Anti Anginal Drugs

1. Calcium Channel Blockers

2. Calcium channels: Types:
1. Receptor operated
2. Voltage gated (operated, sensitive)
3. "Stretch"-operated or "leaky" Ca2+-channels
(important in maintaining vascular smooth muscle tone)
•Voltage gated - three subtypes: L,N,T
 L: long lasting- slow calcium channels
 N: neuronal- calcium channels
 T: transient - calcium channels

3. In heart:
•Ca2+ channels are responsible for depolarization of:
Vascular smooth muscle
S.A. node
A.V. node
In ventricles, Na+ current is mainly responsible
for depolarization
Supraventricular arrhythmias: treat with CCCBs
Ventricular arrhythmias: treat with sodium
channel blocker or defibrillate

4. How calcium contracts the vessel smooth muscle:
•Intracellular calcium binds to calmodulin
•Ca2+-calmodulin complex activates myosin-light-chain
kinase
•This kinase phosphorylates myosin light chain
•Allows interaction between actin and myosin leading to
muscle contraction
How calcium contracts heart muscle:
•Cardiac cell calcium binds to troponin
•This relieves the inhibitory effect of troponin on actin
and myosin resulting in contraction of cardiac muscle

5. CCBs: Five major classes:
1. Phenylalkylamines- Verapamil
2. Benzothiazepine- Diltiazem
3. Dihydrpyridines
Nifedipine
Amlodipine
Felodipine
Nicardapine
Nimodipine
4. Diarylaminopropylamine ethers: Bepridil
5. Benzimidazole-substituted tetralines: Mibefradil

6. Calcium channel blockers:
•Block voltage sensitive (L-type, slow) calcium channels
•Have no effect on receptor or stretch operated channels
and release of calcium
•Bind to 1 subunit of channels and reduce influx of Ca2+
into cells
•Voltage-dependent calcium channels are formed as a
complex of several different subunits: α1, α2,δ, β1-4, and γ.
•The α1 subunit forms the ion conducting pore while the
associated subunits have several functions including
modulation of gating

7. Voltage Gated Calcium Channel

8. •CCBs have negative iono & chronotropic effects
•All CCBs decrease coronary vascular resistance
•Verapamil and diltiazem have effects primarily on heart
•Nifedipine- effects primarily arterioles and dilates them
•Reflex tachycardia with nifedipine due to fall in BP
•Decreased intracellular Ca2+ in arterial smooth muscle
relaxes it resulting in vasodilatation
•Arteriolar dilatation decreases afterload
•Little/no effect on venous beds, therefore no effect on
cardiac preload

9. •Nifedipine-
 Arteriolar resistance
 Systemic blood pressure
Functioning and contractility of ventricles is improved
HR and cardiac output – modest increase
No significant change in venous tone
•Most dihydropyridines have similar effects
•Amlodipine- slow absorption; t½ is 35-50 h
•Reflex tachycardia with amlodipine is less probably due
to its slow absorption

10. •Verapamil and diltiazem depress rate of SA pacemaker
and slow AV conduction- so used in SV tachyarrhythmias
•Bepridil- another Ca2+ blocker, also inhibits both K+ and
Na+ channels- It has following actions:
-ve Ionotropic effect
-ve Chronotropic effect
Prolongation of AV nodal effective refractory period
Prolongation of QTc interval- particularly in presence
of hypokalemia
Can cause torsades de pointes- potentially fatal
ventricular arrhythmia

11. •Felodipine has greater vascular specificity so in
clinically used doses, does not have –ve ionotropic
effect
•Nimodipine has high lipid solubility and is used for
relaxing cerebral vasculature to relief cerebral vessel
spasm after subarachnoid hemorrhage

12. •Clevedipine has rapid onset and a short t½ -2 min
Preferentially dilates arterioles
No effect on veins or heart
Used as I.V. infusion for treatment of severe
hypertension

13. •Mibefradil has T-type calcium channel blocking
activity along with L-type calcium channel blocking
activity
•Withdrawn from market due to drug interactions
 CCBs are arteriolar dilators, have minimal or no
effect on venous beds
 CCBs have little or no effect on nonvascular smooth
muscle (e.g. tracheal smooth muscle)

