES IN CHF: Phosphodiesterase type-3 inhibitors – 2 & Cardiac glycosides:

A
  1. MILRINONE (short-term treatment of acute severe decompensated HF)
  2. 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)
24
Q

MoA of Catecholamines, (e.g. Dobutamine) - 4

A
  1. Catecholamines act by binding to specific adrenergic receptors on target cells, primarily alpha & beta subtypes.
  2. When catecholamines bind to β1 receptors (Gs-protein coupled), they activate adenylyl cyclase, increasing cAMP production.
  3. cAMP activates protein kinase A (PKA), which increases heart rate (chronotropy), the force of contraction (inotropy).
  4. Resulting in enhanced CO & increased heart rate.
25
Q

PDE-3 inhibitor method of action – 4

A
  1. PDE3 inhibitors bind to PDE3, changing the shape of the active site, inhibiting its effect.
  2. By inhibiting PDE3, PDE3 inhibitors prevent breakdown of cAMP, leading to increased cAMP.
  3. Elevated cAMP levels activate protein kinase A (PKA), which increases heart rate (chronotropy), the force of contraction (inotropy).
  4. Resulting in enhanced CO & increased heart rate.
26
Q

POSPHODIESTERASE TYPE 3 INHIBITORS: Benefits 3 vs adverse 3
Beneficial systemic effects:

A
  1. Increased CO
  2. Reduction in right atrial pressure (less risk of pulmonary oedema)
  3. Reduced TPR & reduced cardiac preload (due to peripheral arterial & venous dilatation)
    Adverse reactions:
  4. Lethal arrhythmias with a prolonged use of MILRINONE
  5. Hypotension
  6. Headache
27
Q

Mechanism of digoxin as positive inotrope - 4

A
  1. Inhibition of Na-K ATPase leads to cellular sodium build-up
  2. Activates the reverse mode of the NCX
  3. Increases intracellular Ca & hence more stored in SR & available for release upon next stimuli via the CICR mechanism
  4. Force of contraction is increased
28
Q

Mechanism for digoxin cardiac toxicity & Delayed-After-Dpolarisation (DAD): - 5

A
  1. Digoxin overdose can lead to build up of Ca in the cytoplasm;
  2. Stimulates the forward mode of the NCX: removing the excess of cytosolic Ca outside the cell in exchange for Na+.
  3. The NCX is electrogenic (exchanges 3Na for 1 Ca, i.e. generates +ion flux in direction of net Na movement)
  4. Forward mode moves Na in creating inward movement of + charges into the cell (reduced electronegativity)
  5. Causes membrane depolarisation & triggers a DAD that can lead to arrhythmias
29
Q

Glycosides, Dygoxin: Therapeutic use - 3

A
  1. In worsening or severe HF in patients with normal sinus rhythm
  2. 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.
  3. Reduces sympathetic activity & lessen detrimental effects in CHF patients
30
Q

Glycosides, Dygoxin: Benefits in CHF - 4

A
  1. Anti-arrhythmic helps control stroke risk
  2. Positive cardiac inotrope
  3. Mild diuretic effect in CHF patients
  4. Reduces sympathetic activity (due to improved CO, fluid loss &, improved haemodynamic)
31
Q

CARDIAC GLYCOSIDES: Adverse Effects of DIGOXIN - 4

A
  1. Dose-dependent toxicity
  2. Cardiac tachyarrhythmias (due to DADs from cardiac calcium overload)
  3. GI (gastric irritations, diarrhoea, nausea, vomiting)
  4. CNS: Dizziness, headache, Bradycardia
32
Q

CARDIAC GLYCOSIDES: Factors that may affect plasma levels & toxicity of DIGOXIN - 6

A
  1. Most of digoxin excreted by transporter called P-glycoprotein in the kidneys in the PCT
  2. Drugs that inhibit this protein can cause variable degrees of digoxin retention.
  3. In practice digoxin is most commonly used with amiodarone or verapamil in patients with resistant atrial fibrillation (hence careful monitoring required).
  4. Clinical effectiveness of digoxin treatment influenced by thyroid status of the patient.
  5. Untreated hyperthyroidism require higher doses of digoxin, compared to patient with normal thyroid function.
  6. Hypothyroidism require lower doses.
33
Q

CARDIAC GLYCOSIDES: Factors that may affect plasma levels & toxicity of DIGOXIN: Hypokalaemia

A

Hypokalaemia (e.g. caused by diuretics or hyperaldosteronism)
(Increased binding to the Na-Pump in the heart: more CV effects)

34
Q

CARDIAC GLYCOSIDES: Factors that may affect plasma levels & toxicity of DIGOXIN: Hyperkalaemia

A

Hyperkalaemia (e.g. caused by aldosterone antagonists, ACEIs/ARBs) (Increased plasma levels: more CNS & GI effects)

35
Q

CARDIAC GLYCOSIDES: Factors that may affect plasma levels & toxicity of DIGOXIN: Hyperthyroidism

A

Hyperthyroidism
(If untreated, needs high doses than when treated)

