2. The most common form of heart disease
The single most important cause of
premature death world wide
Death: Male: 1 in 3, Female 1in 4
It is due to atheroma and it complications –
thrombosis - in coronary arteries
CAD, CHD, IHD all synonym
2
3. Risk factors of CAD:
◦ High blood cholesterol levels
◦ High B.P
◦ Cigarette smoking
◦ Obesity
◦ Diabetes mellitus
◦ Sedentary life
◦ Genetic predisposition & Gender
Anginal Drugs
4. The main cause of CAD
◦ Atherosclerotic plaques formation in coronary
arteries
atherosclerotic plaques
◦ A type of lesions formed in the walls of
large and medium sized coronary arteries
◦ Reduces the blood supply to myocardium
Anginal Drugs
5. Unstable angina
◦ Ischaemia caused by dynamic obstruction of
coronary arteries
◦ Due to rupture of atheromatus plaque
◦ Associated with coronary vasospasm
Variant angina (Prinzmetal’suncommon form)
◦ Attacks occurs at rest or during sleep
◦ Due to recurrent localized vasospasm of
atheromatized coronary arteries
5
6. Myocardial Infarction (MI)
◦ Myocardial necrosis caused by acute occlusion of
an artery:
◦ Due to plaque rupture and thrombosis
Heart failure
◦ Myocardial dysfunction due to infarction or
ischaemia
Arrhythmia
◦ Altered conduction due to ischaemia or infarction
Sudden Death
◦ Ventricular arrhythmia, asystole or massive MI
6
10. Severe chest pain caused
by transient myocardial
ischaemia
Occurs due to an
imbalance between
myocardial oxygen
supply and demand
Constitute a clinical
syndrome
The Cause: Coronary
atheroma
10
11. Common form; Attacks predictable; Provoked
by exercises, eating, emotions
Cause:
◦ Ischaemia is due to fixed atheromatous stenosis of
larger coronaries
◦ Blood flow fails to meet the increased demand
◦ Results in an acute & reversible LVF, Left ventricular
failure
11
12. Left Ventricle end diastolic pressure rises from
5 to 25 mm Hg
◦ Diastolic subendocardial crunch
◦ Ischaemia aggravated in the region
Aims of the drug therapy:
◦ To reduce work load on heart
12
14. Uncommon form
◦ Attacks occur at rest / in sleep
Cause:
◦ Transient spasm of localized portion of
atheromatized coronary arteries
Aims of drug therapy:
◦ To prevent and reduce vasospasm
14
15. Rapid increase in duration and severity of
attacks
Ischaemia caused by dynamic obstruction of
coronary arteries
◦ Rupture of atheromatous plaque
◦ Platelets deposition at the site
◦ Progressive occlusion of the artery
Associated with coronary vasospasm
Aim: To reduce the vasospasm
15
23. In classical angina the nitrates:
◦ Reduce cardiac work load
◦ Increase blood flow to ischaemic area
In Variant angina:
◦ Reduce coronary vasospasm by
dilating larger coronaries
Anginal Drugs
24. How exactly nitrates relieve
pain in classical angina
◦By decreasing work load on heart
By reducing preload
By reducing after load
◦By redistributing the coronary
flow to affected area
Anginal Drugs
26. In classical angina the nitrates:
◦ Reduce cardiac work load
◦ Increase blood flow to ischaemic area
◦ By reducing preload
◦ By reducing after load
◦ By redistributing the coronary flow to affected area
In Variant angina
◦ Reduce coronary vasospasm by dilating larger
coronaries
26
27. Dilatation of
◦ Cutaneous vessels: Flushing
◦ Meningeal vessels: Headache
Reduction of Splanchinic and renal blood flow
◦ Shifting of blood from lungs to systemic circulation
◦ Decongestions of lungs
27
28. Relaxation of SM of
◦ Bronchial
◦ Biliary tract
◦ Oesophagus
◦ Genitourinary tract
Variable and insignificant
◦ Intestine
◦ Ureters, and Uterus
28
29. Reduce platelet aggregation through
increased GC-cGMP pathway
NO, oxidizes the ferrous iron of Hb to Ferric
