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Cardiac electrophysiology and pharmacology - drdhriti
 

Cardiac electrophysiology and pharmacology - drdhriti

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A PowerPoint Presentation on Basic Electrophysiology of Heart and Angiotensin Converting Enzymes and their Inhibitors suitable for Undergraduate MBBS level Students

A PowerPoint Presentation on Basic Electrophysiology of Heart and Angiotensin Converting Enzymes and their Inhibitors suitable for Undergraduate MBBS level Students

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  • The fast sodium channel can be modeled as being controlled by a number of gates . Each gate (or gating variable) can attain a value between 1 (fully open) and 0 (fully closed). The product of all the gates denotes the percentage of channels available to conduct Na + . Following the model of Hodgkin and Huxley , the sodium channel contains three gates: m , h , and j . In the resting state, the m gate is closed (zero) and the h and j gates are open (one). Hence, the product denoting the percentage of conducting channels is also zero. Upon electrical stimulation of the cell, the m gate opens quickly while simultaneously the h and j gates close more slowly. For a brief period of time, all gates are open ( i.e. non-zero) and Na + can enter the cell following its electrochemical gradient . If, as above, the resting membrane potential is too positive, the h or j gates may be considerably less than one, such that the product of m , h and j becomes too small upon depolarization.
  • RAS is important in case of normal physiological maintainance of homeostasis. RAS plays an important role in development of hypertension. In most of the cases of hypertension PRA is seen to be raised. The long term effects of persistenly active PRA leads to cardiac hypertrophy (ventricular) and remodelling and also coronary artery hypertrophy and remodelling. Therefore by blocking of the hypertension can be controlled by blocking of ACE practically in most of the hypertensive cases.
  • ACE inhibitors have many indications apart from the hypertension which will be talked when particular diseases are talked, For you now you have to remember is that what are the they are the first line of agent now in most of the cases of hypertension specially in young person and persons with ventricular hypertrophy. In practice they are used as first line of agent as monotherapy or in combination with diuretics and beta-blockers. The advantages of ACEIs are

Cardiac electrophysiology and pharmacology - drdhriti Cardiac electrophysiology and pharmacology - drdhriti Presentation Transcript

  • Department of Pharmacology NEIGRIHMS, Shillong
    • Right Coronary
    • Left Anterior Descending
    • Left Circumflex
    • Superior Vena Cava
    • Inferior Vena Cava
    • Aorta
    • Pulmonary Artery
    • Pulmonary Vein
    • Right Atrium
    • Right Ventricle
    • Left Atrium
    • Left Ventricle
    • Papillary Muscles
    • Chordae Tendineae
    • Tricuspid Valve
    • Mitral Valve
    • Pulmonary Valve
    • Aortic Valve (Not pictured)
    • Layers/myocardium
    • Chambers
    • Valves
    • Veins
    • Sinus
    • SA node
    • AV Junction
    • His-Purkinje
    • Myocardial cells
    • Electrical potential
    • Autonomic Nervous system
  •  
    • Action potential
    • Depolarization
    • Repolarization
    • Critical electrolytes
      • Sodium, potassium, calcium
    • Excitability
  •  
    • Drugs having major action on Heart and Blood vessels and used in various important cardiac disease conditons.
    • They act directly on heart structures or via Autonomic Nervous system (ANS), Central Nervous System (CNS), Kidney, Autacoids or Hormones:
      • Cardiac Glycosides
      • Sympathomimetics
      • Anticholinergic Drugs
      • Antiarrhythmics
      • Electrolytes
      • Thrombolytic
      • Anticoagulants
      • Antihypertensive
      • Analgesics
    • Recall: to function efficiently, heart needs to contract sequentially (atria, then ventricles) and in synchronicity
    • Relaxation must occur between contractions (not true for other types of muscle [exhibit tetany  contract and hold contraction for certain length of time]
    • Coordination of heartbeat is a result of a complex, coordinated sequence of changes in membrane potentials and electrical discharges in various heart tissues
    • 2 types – Pacemaker and non pacemaker
      • Pacemaker and conducting cells – SAN, AVN, Bundle of His and Purkinje`s fibres
      • Non pacemaker – Working Myocardial Cell (WMC) or CMC
    • Sinus rhythm means rhythm originates in SAN
    • Sinus tachycardia means tachycardia but rhythm originates in SAN – fever, exercise etc.
    • Tachycardia = heart rate > 100 per minute
    • Sinus Bradycardia = heart rate < 60 per min.
    • Escape rhythm: Rhythm which is not generated by SAN, but other, e.g. AVN or bundle of His etc.
