Calcium Channel Blockers

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

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

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

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

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

Voltage Gated Calcium Channel

•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

•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

•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

•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

•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

•Mibefradil has T-type calcium channel blocking activity along with L-type calcium channel blocking activity•Withdrawn from market due to drug interactionsCCBs are arteriolar dilators, have minimal or no effect on venous bedsCCBs have little or no effect on nonvascular smooth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

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

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

Myocardial infarction

•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

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

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

Drugs used for treatment:

•Nitrates

-Blockers

•Ca2+ channel blockers?

•Antiplatelet and anti-thrombotic agents

•ACE Inhibitors

•Statins

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

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

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

• 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

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

• 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

•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

Prostaglandins

Prostacyclin

Thromboxane A2

Leukotrines

Lipoxins

Formation of Thromboxane and Prostacyclin

•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

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

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

• Thrombolytics & fibrinolytics are synonyms

• Thrombolytics:

Streptokinase

Urokinase

Alteplase

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)

•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

•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

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

Uses:

•Venous thrombosis

•Pulmonary embolism

•Angina pectoris

•MI

•Coronary angiography•Heparin, LMWH and fondaparinux do not cross

placenta – safe during pregnancy

•Heparin antagonist: protamine sulphate - rapidly neutralizes heparin effects

•Heparin, LMWH & fondaparinux are not absorbed orally

•Heparin can be administered as:Continuous i.v. infusionIntermittent infusion every 4-6 hS.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

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

Oral anticoagulant therapy

•Warfarin sodium:

Reduced Vit K Epoxide (Oxidized Vit K)

Reduced Vit K

NADHNAD

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

•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

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

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

•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

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

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

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

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 bleedingRelative:

•Uncontrolled hypertension, trauma, major surgery within past 3 months, recent internal bleeding, pregnancy, active peptic ulcer