Stable angina, classical and unstable

1. ISCHEMIC HEART
DISEASE
Prof Christian C. Ezeala DLitt et Phil, PhD
MBChB 2 Programme
School of Medicine & Health Sciences

2. LEARNING OUTCOMES
Each participating student should be able to:
1. Demonstrate knowledge of the pathogenesis of
ischemic heart disease/MI
2. State the classes of drugs used for the prevention
and treatment of MI
3. Outline the mechanisms of action of vasodilators;
4. State the clinical uses, contraindications and
adverse effects of these drugs,
at the end of the lesson.

3. PATHOGENESIS OF IHD
• 1o symptom of IHD is angina
• Transient episodes of myocardial ischemia
• Imbalance in O2 demand / supply ratio
• Increased O2 demand – HR, ventricular wall
tension, contractility
• Decreased O2 supply - coronary blood flow
(diastolic pressure of the aorta and duration of
diastole) and oxygen carrying capacity
• Accumulation of metabolites in the muscles

4. DETERMINANTS OF
MYOCARDIAL OXYGEN DEMAND
• Heart rate
• Contractility
• Wall stress:
• Intraventricular pressure
• Ventricular volume
• Wall thickness

5. DETERMINANTS OF
MYOCARDIAL OXYGEN SUPPLY
• Aortic diastolic pressure
• Duration of diastole

6. VASCULAR TONE
• Arterial blood pressure determines the
systolic wall stress
• Venous tone determines the diastolic
wall stress.

7. TYPES OF ANGINA
Stable angina
Occurs on exertion
Unstable Angina
Occurs at rest; increased frequency of
attacks
Variant angina
Coronary spasm
Silent angina

8. CLASSES OF DRUGS USED FOR THE
PREVENTION AND TREATMENT OF MI
• Vasodilators
• Beta adrenergic blockers
• Ca2
+ channel blockers
• Anti-thrombotic and thrombolytic drugs
• HMG Co-A reductase inhibitors
All act by improving the balance between O2
demand and supply

9. VASODILATORS:
NITRATES & NITRITES
• Historically the first vasodilators used for
treatment of angina/IHD.
• Include:
• Nitroglycerine (glyceryl trinitrate)
(sublingual)
• Isosorbide dinitrate (sublingual)
• Amyl nitrite (inhilational)
• Act by relaxing vascular smooth muscles

10. ACTIONS OF NITRO-
VASODILATORS
• Denitrated by glutathione S transferase to
release NO2
-, which is then converted to NO;
• NO activates guanylyl cyclase cause an
increase in cGMP

11. Mechanism of
action of nitrates,
nitrites, and other
substances that
increase the
concentration of
nitric oxide (NO) in
vascular smooth
muscle cells. Steps
leading to relaxation
are shown with blue
arrows.

12. • Hemodynamically they cause
• Venodilation (also arteriolar dilatation
in high doses)
• reduction in preload (and afterload)
• Reduction in EDV and CO
• Reduced wall stress
• Reduced O2 demand

13. OTHER EFFECTS
• Relaxation of other smooth muscles
(bronchi, GIT, and genitourinary tract
• Increase in cGMP in platelets inhibits
platelet aggregation
• Nitrite ion can react with Hb to form MetHb

14. • Clinical uses: Treatment of angina pectoris, MI
• Adverse Effects: orthostatic hypotension, throbbing
headache, pseudocyanosis in high doses, reflex
tachycardia.
• Carcinogenicity: nitrates (in food are known to
cause esophageal and gastric cancers)
• Contraindications: elevated intracranial pressure
• Tolerance: continuous exposure to nitrates cause
tolerance to develop

15. CA2
+ CHANNEL BLOCKERS
• Generally block Ca2
+ entry into muscle cells
• Vasodilation, decreased vascular resistance
• reduced O2 demand
• Two classes:
• Dihydropyridine – e.g. nifedipine
• Non-dihydropyridine – verapamil, diltiazem
• Decreased cardiac contractility and
vasodilation

17. • Clinical uses: Treatment of angina pectoris,
hypertension, supraventricular tachycardia,
hypertrophic cardiomyopathy, Raynaud’s
syndrome.
• Adverse Effects: cardiac depression, arrest,
orthostatic hypotension, throbbing headache,
*short acting blockers can precipitate adverse
cardiac events .
• Minor side effects: flushing, dizziness, nausea,
constipation, headache, peripheral edema.

18. BETA ADRENERGIC BLOCKING
DRUGS
• Block beta adrenergic receptors
• May be selective or non-selective
• Non-selective drugs block both B 1 and B2
receptors (contraindicated in asthma)
• Selective drugs block only B1 receptors (present
in the myocardium)

19. BETA BLOCKERS
• Non-selective
• Example: Propranolol, Timolol
• blocks beta 1 and beta 2 receptors)
• Effects: ↓ cardiac output, vasodilation,
decreased HR, bronchoconstriction
• Selective for B1: E.g. Metoprolol
• Preferentially block beta 1; no beta 2 effects
• ↓ cardiac output, vasodilation, decreased HR
decreased oxygen demand