    • A transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative with respect to outside the cell
      • (-90mv) and (+30mv) inside and outside the cell
    • Caused by unequal distribution of ions inside vs. outside cell
      • Na+ higher outside than inside cell
      • Ca+ much higher “ “ “ “
      • K+ higher inside cell than outside
    • Maintenance by ion selective channels, active pumps and exchangers
    • Divided into five phases (0,1,2,3,4)
      • Phase 4 - resting phase (resting membrane potential)
        • At (-90mv) stable
        • Phase cardiac cells remain in until stimulated
        • Associated with diastole portion of heart cycle
    • Addition of current into cardiac muscle (stimulation) causes
      • Phase 0 – opening of fast Na channels and rapid depolarization
        • Drives Na + into cell (inward current), changing membrane potential
        • Transient outward current due to movement of Cl - and K +
      • Phase 1 – initial rapid repolarization
        • Closure of the fast Na + channels
        • Phase 0 and 1 together correspond to the R and S waves of the ECG
  •  
    • Phase 2 - plateau phase
      • sustained by the balance between the inward movement of Ca+ and outward movement of K+
      • Has a long duration compared to other nerve and muscle tissue
      • Normally blocks any premature stimulator signals (other muscle tissue can accept additional stimulation and increase contractility in a summation effect)
      • Corresponds to ST segment of the ECG.
    • Phase 3 – repolarization
      • K+ channels remain open,
      • Allows K+ to build up outside the cell, causing the cell to repolarize
      • K + channels finally close when membrane potential reaches certain level
      • Corresponds to T wave on the ECG
  •  
  • R S T
    • Present in SAN and AVN and His –Purkinje cells
    • Most characteristic feature is in Phase-4, or slow diastolic depolarization.
    • After repolarization membrane potential decays spontaneously and sudden automatic depolarization
    • Therefore capable of generating own impulses
    • Normally SAN has steepest phase-4
    • Characteristics:
      • Initiation at higher threshold (less negative (-75mv)
      • Slow depolarization
      • Low overshoot (+10mv), low amplitude
      • Very slow a propagation
      • Phase-1 and 3 are not clearly demarcated
      • Can occur in fibres depolarized too much to support fast channels
    • Funny current ( I f )
    • Rate of conduction through a fibre is a function of membrane responsiveness
    • The more polarized membrane depolarization is faster and so conduction – seen in case of atrial and ventricular fibres (fast channels)
    • SAN and AVN cells remain refractory even after attainment of maximal RMP
    • Lesser the negativity of RMP, fewer are the Na+ channels available – slope of “0”, AP duration and conduction velocity reduced
    • Drugs which reduces “0 phase” - reduce conduction velocity
    • Action Potential Duration (APD): Duration of Cardiac action potential. Greater the action potential, longer the refractoriness.
    • Absolute refractory period (ARP): A period when heart muscle does not show any response to stimulus however strong the stimulus may be, But Pharmacologically more important is
    • Effective Refractory Period (ERP): Minimum interval between two propagating action potentials. AP can be evoked in Fast channels before completion of Repolarization.
    • In fast channels: ERP/APD<1, but in slow channels ERP/APD>1
      • Na+ and Ca++ channels
  •  
    • What is Renin – Angiotensin System?
    • (Physiological Background)
    • Renin is a proteolytic enzyme and also called angiotensinogenase
    • It is produced by juxtaglomerular cells of kidney
    • Renin acts on a plasma protein – Angiotensinogen (a glycoprotein synthesized and secreted into the bloodstream by the liver) and cleaves to produce a decapeptide Angiotensin-I
    • Angiotensin-I is rapidly converted to Angiotensin-II (octapeptide) by Angiotensin Converting Enzyme (ACE) (present in luminal surface of vascular endothelium)
    • Furthermore degradation of Angiotensin-II by peptidases produce Angiotensin-III
  • Vasoconstriction Na+ & water retention (Adrenal cortex) Kidney Increased Blood Vol. Rise in BP
    • It is secreted in response to:
    • Decrease in arterial blood pressure – also fall in BP and blood volume
    • Decrease Na+ in macula densa
    • Increased sympathetic nervous activity
    (-) (-)
    • Circulating: Renin is the rate limiting factor of AT-II release
      • AT-I is less potent (1/100 th ) than of AT – II
      • Plasma t1/2 of Renin is 15 minutes
      • AT-I is rapidly converted to AT-II by ACE
      • Degradation product is AT-III
      • Both AT-II and AT-III stimulates Aldosterone secretion from Adrenal Cortex (equipotent)
    • Tissue RAS: Many tissues Heart, brain, blood vessels, kidneys, adrenals capture Renin and Angiotensin to produce AT-II
      • Important factor in these organs
    • Powerful vasoconstrictor particularly arteriolar and venular
      • direct action - release of Adr/NA release (adrenal and adrenergic nerve endings)
      • increased Central sympathetic outflow
        • Promotes movement of fluid from vascular to extravascular
    • More potent vasopressor agent than NA –promotes Na+ and water reabsorption and no tachyphylaxis
    • Overall Effect – Pressor effect (Rise in Blood pressure)
    • Cardiac action:
    • Increases myocardial force of contraction (CA++ influx promotion)
    • Increases heart rate by sympathetic activity, but reflex bradycardia occurs
    • Cardiac output is reduced
    • Cardiac work increased (increased Peripheral resistance)
    • Ill effects on chronic basis of exposure (Mitogenic effect!)