state, Methemoglobin:
◦ Low affinity for O2
◦ Pseudocyanosis, Tissue hypoxia
◦ Death in high doses
29
30. Lipid soluble molecules
Well absorbed from skin, buccal mucous and
intestine
Extensive First Pass Metabolism
Denitrated by GSH-reductase
GTN acts rapidly and short acting
sublingually, long acting orally
30
31. Fullness in head, throbbing headache
Flushing weakness, sweating, palpitation,
dizziness, and fainting
Methemoglobinemia
Rashes
Tolerance
Dependence
Drug interactions with sildenafil
31
32. Explosive liquid stuffed in tablets
Route: Sublingual for acute attacks
◦ Onset: 1- 2 min, t1/2= 2 min
Sublingual spray: Very rapid effect
Oral dosage forms: For prophylaxis
◦ Dose: Large (5-15 mg)
For long acting: Sustained release dosage
forms for chronic prophylaxis
32
33. Transdermal patch: Onset – 60 min
◦ For 24 hr action
◦ Limitations: Tolerance
Transmucosal patch: Onset - 5 min
◦ For 4 - 6 hr
IV infusion: For rapid and steady effect
◦ Used for unstable angina, coronary vasospasm, LVF
with MI, Hypertension
33
34. Solid substance
Properties same as GTN
Sublingually for acute attacks
Orally for chronic prophylaxis
Pronounced pre-systemic effect by p.o.
t1/2: 40 min; SR: 6-10 hr
Last dose to be taken: Before 6pm
34
35. Metabolite of isosorbide dinitrate
Less first pass effect, given orally
High bio-availability
Long acting; t1/2 4-6 hrs
Last dose: In the afternoon
SR tablet: OD in the morning
35
36. Long acting nitrates
Used only for chronic prophylaxis
SR preparation on BD- QID dosing
First pass metabolism is saturated on daily
dosing
Duration of action: 4-6 hrs
36
37. Angina Pectoris
◦ Questions: How are nitrates useful in angina?
◦ What are the limitations of nitrates?
◦ Are nitrates effective in unstable angina?
Myocardial infarction
◦ Question: How is GTN useful in MI?
CCF and acute LVF
◦ Question: Explain the rationale behind the use of
IV GTN in LVF
Interventional cardiac procedures
Biliary colic due to disease or morphine:
Sublingual GTN
Oesophageal spasm: Sublingual GTN before
food
37
38. In Cyanide poisoning: The Rationale use
Haemoglobin
↓ NaNO2 iv (10 ml, 3%)
Methaemoglobin
↓ Cyanide molecules
Cyanomethaemoglobin
↓ Hypo iv (50ml, 30%)
Methaemoglobin + Sod. thiocynate (Urine)
38
39. Drugs that block the voltage sensitive L –type
of calcium channels
Calcium channels- L-Type
◦ Muscles: Excitation and contraction
◦ SA and AV nodes: Conduction
◦ Endocrine cells: Hormone release
◦ Neurones: Transmitter release
Blockers
◦ Nifedipine, diltiazem, verapamil
Inactivation rate: Slow
39
41. Inhibit calcium mediated slow channel AP in
cardiac and smooth muscles
Smooth muscle relaxation
◦ Vascular and others
Negative inotropic and chronotropic actions
on heart
41
42. Markedly dilate arterioles
Mild relaxation effects on veins smooth
muscles
Extra-vascular muscles relaxed
◦ Bronchial, Biliary, Intestinal and Uterine
DHPs eg., Nifedipine & Amlodipine have got
prominent action on smooth muscles
42
43. Action on atrial and ventricle muscles
◦ Negative inotropic
Actions on conducting tissues
◦ SA and AV Nodes: Reductions in slope of Phase-4 →
Reduced automaticity
◦ AV Nodal conduction: Prolonged
Verapamil > Diltiazem; DHPs: Nil
43
44. Dilates arterioles
Blocks alpha receptors as well
Decreases tPVR → BP falls
COP maintained due to Preload
Coronary flow is increased
-ve inotropic and chronotropic
Contraindicated in CCF
44
45. Common effects
◦ Nausea, Constipation, Bradycardia
Less common
◦ Flushing, headache, ankle edema
Conduction defects
◦ Contraindicated in AV-bocks, CCF
Cardiac arrest upon iv in Sick Sinus
45
