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Ischeamic Heart Disease Therapeutic Intervention
Major Determinants of Myocardial Oxygen
Consumption
Myocardial O2 Supply
Myocardial O2 Demand
Diastlic perfusion pressure
Coronary vascular resistance
O2 carrying capacity
Wall resistance
Heart rate
Contractility
Therapeutic Goals are to REDUCE MYOCARDIAL
OXYGEN DEMAND!!
1. Negative Inotropic and Chronotropic (↓contractility and
↓heart rate)
a. Negative inotropic and chronotropic agents
i. Beta blocker
1. Selective
a. Atenolol
2. Non-selective
a. Propanolol
ii. If channel inhibitor
1. Ivabradine
b. Negative inotropic, chronotropic and dromotropic
agents
i. Calcium channel blocker
1. Verapamil
2. Diltiazem
2. ↓Preload
a. Calcium channel blocker
i. Nifedipine
b. Nitrates
i. Glyceryltrinitrate
3. ↓Preload
a. Calcium Channel Blocker
i. Nifedipine
b. Nitrates
i. Glyceryltrinitrate
4. ↑myocardial glucose utilization
a. Anti-ischeamic metabolic agent
i. Trimetazidine
5. Antiplatelet agents
a. Non-selective NSAIDs
i. Aspirin
Drug Name/ Infos
Non selective Beta Blocker
1. Propranolol
Contraindicated in
1. Asthma
2. COPD
3. Heart block
4. Peripheral vascular
disease
If Channel Blocker
Ivabradine
Negative Inotropic, Chronotropic and Dromotropic Agents
Mechanism of Action
1. Blocking:
4. Kidney
a. Beta 1
a. ↓in Bp may:
b. Beta 2
i. ↓renal prefusion
2. Actions:
ii. ↓in:
a. Cardiovascular system
1. Na+ retention
i. (-) in :
2. Plasma volume
1. Inotropic
5. Disturbance in glucose
2. Chronotropic
metabolism:
ii. Causing in:
a. ↓in:
1. ↓cardiac output
i. Glucogenolysis
2. ↓cardiac work
1. Glucagon secretion
3. ↓oxygen
b. May lead to
consumption
hypoglycemia in
3. Respiratory system
i. Insulin dependent
a. Blocking the Beta 2
diabetic patient
receptor will:
Careful monitoring is required
i. Deteriorated the
respiratory disease in
COPD patient
ii. Therefore
contraindicated for
COPD and Asthma pts
1. Block the HCN channel/ Funny channel
a. ↓pacemaking activity of SA node
b. ↓heart rate
c. ↓cardiac workload
d. ↓cardiac oxygen demand
2. There is no effect on cardiac contractility
Adverse Effects
1. AV block
2. Masked hypoglyceamia
a. If pts in insulin tx with blockers
can both get hypo ADR
(dizziness)
1. Luminous phenomena
2. Headache
3. Bradycardia
Calcium Channel Blocker
Contraindication
1. Sinus bradycardia
2. AV conduction defect
Drug Name/ Infos
Benzothiazepine
1. Diltiazem
Both arteriole and heart
(intermediate)
Phenylalkylamines
1. Verapamil
Only acts on heart
Drug Name/ Infos
Dihydropyridines
1. Nifedipine
More on arteriole not heart
3. Severe cardiac failure
Drug interaction
1. Cimetadine (CYP450 inhibitor)
Mechanism of Action
1. Acts on both cardiomyocytes and smooth muscle cells of
arterioles
2. At the heart
a. ↓slow pacemaker activity
i. ↓heart rate
b. ↓impulse conduction between atria and ventricle
i. ↓strength of contraction
ii. ↓stroke volume
Therefore ↓ blood pressure
1. At the heart
a. ↓slow pacemaker activity
iii. ↓heart rate
b. ↓impulse conduction between atria and ventricle
iv. ↓strength of contraction
v. ↓stroke volume
c. Therefore ↓ blood pressure
Agents Used in ↓ Afterload
Calcium Channel Blocker
Mechanism of Action
1. Primary action is at the smooth muscles of arterioles not vein
2. Vasodilation due to blockage of calcium channel, no
contraction of smoth muscle cells
3. ↓after load but not preload
4. ↓Total Peripheral Resistance
5. ↓Blood pressure
Adverse Effects
1. Edema
2. Headache
3. ↑sympathetic outflow
Adverse Effects
1. Reflex Tachycardia
a. Administer together with Beta
Blocker to counteract the side
effect
2. Coronary Steal Syndrome
3. Hypotension
4. Edema
5. Flushing
6. Dizziness
Drug Name/ Infos
Sublingual Glyceryltrinitrate
(GTN)
1.
