ISCHEMIC HEART

DISEASE
Prof Christian C. Ezeala DLitt et Phil, PhD
MBChB 2 Programme
School of Medicine & Health Sciences
 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.
 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
 DETERMINANTS OF
MYOCARDIAL OXYGEN DEMAND

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

• Aortic diastolic pressure

• Duration of diastole
 VASCULAR TONE

• Arterial blood pressure determines the

systolic wall stress

• Venous tone determines the diastolic wall

stress.
 TYPES OF ANGINA

Stable angina
Occurs on exertion
Unstable Angina
Occurs at rest; increased frequency of
attacks
Variant angina
Coronary spasm
Silent angina
 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
 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
 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
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.
• 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
 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
• 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
 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
• 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.
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)
 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
• 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
ANTITHROMBOTIC DRUGS

Fibrinolytics
ANTITHROMBOTIC DRUGS

Fibrinolytics
ANTITHROMBOTIC DRUGS

Fibrinolytics
ANTITHROMBOTIC DRUGS

Fibrinolytics
 ANTIPLATELET DRUGS

Antiplatelet drugs

Acetylsalicylic P2Y12 Dipyridamole GPIIb/IIIa

acid (aspirin) antagonists antagonists

Used widely Beneficial in the Secondary Administered

in patients treatment and prevention in intravenously, are
at risk of prevention of ACS patients following effective during
thromboembolic and the prevention stroke, often in percutaneous
disease of thromboembolic combination with coronary
events aspirin intervention (PCI)
PLATELET FUNCTION
PLATELET FUNCTION
PLATELET FUNCTION
PLATELET FUNCTION
ACETYLSALICYLIC ACID –
MECHANISM OF ACTION
ACETYLSALICYLIC ACID –
MECHANISM OF ACTION
ACETYLSALICYLIC ACID –
MECHANISM OF ACTION
ACETYLSALICYLIC ACID –
MECHANISM OF ACTION
ACETYLSALICYLIC ACID –
MECHANISM OF ACTION
 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)
 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
 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

ADP-RECEPTOR ANTAGONISTS –
MECHANISM OF ACTION
ADP-RECEPTOR ANTAGONISTS –
MECHANISM OF ACTION
ADP-RECEPTOR ANTAGONISTS –
MECHANISM OF ACTION
ADP-RECEPTOR ANTAGONISTS –
MECHANISM OF ACTION
 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
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
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
THROMBOLYTIC DRUGS –
MECHANISM OF ACTION
THROMBOLYTIC DRUGS –
MECHANISM OF ACTION
THROMBOLYTIC DRUGS –
MECHANISM OF ACTION
THROMBOLYTIC DRUGS –
MECHANISM OF ACTION
 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
 Thrombolytic drugs – major use

• 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 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
WHAT HAVE YOU LEARNED?