46. With β-blockers
◦ Additive sinus depression
◦ Conduction defects or asystole occur
With digoxin
◦ Increases the concentration of Digoxin
Should not be given with cardiac depressants
like disopyramide or quinidine
46
47. Less potent vasodilator
Cardiac action equal to verapamil
Normal doses: Consistent fall in BP
Little change in heart rate
Dilates coronary arteries
Low incidence of side effects
◦ Same profile as verapamil
47
48. A most prominent arteriolar dilator
↓ in tPVR → Rapid fall in BP
A weak –ve inotropic effect (Nil)
No conduction blockade action
Reflex sympathetic stimulation
◦ Tachycardia is pronounced
↑ COP and coronary out flow
48
49. Frequent effects
◦ Palpitation, flushing, ankle edema, hypotension,
headache, drowsiness
Enhances the frequency of angina
◦ Paradoxical effect in post MI cases
Safe with beta-blockers/digoxin
Difficulty in urination
Reduces insulin release
49
50. Pharmacokinetically distinct DHP
Complete and slow oral absorption
Higher and most consistent oral bio-availability
Very long duration of action
◦ 5-10 mg OD
S(-) amlodipine effective at ½ dose& less incidences
of ankle edema
Early vasodilator effects are largely avoided
(Palpitation,flushings, headache, postural dizziness)
50
51. 1. Angina pectoris: Classical and variant.
◦ The short acting DHPs harmful in MI
A drop in coronary out flow
Reflex tachycardia
Coronary steal
◦ Best CCBs in MI: Verapamil or diltiazem
2. Hypertension: All three class of drugs
3. Arrhythmias: Only verapamil in PSVT & SVT
4. Premature labour: Nifedipine
5. In Raynaud’s episodes: DHPs
6. Nocturnal leg cramps: Verapamil
51
56. Dipyridamole
◦ Inhibits platelet agregation by PGI2 pathway and ↑
cAMP in platelets
◦ Powerful arteriodialator
◦ Failure of this drug is because of coronary steel
phenomena
56
57. Trimetazidine
◦ Novel antianginal drug acts by non-hemodynamic
mechanisms
◦ MOA is not known but proposed MOAs as follows
Inhibiting Mitochondrial long chain 3- ketoacyl CoA
thiolase (LC3-KAT) a key enzyme for fatty acid
oxidation. It has been labeled as pFOX (fatty acid
oxidation pathway) inhibitor
Limiting the intracellular acidosis and Ca, Na,
accumulation during ischemia
Protecting the Free Radical induced damage
57
58. Trimetazidine
◦ Absorbs orally
◦ Partly metabolised, Excreted unchanged in urine
◦ T1/2 is 6 hrs
◦ ADRs : GI burning, Dizziness, fatigue, Muscle
cramps, reversible Parkinsonism
It is also advocated in Visual disturbances,
Tinnitus, Meneir’s disease, etc
58
59. Ranolazine
◦ Trimetazidine congener LC3-KAT inhibitor
◦ Orally absorbed Bioavailability is 30-50%
◦ T ½ is 7 hrs
◦ ADRs: Dizziness, Weakness, constipation, postural
hypotension, Headache, dyspepsia, Prolongation of
QT interval, torsade de pointes is a risk
◦ Used along with Atenolol, amlodipine, diltiazem
59
60. Pain, anxiety, apprehension
◦ Morphine/ pethidine or Diazepam
Oxygenation: Inhalation of O2
Maintenance of Blood volume, tissue
perfusion & microcirculation
◦ Saline/ Low molecular weight dextran
Correction of acidosis
◦ Sod bicarbonate iv
Prevention & treatment of arrhythmia
◦ i.v β blockers subsequently by lidocaine etc
60
61. Pump failure:↑ CO by
◦ Frusemide / Vasodilators like ON
◦ Inotropic drugs: dopamine/ dobutamine
Prevention of thrombus extension,
embolism & venous thrombosis
◦ Aspirin (165-325 mg chewing/ swallowing)
Thrombolytics & reperfusion
◦ Thrombolytics Streptokinase/ Urokinase/
alteplase
Prevention of remodeling & subsequent CHF
◦ ACE inhibitors/ ARBs
Prevention of future attacks
◦ Aspirin/ β blockers / Hypolipidemic drugs
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