      • Directly: Induces hypertrophy, hyperplesia and increased cellular matrix of myocardium and vascular smooth muscles – by direct cellular effects involving proto-oncogens and transcription of growth factors
      • Indirectly: Volume overload and increased t.p.r in heart and blood vessels
        • Hypertrophy and Remodeling (abnormal redistribution of muscle mass)
      • Long standing hypertension – increases vessel wall thickness and Ventricular hypertrophy
      • Myocardial infarction – fibrosis and dilatation in infarcted area and hypertrophy of non-infarcted area of ventricles
      • CHF – progressive fibrotic changes and myocyte death
      • Risk of increased CVS related morbidity and mortality
    • ACE inhibitors reverse cardiac and vascular hypertrophy and remodeling
  •  
    • Adrenal cortex: Enhances the synthesis and release of Aldosterone
      • In distal tubule Na+ reabsorption and K+ excretion
    • Kidney: Enhancement of Na+/H+ exchange in proximal tubule – increased Na+, Cl- and HCO3 reabsorption
      • Also reduces renal blood flow and promotes Na+ and water retention
    • CNS: Drinking behaviour and ADH release
    • Peripheral sympathetic action: Stimulates adrenal medulla to secrete Adr and also releases NA from autononic ganglia
    • 2 (two) subtypes: AT 1 and AT 2 – most of known Physiologic effects are via AT 1
      • Both are GPCR
    • Utilizes various pathways for different tissues
      • PLC-IP3/DAG: AT 1 utilizes pathway for vascular smooth muscles by MLCK
      • Membrane Ca++ release: aldosterone synthesis, cardiac inotropy, CA release - ganglia/adrenal medulla action etc.
      • Adenylyl cyclase: in liver and kidney (AT 1 )
      • Intrarenal homeostatic action: Phospholipase A2
    • Mineraocorticoid secretion
    • Electrolyte, blood volume and pressure homeostasis: Renin is released when there is change in blood volume or pressure or decreased Na+ content
      • Reduction in tension in afferent gromerulus - Intrarenal Baroreceeptor Pathway activation – PG production - Renin release
      • Low Na+ conc. in tubular fluid – macula densa pathway – COX-2 and nNOS are induced – release of PGE2 and PGI2 – more renin release
      • Baroreceptor stimulation increases sympathetic impulse – via beta-1 pathway – renin release
    • Renin release – increased Angiotensin II production – vasoconstriction and increased Na+ and water reabsorption
    • Rise in BP – decreased Renin release - Long term stabilization of BP is achieved – long-loop negative feedback mechanism
    • Short-loop negative feedback mechanism:
      • activation of AT1 receptor in JG cells – inhibition of Renin release
      • Long term stabilization of salt and water intake
    • Pharmacological importance:
      • Drugs Increasing Renin release:
        • ACE inhibitors and AT1 antagonists enhance Renin release
        • Vasodilators and diuretics stimulate Renin release
        • Loop diuretics increase renin release
      • Decrease in Renin release:
        • Beta blockers and central sympatholytics
        • NSAIDs and selective COX-2 inhibitors decrease Renin release
    • Hypertension
    • Secondary hyperaldosteronism
    • Inhibitors of RAS:
    • Sympathetic blockade
    • ACE inhibitors
    • AT 1 receptor antagonists
    • Aldosterone antagonists
    • Renin inhibitory peptides and Renin specific antibodies
    • Captopril, lisinopril, enalapril, ramipril and fosinopril etc.
