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