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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
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Dr. D. K. BrahmaDepartment of Pharmacology
NEIGRIHMS, Shillong
1. Right Coronary2. Left Anterior Descending3. Left Circumflex4. Superior Vena Cava5. Inferior Vena Cava6. Aorta7. Pulmonary Artery 8. Pulmonary Vein9. Right Atrium10. Right Ventricle11. Left Atrium12. Left Ventricle13. Papillary Muscles14. Chordae Tendineae15. Tricuspid Valve16. Mitral Valve17. Pulmonary Valve18. 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:
1. Cardiac Glycosides2. Sympathomimetics3. Anticholinergic Drugs4. Antiarrhythmics5. Electrolytes6. Thrombolytic7. Anticoagulants8. Antihypertensive9. 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 (If)
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 (1/100th) 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: AT1 and AT2 – most of known Physiologic effects are via AT1
Both are GPCR Utilizes various pathways for different tissues
PLC-IP3/DAG: AT1 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 (AT1) Intrarenal homeostatic action: Phospholipase A2
1. Mineraocorticoid secretion2. 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
3. Hypertension4. Secondary hyperaldosteronism
Inhibitors of RAS: Sympathetic blockade ACE inhibitors AT1 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 1st
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
1st 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 1st 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