Cardio L26 Drug therapy 3 Flashcards
Angina definition
A condition marked by severe chest pain, often also spreading to the shoulders, arms and neck, caused by an inadequate blood supply to the heart.
Clinical definition of angina
Angina is chest pain or discomfort that occurs when an area of your heart muscle doesn’t get enough oxygen-rich blood.
Angina pectoris
Pain localized to the chest that can be abrupt (acute) or persistent (chromic)
Causes of angina pectoris
Decreasing o2 supply
Increase Cardiac work = o2 consumptions increased
→ Lack of supply and build up of metabolites leads to ischemic pain.
Common Causes of Angina Pectoris
- Restriction (usually incomplete) in blood supply to working heart muscle.
→ Partial occlusion of blood vessels Atheroma Thrombus →Vasopasm in coronary arteries Overly reactive vessels Drugs e.g. cocaine, smoking → Severe anaemia
Types pf angina pectoris
- Chromic stable angina (exercise induced)
- Unstable angina (sudden rupture of atherosclerotic plaque)
- Prinzmetals (angina inversa)
• Vasospasm due to oversensitivity to vasoconstrictors
Atheroma process
→Damage to endothelium
→ Cholesterol accumulation
→ Monocyte invasion
→ Foam cell degeneration
Foam cell degeneration
- Fibrous tissue, calcium salts
- Artery narrows
- Increasing stiffness at margin
Monocyte invasion
- Convert to macrophages
* Convert to foam cells
Cholesterol accumulation
- Oxidation
* Inflammatory response
Damage to endothelium
• Exposes intima matrix above smooth muscle layer
Prevent atherosclerosis
- Statins
- Fibrates
- Bile acid binding resins
Angina control
Nitrates
Beta-blockers
Ca2+ channel blockers
(Aspirin)
Treatment – possibly after first
MI
- Ranolazine, aspirin
2. Bypass surgery, stents, angioplasty, clot disrupting drugs (enzymes)
Process of cholesterol formation
3-Hydroxy-3- methyl-glutaryl-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, which produces cholesterol and other isoprenoids.
Lovastin and Atorvastatin action
Inhibit 3-Hydroxy-3- methyl-glutaryl-CoA reductase leading to:
a. Decreased liver cholesterol synthesis
b. Increased VLDL and LDL receptor expression, and decreasing LDL in blood
Side effects: HMG CoA reductase inhibitors:
a. Myalgias
b. Muscle cramps
c. Rhabdomyolysis (leading to kidney failure)
d. GI tract disturbances
e. Malabsorption of lipid soluble vitamins (A,D,E,K) and lipid soluble drug
Fibrates: definition
Fibrates are amphiphatic carboxylic acids.
Fibrates: Example drugs
Bezafibrate
Ciprofibrate
Agonists of the peroxisome proliferator-activated receptor alpha (PPAR – alpha) receptor leads to:
- Increased Beta-pxidation in the liver
- Decreased hepatic triglyceride secretion
- Increased lipoprotein lipase activity → increased VLDL clearance
- Increased HDL
Main use of fibrates
Hypercholesterolemia
Side effects of fibrates
- Mild stomach upset and myopathy (muscle pain with CPK elevations)
- Increased risk for gallstones due to increased cholesterol in bile.
- Increased risk of rhabdomyolysis – especially if added to statins.
Bile acid recycling
Between intestine and liver
What binds bile acid
Cholestipol and Cholestyramine in gut leading to increased loss.