14. Uses of CCBs:
•Variant angina- spasm
•Effort (exertional) angina
•Unstable angina
•Myocardial infarction
•CHF
•Cardiac arrhythmia
•Verapamil- for prophylaxis of migraine headache
•Nimodipine- subarachnoid hemorrhage
•Symptomatic relief in Raynaud’s disease

15. ADRs:
•Headache, flushing, dizziness, peripheral edema
•Amlodipine may cause ankle oedema
• Inhibition of LES tone/contraction so may precipitate or
aggravate GERD
•Rash, Constipation
•Elevation of liver enzymes
•Verapamil blocks p-glycoprotein, a drug transporter
which is responsible for both hepatic and renal elimination
of digoxin.
•CCBs with quinidine may cause excessive hypotension

16. Myocardial infarction

17. •MI or acute myocardial infarction (AMI) or heart attack
is interruption of blood supply to a part of the heart
causing heart cells to die.
•Usual cause: occlusion of coronary artery following
rupture of a vulnerable atherosclerotic plaque
•Atherosclerotic plaque is a collection of lipids and
WBC in the arterial wall
•The resulting ischemia, if untreated for sufficient period
of time, can cause damage or death (infarction) of the
particular part of heart muscle

18. Symptoms:
•Sudden chest pain, radiation to the inner part of left arm
or to the scapula
•Shortness of breath
•Nausea and/or vomiting
•Palpitations
•Sweating
•Anxiety
•May be silent MI- no symptoms

19. Aims of treatment:
•Relief of pain- visceral
•Reducing the size of the infarct
•Preserving or retrieving the viable tissue
by reducing myocardial O2 demand
•Preventing ventricular remodeling

20. Drugs used for treatment:
•Nitrates
•-Blockers
•Ca2+ channel blockers?
•Antiplatelet and anti-thrombotic agents
•ACE Inhibitors
•Statins

21. Nitrates:
•Reduce ischemic pain
•Nitrates do not improve mortality in patients of MI
•They are relatively contraindicated in patients with
associated hypotension
•Nitrates decrease preload and provide relief in
pulmonary congestion
•Morphine/Pethidine/Buprenorphine?
•Morphine may increase morbidity/mortality

22. Pharmacotherapy of acute myocardial infarction:
•Aspirin- 162-300 mg orally immediately
•Oxygen therapy and absolute bed rest
•If diagnosis is made within 24 h, start thrombolytic
drugs- streptokinase or urokinase
•Nitrates/Morphine/Pethidine for relief of pain-
pentazocine is contraindicated in MI since it can cause
rise in HR and BP
•Maintenance of fluid and electrolyte and blood pH
•Prevention of complications and future attacks- -
blockers, CCBs, ACE inhibitors, Statins

23. Beta Blockers:
• Beta blocker therapy is recommended within 12 h
of MI symptoms and continued indefinitely
• Treatment with beta blockers decreases:
 Incidence of ventricular arrhythmia
 Recurrent ischemia
 Re-infarction
 Infarct size
 Short term mortality

24. • Beta blockers decrease rate and force of myocardial
contraction and decrease overall myocardial oxygen
demand
• Reduction in myocardial oxygen demand minimizes
risk of myocardial injury and death
• Some beta blockers prevent remodelling of heart-
metoprolol, carvediolol
• ADRs: Heart failure, bradycardia, bronchospasm

25. Calcium Channel Blockers:
• They may reduce the incidence of post myocardial
infarction arrhythmia and infarct size
• Scientific evidence does not support their use in MI
• Presently, therapy with CCBs in MI is not
recommended specially where concomitant left
ventricular dysfunction is also present
• They may be used for secondary prophylaxis in
cases where beta blockers are contraindicated

26. • Statins: to normalize lipids profile
• ACE Inhibitors: Have beneficial effects in post MI
patients mainly by preventing remodelling of heart
and thereby preventing left ventricular dysfunction