2.
3.
4.
To relieve acute attack of angina
Rapid onset  rapid reliever
Readily absorp through sublingual
mucosa
Overpass the 1st pass metabolism
 ↑bioavailibity
Oral Isosorbide-5mononitrate
1.
Prophylaxis treatment for stable
angina
2. Slow onset
3. Extensively undergoes 1st pass
metabolism
a. Therefore, pharmacist fomulated
isosorbide mononitrate in the
form of modified release tablet in
order to ↓extensive breakdown
through 1st pass metabolism
Other modes of admin
1.
2.
3.
4.
Transdermal
Inhalation
IV
Infusion
Drug drug interaction
1. Sildenafil (Viagra®)
a. Viagra® is a potent vasodilator
b. Given together with nitrate will
lead to massive reduction of BP,
may cause
i. Syncope
ii. MI
Nicotinamide Nitrate Ester
1. Nicorandil
Nitrates (Reduction in Afterload and Preload)
Mechanism of Action
1. Effects on all vessels in vascular system
a. Veins
i. Venodilation in only small dose
b. Large (muscular and elastic) arteries
i. Arterial vasodilation in slightly higher dose
ii. Coronary arteries
1. Concentric artheroma (unstable plaque) less responsive towards nitrates
a. Post stenotic artery tends to dilate as a part of compensatory
mechanism
b. ↓blood flow trhough the stenosed artery
c. Dilatation of pre-stenotic artery will diverge the blood flow to other
arterial branches; further ↓blood flow
i. Considered as CORONARY STEAL SYNDROME
2. Eccentric artheroma (stable plaque) permits dilatory effect of nitrates
a. Enables dilation of smooth muscle side away the lesion
b. Does not cause coronary steal syndrome
c. Arterioles and percapillary spinchter less responsive
i. Mutually depends on the capability of tissue to produce nitric oxide
MOA
1. Release Nitric Oxide
2. Activates Guanylylcylase
3. ↑cGMP pathway
4. ↓PIP3
5. ↓Ca release from Sarcoplasmic
Reticulum
6. Relaxation of smooth muscle cells
a. Coronary artery vasodilation
i. ↓afterload
ii. ↓cardiac workload
iii. ↓oxygen demand
b. Venodilation
i. Pooling of blood in the lower
extremities
ii. ↓preload
iii. ↓cardiac workload
iv. ↓cardiac oxygen demand
7. Effect on platelet
c. Activation of Guanylate Cyclase
d. ↓platelet
i. Aggregation
ii. Adhesion
1. Vasodilatory effects through a complex mechanism
2. ↓ both
a. Preload
b. Afterload
3. Myocardial protection through activation of K+ ATP channels
Adverse Effects
1. Acute adverse effects
a. Associated with
vasodilatory effects
i. Orthostatic
hypotension
ii. Reflex tachycardia
iii. Throbbing
headache
2. Tolerence
a. Associated with
prolonged use of
nitrates
b. More prominent in
dosage form of
i. Oral
ii. Transdermal
iii. Continous IV infusion
1.
2.
3.
4.