    • Acts on A-I, but not on A-II
    • Depends on Na+ status and level of RAS
    • In normotensives:
      • With normal Na+ level – fall in BP is minimal
      • But restriction in salt or diuretics - more fall in BP
    • Renovascular and malignant hypertension – greater fall in BP
    • Essential hypertension: 20% hyperactive RAS and 60% hypoactive in RAS
      • Contributes to 80% of maintainence of tone – lowers BP
      • But no long term relation of fall in BP by captopril and RAS activity
    • Actions:
      • Decrease in peripheral Resistance
      • Arteriolar dilatation to fit with larger arteries
      • Fall in Systolic and Diastolic BP
      • No effect on Cardiac output
      • No Postural hypotension
      • No reflex sympathetic stimulation
      • Can be used safely in IHD patients
      • Renal blood flow is maintained – greater dilatation of vessels
    • Pharmacokinetics:
      • 70% absorbed, partly metabolized and partly excreted unchanged in urine
      • Food interferes absorption
      • T1/2 = 2 Hrs (6-12 Hrs)
    • Cough – persistent brassy cough in 20% cases – inhibition of bradykinin and substanceP breakdown in lungs
    • Hyperkalemia in renal failure patients with K+ sparing diuretics, NSAID and beta blockers (routine check of K+ level)
    • Hypotension – sharp fall may occur – 1st dose
    • Acute renal failure: CHF and bilateral renal artery stenosis
    • Angioedema: swelling of lips, mouth, nose etc.
    • Rashes, urticaria etc
    • Dysgeusia: loss or alteration of taste
    • Foetopathic: hypoplasia of organs, growth retardation etc
    • Neutripenia
    • Contraindications: Pregnancy, bilateral renal artery stenosis, hypersensitivity and hyperkalaemia
    • It’s a prodrug – converted to enalaprilate
    • Advantages over captopril:
      • Longer half life – OD (5-20 mg OD)
      • Absorption not affected by food
      • Rash and loss of taste are less frequent
      • Longer onset of action
      • Less side effects
    • It’s a popular ACEI now
    • It is also a prodrug with long half life
    • Tissue specific – Protective of heart and kidney
    • Uses: Diabetes with hypertension, CHF, AMI and cardio protective in angina pectoris
    • Blacks in USA are resistant to Ramipril – addition of diuretics help
    • Dose: Start with low dose; 2.5 to 10 mg daily
    • EBM Reports: 1) improves mortality rate in early AMI cases 2) reduces the chance of development of AMI 3) reduces the chances of development of nephropathy etc. (1.25, 2.55 … 10 mg caps)
    • It’s a lysine derivative
    • Not a prodrug
    • Slow oral absorption – less chance of 1 st dose phenomenon
    • Absorption not affected by food and not metabolized – excrete unchanged in urine
    • Long duration of action – single daily dose
    • Doses: available as 1.25, 2.5, 5, 10 1nd 20 mg tab – start with low dose
    • 1 st line of Drug:
      • No postural hypotension or electrolyte imbalance (no fatigue or weakness)
      • Safe in asthmatics and diabetics
      • Prevention of secondary hyperaldosteronism and K+ loss
      • Renal perfusion well maintained
      • Reverse the ventricular hypertrophy and increase in lumen size of vessel
      • No hyperuraecemia or deleterious effect on plasma lipid profile
      • No rebound hypertension
      • Minimal worsening of quality of life – general wellbeing, sleep and work performance etc.
    • Hypertension
    • Congestive Heart Failure
    • Myocardial Infarction
    • Prophylaxis of high CVS risk subjects
    • Diabetic Nephropathy
    • Schleroderma crisis
    • Competitive antagonist and inverse agonist of AT1 receptor
    • Does not interfere with other receptors except TXA2
    • Blocks all the actions of A-II - vasoconstriction, sympathetic stimulation, aldosterone release and renal actions of salt and water reabsorption
    • No inhibition of ACE
    • Theoretical superiority over ACEIs:
      • Cough is rare – no interference with bradykinin and other ACE substrates
      • Complete inhibition of AT1 – alternative pathway remains for ACEIs
      • Result in indirect activation of AT2 – vasodilatation (additional benefit)
      • Clinical benefit of ARBs over ACEIs – not known
    • However, losartan decreases BP in hypertensive which is for long period (24 Hrs)
      • heart rate remains unchanged and cvs reflxes are not interfered
      • no significant effect in plasma lipid profile, insulin sensitivity and carbohydrate tolerance etc
      • Mild uricosuric effect
    • Pharmacokinetic:
      • Absorption not affected by food but unlike ACEIs its bioavailability is low
      • High first pass metabolism
      • Carboxylated to active metabolite E3174
      • Highly bound to plasma protein
      • Do not enter brain
    • Adverse effects:
      • Foetopathic like ACEIs – not to be administered in pregnancy
      • Rare 1 st dose effect hypotension
      • Low dysgeusia and dry cough
      • Lower incidence of angioedema
    • Available as 25 and 50 mg tablets
    • ACEIs mechanism of action
    • Therapeutic uses of ACEIs and adverse effects
    • Present status of ACEI/SRBs
    • Role of ACEIs/ARBs in management of Hypertension
    • Study yourself – Plasma kinins
  • Next Class – Cardiac Glycosides