27. •Aspirin: Low dose- 162-300; 150-300 mg/day orally,
chewed or dissolved or sublingually
•Analgesic dose of aspirin is 324-1000 mg every 4-6 h
•Selectively inhibits COX-1 in platelets so thromboxane
A2 formation is inhibited- of platelet aggregation &
vasoconstriction
•Irreversible inhibition of platelet COX-1 lasts lifetime
of platelets (7-10 days)
•Platelets are anucleate so cannot synthesize COX-1
•Salicylic acid is a weak, reversible, competitive
inhibitor of platelet COX-1

28. Arachidonic
Acid
Cyclooxygenases
(COX 1)
Phospholipase
A2 enzyme
Lipoxygenases
(LOX)
Prostaglandins
Prostacyclin
Thromboxane A2
Leukotrines
Lipoxins
Formation of Thromboxane and Prostacyclin

29. •Platelets contain two purinergic receptors P2Y1 &
P2Y12
•P2Y12 receptor couples to Gi and upon activation by
ADP inhibits adenylyl cyclase
•There is less cAMP formation and therefore cAMP
dependent platelet activation is inhibited
•Activation of both receptors is necessary for platelet
activation while inhibition of one receptor is sufficient
to prevent platelet aggregation

30. Drugs used in aspirin sensitive/intolerant
patients:
•Ticlopidine and clopidogrel
•Clopidogrel is closely related to ticlopidine
•Both produce irreversible inhibition of platelet
P2Y12
•No hypersensitivity reaction which may be seen
with aspirin
•Combination of aspirin and clopidogrel is
superior to aspirin alone

31. Drugs used to prevent clotting and clot formation:
•Two categories: Anticoagulants and fibrinolytics
Anticoagulants:
•Parenteral : Heparin and LMWH
•Oral anticoagulants: warfarin sodium,
acenocoumarol and phenprocoumon
•Antiplatelet drugs:
 Aspirin
 Ticlopidine
 Clopidigrel
 Dipyridamole

32. • Thrombolytics & fibrinolytics are synonyms
• Thrombolytics:
 Streptokinase
 Urokinase
 Alteplase

33. Heparin:
•Formed in mast cells
•Molecular weight 15000 Da
•LMWH: Mol. Weight 5000 Da (derived from
animal tissues)
•Fondaparinux: Mol. Weight 1500 Da (synthetic)
•Mechanism:
•No intrinsic anticoagulant activity
•Binds to antithrombin and accelerates the rate at
which it inhibits various coagulation factors
•Antithrombin inhibits activated coagulation factors
•Heparin inhibits both factor Xa and IIa (thrombin)

34. •LMWH inhibits factor Xa more than IIa
•Fondaparinux inhibits only factor Xa
•After binding to antithrombin and promoting formation
of complex between antithrombin and coagulation
factors, heparin, LMWH and fondaparinux dissociate and
can act on another antithrombin molecule
•Heparin inhibits both factor IXa and Xa due to which
aPTT is prolonged, monitoring of aPTT is necessary

35. •High doses of heparin may inhibit platelet aggregation
and prolong bleeding time
•Heparin releases lipoprotein lipase which hydrolyses
triglycerides to glcerol and FFA and clears lipemic
plasma
•LMWH & fondaparinux do not inhibit platelet
aggregation and do not prolong aPTT so monitoring is
not required

36. Differences between Heparin and LMWH
Heparin LMWH
Average Mol. Wt. 15 kDa 4.5 kDa
Dosing IV infusion SC, OD or BD
Monitoring APTT Needed Nod needed
Osteoporosis +++ +
Bleeding tendency +++ +
Thrombocytopenia +++ +
Protamine sulfate Antidote Limited effect
PTT (partial thromboplastin time) & APTT (activated partial
thromboplastin time) are same

37. Uses:
•Venous thrombosis
•Pulmonary embolism
•Angina pectoris
•MI
•Coronary angiography
•Heparin, LMWH and fondaparinux do not cross
placenta – safe during pregnancy

38. •Heparin antagonist: protamine sulphate - rapidly
neutralizes heparin effects
•Heparin, LMWH & fondaparinux are not absorbed
orally