36
Q

CARDIAC GLYCOSIDES: Factors that may affect plasma levels & toxicity of DIGOXIN: Impaired kidney function

A

Impaired kidney function
(less excretion, increased plasma levels)

37
Q

CARDIAC GLYCOSIDES: Factors that may affect plasma levels & toxicity of DIGOXIN: Drugs affecting renal excretion

A

Drugs affecting renal excretion
(P-gp substrates or inhibitors (e.g. Amiodarone, Spironolactone, CCBs e.g. Verapamil, Nifedipine)

38
Q

CARDIAC GLYCOSIDES: Factors that may affect plasma levels & toxicity of DIGOXIN -

A
  1. Cytotoxic agents &/or radiotherapy can damage the intestine lining, reduces absorption of digoxin tablets
  2. Non-renal (biliary) excretion of digoxin small, but absorption from gut can be influenced by diseases/chronic inflammation of GIT.
  3. Increased plasma K+ displace digoxin > clearance
  4. Untreated hyperthyroid patients require higher doses of digoxin
  5. Untreated hypothyroid patients require lower doses. Evidence that GFR is changed by thyroid status & this could account for these observations
39
Q

CARDIAC GLYCOSIDES: Treatment and prevention of DIGOXIN toxicity - 6

A
  1. If with CCBs: lower dose (renal & non-renal increase in plasma levels)
  2. If hypokalaemia – Oral K+ supplements, increase plasma K+, increase plasma digoxin
  3. If hyperkalaemia – use of digoxin-specific immunoglobulin fragments, Fab – a digoxin-immune fragment binds digoxin more potently than Na/K ATPase, increasing Cl
  4. Tachyarrhythmia: Anti-arrhythmic propranolol (a beta-blocker)
  5. Bradycardia management: atropine.
  6. Steroid-binding resins: Cholestyramine bind to digoxin in GIT, reducing its BA.
40
Q

ARNI: DUAL ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITORS: Targets - 2

A
  1. RAAS
  2. Natriuretic Peptide (NP) systems
41
Q

Expression of Nartiuretic peptides - 4

A
  1. Tissue expression of Natriuretic Peptides, proteolytic activation processing from pre-prohormones to mature & biologically active peptides.
  2. Tubular cells in the kidney release the NP, urodilatin, acts locally in the kidney & excreted via kidney.
  3. BNP & NT-proBNP are more stable in plasma compared to ANP/NT-proANP, due to being less sensitive to breakdown by neutral endopeptidase.
  4. Pre-pro-BNP is transcriptionally regulated & synthetised when ventricles are stretched by excess of blood & then released as proBNP.
42
Q

Natriuretic peptide Types - 3

A
  1. Atrial NP (ANP) - Atria/Ventricles
  2. Brain NP (BNP) - Ventricles/Atria
  3. C-type NP (CNP) - wider sources
43
Q

Processing of Natriuretic peptides - 5

A
  1. Produced as pre-pro-NPs, processed, then released as pro-NPs.
  2. Pro-ANP is stored in vesicles in atrial myocytes – quickly released.
  3. Pro-NPs then converted by surface proteases to active hormones & inactive NT-pro-NPs segments
  4. Raised BNP & NT-proBNP correlate with degree of left ventricular dysfunction in HF.
  5. BNP & NT-proBNP are important biomarkers in diagnosis of HF.
44
Q

Key points on NP system - 4

A
  1. NPs act via membrane-bound NP receptors:
    NPRA (ANP=BNP)
    NPRB (CNP)
  2. NRPA/NRPB are guanylyl cyclase-coupled receptors (increase in cGMP/PKG)
  3. NPRC (no GC-domain)- Involved in Clearance of
    ANP = CNP>BNP
  4. Degradation by NEP (neprilysin or neutral endopeptidase)
45
Q

INTERACTIONS WITH THE RAAS & BRADYKININ & THERAPEUTIC POTENTIAL OF NEP INHIBITORS - 5

A
  1. Renin to angiotensin to Ang I converted by ACE to Ang II
  2. Ang II causes ANP & BNP produce NPR-A.
  3. Ang II converted by ACE to AT1R.
  4. Each system counteracts each other’s effect on the organs.
  5. Bradykinin also effects blood vessels e.g. vasoconstriction
46
Q

THE NP SYSTEM: MoA of LCZ696 (Sacubitril/Valsartan - 8

A
  1. ProBNP processed into NT-ProBNP & BNP
  2. BNP acts (e.g. vasodilation) & undergoes degradation into breakdown products.
  3. RAAS system: Angiotensin (liver) acted on by renin (kidneys)
  4. Produces Angiotensin I, ACE (lungs) produces Angiotensin II, which acts on its receptor.
  5. LCZ 696 metabolised into AHU 377, then LBQ 657, acting as Neprilysin inhibitor.
  6. 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.
  7. LCZ 696 also metabolised into Valsartan, an ARB.
  8. NEP inhibitor blocked both NP system & RAAS system.

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