Cholestipol and Cholestyramine binding leads to:
- Decreased enterohepatic recirculation of bile salts
- Increased synthesis of new bile salts by the liver
- Decreased liver cholesterol
- Increased LDL receptor expression, and decreasing LDL in blood
Side effects of bile acid binding agents
- Increased in VDLD and triaylglycerides synthesis
- GIT disturbances
- Malabsorption of lipid soluble vitamins (A,D,E,K) and lipid soluble drugs
Nitric oxide is
Endothelium-derived relaxing factor
What increases NO production
Organic nitrates
Function of nirtrates
Venous vasodilation/pre-load reduction Arterial dilation/ after-load reduction Coronary artery vasodilation Prevention of coronary vasoconstriction Enhancement of coronary collateral flow Antiplatelet and antithrombotic effects
Nitrates action
All increase NO (EDRF)
Types of nitrates
- Nitroglycerin sI (fast acting)
- Isosorbide mononitrate
- Isosorbide dinitrate
- Transdermal patches (long acting)
- Alkyl Nitrates (Poppers)
nitrates Side effects
Headaches Flushing Palpitations Tolerance Major interaction with drugs for impotence (Viagra etc.) leading to hypotensive crisis
Nitrates are metabolites to
To increase NO
NO is
EDRF
NO stimulates
Guanylate cyclase
Gaunylate cyclase synthesizes
cyclic guanosine monophosphate (cGMP)
cGMP activates
cCGMP – dependent protein kinase
cGMPdK activates
Myosin light chain phosphate (s) (MLCP)
Myosin light chains in smooth muscle cells are
Dephosphorylated
The contractile state of smooth muscle depends
On phosphorylation if the myosin light chains (calmodulin – dependent kinase phosphorylate)
Beta-Blockers: Function
Reduce myocardial Oxygen demand
Beta-Blockers: Used for
First line therapy in the treatment of chronic stable angina (esp, effort-induced angina)
Beta-Blockers: Examples
- Propanolol → non-selective Beta1, Beta2 (not in asthma)
- Atenolol →metroprolo more Beta1 – selective
- Carvedilol → also block alpha-receptors improving coronary perfusion
Beta-Blockers: Side effects
Constipation, indigestion Hypotension Sleep disturbance, hallucinations (rare) Reduce aqueous humour secretion →glaucoma Skin reactions e.g. hives, psorias
Calcium channel blockers: Calcium entry
Entry into SM depends on activity of voltage dependent Ca2+ channels (mainly L-type VDCC)
Main classes of L-type VDCC antagonists are:
- Dihyropyridines e.g. Nifedipine (all dipines)
- Phenylakyllamines e.g. verapamil
- Benzothiazepines e.g. Diltiazem (also non-selective VDCC blockers e.g. Fluspiriline)
Side effects calcium channel blockers
- Peripheral vasodilation: Dizziness, headache, erythema
- Constipation
- Heart rate changes
- Gingival overgrowth
calcium channel blockers Reason for use
To reduce myocardial oxygen demand and reverse coronary vasospasm.
calcium channel blockers Don’t want
Reflex sympathetic activation due to peripheral effects.
Verapamil
Selective for myocardium
→ Hence minimal peripheral vasodilatory effects (compared with dihydropyridines
Benzothiazepine calcium channel blocker are
Intermediate between phenylalkylamine and dihydropyridines in their selectivity for vascular calcium channels.
→ Cardiac depressant and vasodilator actions
→ Reduce arterial pressure without producing as much reflex cardiac stimulation cause by dihydropyridines
Clopidegrel
A prodrug, and blocks an ADP receptor on platelet cell membranes.
Antiplatelet drugs: Action
- Blockage of this receptor inhibits platelet aggregation by blocking activation of the glycoprotein IIb/IIIa pathway and formation of IIb/IIIa complex.
- The Iib/ IIIa complex is a receptor mainly for fibrinogen and vitronectin but also for fibronectin and von Willebrand factor.
- By blocking croos-linking of platelets by fibrin help prevent clot formation
Antiplatelet drugs: Side effects
Haemorrhage
Severe neutropenia
Thrombotic thrombocytopenic purpura (paradoxical)
Ranolazine blocks
Late Na+- entry reducing cardiac dysfunction following ischemia.
- Increases QT interval
- Decreases angina episodes in individuals with coronary artery disease on maximal doses of amlodipine and exercise tolerance in those taking atenolol, amlodipine or diltiazem.
Ranolazine side effects
Worsen electrical dysfunction in long QT syndrome → risk of sudden cardiac death