39. •Heparin can be administered as:
Continuous i.v. infusion
Intermittent infusion every 4-6 h
S.C. every 8-12 h
•LMWH and fondaparinux are given s.c. once daily dose
•Fondaparinux should not be used in patients of renal
failure since it is excreted by the kidney
ADRs:
•Bleeding- incidence is less with LMWH and
fondaparinux
•Heparin induced thrombocytopenia
•Osteoporosis- maximum risk with heparin, less with
LMWH & fondaparinux

40. Direct thrombin inhibitors:
•Hirudin
•Bivalirudin- synthetic, direct  of thrombin
•Lepirudin- recombinant derivative of hirudin
•Desirudin- recombinant derivative of hirudin
•Argatroban- synthetic, reversibly binds to thrombin
•Antithrombin- recombinant form of human antithrombin,
used in patients with hereditary deficiency of antithrombin
•Drotrecogin alfa- recombinant form of human activated
protein C that inhibits coagulation by proteolytic
inactivation of factors Va and VIIIa. Also has anti-
inflammatory effects

41. Oral anticoagulant therapy
•Warfarin sodium:
Reduced Vit K Epoxide (Oxidized Vit K)
Reduced Vit K
NADHNAD
Inactive coagulation factors II, VII,
IX, X & anticoagulat proteins C
and S
Activated factors and proteins
-Glutamyl
carboxylase
Vit K
epoxide
reductase
Inhibited by
warfarin
sodium
NAD- nicotinamide adenine dinucleotide

42. •Warfarin can be administered orally, i.v. or rectally
•Well absorbed from all routes, high plasma binding
ADRs:
•Bleeding tendencies
•Birth defects and abortion if given during pregnancy-
warfarin crosses the placenta with fetal concentrations
being equal to mother
•Skin necrosis
•Acenocoumarol and phenprocoumon- similar to warfarin
•Rodenticides- bromadiolone; brodifacoum;
diphenadione; chlorophacinone and pindone

43. New Oral Anticoagulants:
•Dabigatran Etexilate
 Prodrug, converted rapidly to dabigatran
 Reversibly blocks the active site of
thrombin
•Rivaroxaban
 Inhibits factor Xa
 Does not require monitoring of
coagulation factors

44. Fibrinolytic (thrombolytic) drugs:
•Drugs that activate conversion of plasminogen to
plasmin that hydrolyses fibrin and thus dissolves the clot
•Clot dissolution and re-perfusion occur with a higher
frequency when therapy is initiated early after clot
formation
•Clots become more resistant to lysis with age
•Used to dissolve clots for treating:
•Deep vein thrombosis
•Pulmonary embolism
•Acute MI
•Peripheral arterial thrombosis

45. •Alteplase, reteplase, tenecteplase
•Anistreplase
•Streptokinase
•Urokinase
•Alteplase:
•Binds to fibrin and activates fibrin-bound plasminogen
to plasmin
•It has little activity in the absence of fibrin
•Activates fibrin bound plasminogen more rapidly than
circulating plasminogen
•Produced by DNA recombinant technology
•ADRs: Bleeding

46. Anistreplase:
•Prodrug
•Preformed complex of streptokinase and plasminogen
that has been acylated to protect the active site
•Upon administration the acyl group gets hydrolysed
releasing the active complex

47. Streptokinase:
•Protein derived from -haemolytic streptococi
•No intrinsic activity
•Forms stable non-covalent complex with
plasminogen to activate it
•Has allergenic properties
•Should never be repeated after first administration
•Cheap, but rarely used

48. Urokinase:
•Protease enzyme
•Isolated from human urine earlier, now produced
from cultured human kidney cells
•Direct plasminogen activator
•Can degrade both fibrin and fibrinogen
•Non-allergenic and non-pyrogenic
•Does not produce hypotension
•t½ is 20 min
•Cheap as compared to newer drugs
•Recombinant pro-urokinase- gets converted to
urokinase on binding to a fibrin clot

49. Contraindications for fibrinolytic therapy:
 Absolute:
•Prior intracranial hemorrhage
•Known cerebral vascular lesion
•Known malignant intracranial neoplasm
•Ischemic stroke within past 3 months
•Suspected aortic dissection
•Active bleeding
 Relative:
•Uncontrolled hypertension, trauma, major surgery
within past 3 months, recent internal bleeding,
pregnancy, active peptic ulcer