20. • Clinical uses: Treatment of angina pectoris
(improves exercise tolerance), MI, hypertension,
tremor, arrhythmia, etc.
• Adverse Effects: increased EDV may offset their
benefits; concomitant use of nitrates
recommended.
• Contraindications: bronchospastic conditions,
severe bradycardia, AV block, left ventricular
failure

21. ANTITHROMBOTIC DRUGS
Fibrinolytics

22. ANTITHROMBOTIC DRUGS
Fibrinolytics

23. ANTITHROMBOTIC DRUGS
Fibrinolytics

24. ANTITHROMBOTIC DRUGS
Fibrinolytics

25. ANTIPLATELET DRUGS
Antiplatelet drugs
Acetylsalicylic
acid (aspirin)
P2Y12
antagonists
Dipyridamole GPIIb/IIIa
antagonists
Used widely
in patients
at risk of
thromboembolic
disease
Beneficial in the
treatment and
prevention of ACS
and the prevention
of thromboembolic
events
Secondary
prevention in
patients following
stroke, often in
combination with
aspirin
Administered
intravenously, are
effective during
percutaneous
coronary
intervention (PCI)

26. PLATELET FUNCTION

27. PLATELET FUNCTION

28. PLATELET FUNCTION

29. PLATELET FUNCTION

30. ACETYLSALICYLIC ACID –
MECHANISM OF ACTION

31. ACETYLSALICYLIC ACID –
MECHANISM OF ACTION

32. ACETYLSALICYLIC ACID –
MECHANISM OF ACTION

33. ACETYLSALICYLIC ACID –
MECHANISM OF ACTION

34. ACETYLSALICYLIC ACID –
MECHANISM OF ACTION

35. ACETYLSALICYLIC ACID –
PHARMACOKINETICS
• Rapid absorption of aspirin occurs in the
stomach and upper intestine, with the peak
plasma concentration being achieved 15-20
minutes after administration
• The peak inhibitory effect on platelet
aggregation is apparent approximately one
hour post-administration
• Aspirin produces the irreversible inhibition of
the enzyme cyclo-oxygenase and therefore
causes irreversible inhibition of platelets for the
rest of their lifespan (7 days)

36. ACETYLSALICYLIC ACID –
MAJOR USE
• Secondary prevention of transient ischaemic attack
(TIA), ischaemic stroke and myocardial infarction
• Prevention of ischaemic events in patients with angina
pectoris
• Prevention of coronary artery bypass graft (CABG)
occlusion

37. ACETYLSALICYLIC ACID –
MAJOR DRAWBACKS
• Risk of gastrointestinal adverse events (ulceration
and bleeding)
• Allergic reactions
• Is not a very effective antithrombotic drug but is
widely used because of its ease of use
• Lack of response in some patients (aspirin
resistance)
• The irreversible platelet inhibition

38. ADP-RECEPTOR ANTAGONISTS –
MECHANISM OF ACTION

39. ADP-RECEPTOR ANTAGONISTS –
MECHANISM OF ACTION

40. ADP-RECEPTOR ANTAGONISTS –
MECHANISM OF ACTION

41. ADP-RECEPTOR ANTAGONISTS –
MECHANISM OF ACTION

42. ADP-RECEPTOR ANTAGONISTS –
PHARMACOKINETICS
• Both currently available ADP-receptor
antagonists are thienopyridines that can
be administered orally, and absorption is
approximately 80-90%
• Thienopyridines are prodrugs that must
be activated in the liver

43. ADP-RECEPTOR ANTAGONISTS –
MAJOR USE
• Secondary prevention of ischaemic
complications after myocardial infarction,
ischaemic stroke and established peripheral
arterial disease
• Secondary prevention of ischaemic
complications in patients with acute coronary
syndrome (ACS) without ST-segment elevation

44. ADP-RECEPTOR ANTAGONISTS –
MAJOR DRAWBACKS
• Clopidogrel is only slightly more effective
than aspirin
• As with aspirin, clopidogrel binds irreversibly
to platelets
• In some patients there is resistance to
clopidogrel treatment

45. THROMBOLYTIC DRUGS –
MECHANISM OF ACTION

46. THROMBOLYTIC DRUGS –
MECHANISM OF ACTION

47. THROMBOLYTIC DRUGS –
MECHANISM OF ACTION

48. THROMBOLYTIC DRUGS –
MECHANISM OF ACTION

49. THROMBOLYTIC DRUGS –
PHARMACOKINETICS
• The plasma half-life of the third
generation drugs is 14-45 minutes,
allowing administration as a single or
double intravenous bolus. This is in
contrast to second generation t-PA, which
with a half-life of 3-4 minutes, must be
administered an initial bolus followed by
infusion

50. • Thrombolysis in patients with acute myocardial
infarction (MI)
• Thrombolysis in patients with ischaemic stroke
• Thrombolysis of (sub)acute peripheral arterial
thrombosis
• Thrombolysis in patients with acute massive
pulmonary embolism
• Thrombolysis of occluded haemodialysis shunts
Thrombolytic drugs – major use

51. THROMBOLYTIC DRUGS –
MAJOR DRAWBACKS
• Treatment is limited to acute in-hospital treatment.
There is a high risk of bleeding inherent in this
treatment
• Patients using anticoagulants are contraindicated
for treatment with thrombolytics

52. WHAT HAVE YOU LEARNED?