Palpatation
Flushing
Weakness
Headache
Drug Name/ Infos
Trimetazidine
↑Myocardial Glucose Utilization
Anti-ischeamic Metabolic Agent
Mechanism of Action
1. ↑myocardial glucose utilization through inhibition of fatty acid
metabolism
2. Preserve myocardial energy reservoir through
a. Inhibits ↓in intracellular ATP level
b. Thereby,
i. Ensuring proper functioning of
1. Ionic pumps
2. Trnasmembranous Na+K+ flow
ii. Maintaining celullar hemostasis
c. Inhibits fatty acid oxidation in blood vessels
Adverse Effects
1. High safety and
tolerability profile
2. No known drug drug
interaction
Drug
Acetylsalicylate Acid
(ASPIRIN)
Pharmacological Effects
1. Anti-inflammatory
2. ↓coagulation (the ONLY NSAIDs)
3. Anti-pyretic
4. Analgesia
Contraindication
1. Relative C/I
a. Bronchial asthma
i. Inhibit synthesis of PG
(bronchodilator)
2. Absolute C/I
a. Gouty arthritis
i. ↓dose (anti-platelete)
1. No effect on uric acid renal
secretion
ii. Usual OTC dose
(analgesia/antipyretic)
1. Inhibits uric acid renal
secretion
iii. ↑dose (Tx of RA)
1. Blocks reabsorption of uric
acid (uricosuric effect)
b. Children with influenza or cold
i. Reye’s syndrome
1. Potentially fatal
c. Pregnant ladies
i. Antiplatelet effects on 3rd
trimester
1. ↑risk of bleeding
ii. PG prolongs labour
Therapeutic Uses
1. Fever
2. Ischeamic heart disease
3. Arthritis
Antiplatelet Agent
Non-Selective Cycloxygenase (COX) Inhibitor
Pharmacokinetic
Mechanism of Action
Absorption
1. Best absorp in acidic condition
a. It’s a weak acid in nature;
gastric environment is highly
acidic. Therefore aspirin will
remain unionized in the
stomach
b. Acidic drug tends to be lipid
soluble; readily being absorp
in through the GI mucosa
2. Most absorp at intestinal
mucosa due to high surface
area and low motility
Distribution
1. Hydrolyzes by esterases in tissue
and blood by
a. Acetic acid
b. Salicylate
2. Salicylate is highly plasma
protein bound (albumin)
Metabolism
1. Hepatic metabolism
(conjugation)
a. Conjugate with glycine =
salicyluric acid
b. Conjugate with glucuronic =
salicyl acyl + phenolic
glucuronide
Excretion
1. Renal excretion through
a. Glomerular filtration
b. Tubular secretion
2. Highly sensitive to pH changes
3. Interfere with uric acid
excretion*
1. Non-selective COX inhibitor, IRREVERSIBLY inhibits
both
a. COX 1 (constitutional enzyme) which coverts
arachidonic acid into
i. PGE2
1. Renal vasodilation
2. Bronchodilation
a. Inhibition of this will exarcebate asthmatic
pts (relative contraindication)
ii. TXA2
1. ↑platelete aggregation
a. Inhibition leads to anti-platelet activity
i. ↓risk for AMI
ii. ↓risk of CVA
iii. PGI2
1. ↑gastric mucus secretion
a. Inhibition of this will reduce mucus
secretion, exarcebate gastritis
b. COX 2 (inducible enzyme) which converts
arachidonic acid into
i. Prostaglandins which involved in
1. Inflammation
a. Vasodilation (hypereamia)
b. ↑capillary permeability (edema)
i. Inhibition will ↓inflammation
2. Pain sensation
a. Directly binds to pain receptor and elicit
pain sensation (not visceral pain)
i. Inhibition will lead to analgesia
3. Pyrexia (fever)
a. Prostaglandin together with IL-1b
stimulates thermostat at the OVLT to
increase temperature set point higher
than normal
i. Inhibition will return the temperature set
point to normal
Adverse Effects
1. Gastritis
a. Ion trapping inside the
gastric mucosa
b. Inhibition of PG12
synthesis ↓mucus
secretion
c. Prophylaxis tx with
Misosprostol (PGE1
analogue)
2. Hepatotoxicity
3. Allergic action
a. Periorbital edema
b. Rash
Drug-drug Interaction
1. Warfarin
a. Due to its higher
affinity towards
albumin compared
to warfarin, aspirin
may displace
warfarin and lead to
↑in warfarin toxicity