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antiarrhytmic drugs
• Irregular rhythm
• Abnormal Rate
• Conduction abnormality
What causes an arrhythmia?
• Changes in automaticity of the PM
• Ectopic foci causing abnormal APs
• Reentry tachycardias
• Block of conduction pathways
• Abnormal conduction pathways (WPW)
• Electrolyte disturbances and DRUGS
• Hypoxic/Ischaemic tissue can undergo
spontaneous depolarisation and become an
ectopic pacemaker
Normal heartbeat and atrial arrhythmia
AV septum
Definition of arrhythmia
• Cardiac arrhythmia is an abnormality of the
heart rhythm
• Bradycardia – heart rate slow (<60 beats/min)
• Tachycardia – heart rate fast (>100 beats/min)
Spontaneous
depolarisation
Cardiac Action Potential
• Divided into five phases (0,1,2,3,4)
– Phase 4 - resting phase (resting membrane potential)
• Phase cardiac cells remain in until stimulated
• Associated with diastole portion of heart cycle
• Phase 3 – repolarization
– K+ channels remain open,
– Allows K+ to build up outside the cell, causing the cell to repolarize
– K + channels finally close when membrane potential reaches certain level
– Corresponds to T wave on the ECG
Sinoatrial Node
Action Potential
•Phase 4: slow
depolarization due to Na+
and Ca2+ leak until threshold.
Note fast Na+ channels are
inactive at -60 to -40 mV.
•Phase 0: at threshold, Ca2+
channels open.
•Phase 3: As in nerves, K+
channels open during
repolarization.
•Finally, note the slow rise
and fall of the SA AP
compared to that of the
nerve AP, and the rhythmic
firing.
Cardiac Na+ channels
Contraction of
ECG (EKG) ventricles
showing
wave segments
Repolarization of
Contraction
ventricles
of atria
normal
Sinus bradycardia
Sinus Tachycardia
Sinus Arrest
Therapeutic overview
• Na+ channel blockade
• β-adrenergic receptor blockade
• Prolong repolarization
• Ca2+ channel blockade
• Adenosine
• Digitalis glycosides
The Basics
• SA Node and AV node cells are slow
conductors activated by calcium, thus
blocked by calcium channel blockers such
as verapamil
ECG : P – R interval
Memanjang
QRS Comp
Q – T interval → torsade de pointes.
Farmakokinetik:
- diserap per-oral komplit
- 80 % berikatan dengan plasma protein
Kontra – Indikasi
A.V Block
C.H.F
Hipotensi
Hati – hati :
pemberian digitalis
hiperkalemia
miastenia gravis == why ?
Prokainamid :
- efek hampir = kinidin dengan perbedaan
- sumber
- antimuskarinik <<
- asetilasi dilever ada yang fast ada yang
rapid acetylator.
- menimbulkan lupus (80% akan mendapat
titer anti nuklear yang tinggi 30%
lupus )., dose-related, biasanya pada yang
slow acetylator.
- dosis besar : agranulositosis.
Subclass IB
• Weak Phase 0 depression
• Shortened depolarization
• Decreased action potential duration
• Includes
–Lidocaine (also acts as local anesthetic) – blocks
Na+ channels mostly in ventricular cells, also
good for digitalis-associated arrhythmias
–Mexiletine - oral lidocaine derivative, similar
activity
–Phenytoin – anticonvulsant that also works as
antiarrhythmic similar to lidocane
Lignocaine (Lidocaine)
• Class Ib (blocks Na+ channels, reduces AP duration)
• Ventricular arrhythmias (acute Rx)
• IV infusion only (2 hour half life, high first pass
metabolism)
• Hepatic metabolism (inhibited by cimetidine,
propranolol)
• SE mainly CNS - drowsiness, disorientation,
convulsions, hypotension
Subclass IC
• Strong Phase 0 depression
• No effect of depolarization
• No effect on action potential duration
• Includes
– Flecainide (initially developed as a local anesthetic)
» Slows conduction in all parts of heart,
» Also inhibits abnormal automaticity
– Propafenone
» Also slows conduction
» Weak β – blocker
» Also some Ca2+ channel blockade
Flecainide
• Class Ic (block Na+ channels, no change to AP)
• Slows conduction in all cardiac cells
• Acute Rx /prophylaxis
• Supraventricular tachycardias
• Paroxysmal atrial fibrillation
• Ventricular tachycardias
• Oral/IV
• Long acting (T1/2 14 hours)
• Hepatic metabolism, urinary elimination
Flecainide
• CAST (Cardiac Arrhythmia Suppression Trial)
1989 – increased mortality post MI (VF
arrest)
• Side-effects:
= cardiac failure,= ventricular-
arrhythmias,blurred vision, abdominal
discomfort, nausea, paraesthesia, dizzyness,
tremor, metallic taste
Class II Anti Arrhytmic drugs
• β–adrenergic blockers:
– Includes
• Verapamil – blocks Na+ channels in
addition to Ca2+; also slows SA node in
tachycardia
• Diltiazem
Verapamil
• Class IV (calcium channel blocker)
• Prolongs conduction and refractoriness in AV node,
slows rate of conduction of SA node
• Used IV/oral
• SUPRAVENTRICULAR NOT VENTRICULAR
ARRHYTHMIAS (cardiovascular collapse)
• Do not use IV verapamil with ß- blocker (heart
block)
• T1/2 6-8 hours
Verapamil- adverse effects
• Heart failure
• Constipation
• Bradycardia
• Nausea
Adenosine
• Purine nucleoside
• Acts on A1 adenosine receptors
• Opens Ach sensitive K channels
• Inhibits Ca in current – Suppresses Ca dependent AP
(Nodal)
• Increases K out current – Hyperpolarisation
• Inhibits AVN > SAN
• Increases AVN refractory period
ADENOSINE
• Interrupts re-entry and aberrant pathways through AVN
– Diagnosis and Treament
• Drug for narrow complex PSVT
• SVT reliant on AV node pathway
• NOT atrial flutter or fibrillation or VT
• Contraindications:
• VT – Hypotension and deterioration
• High degree AV block
• Poison or drug induced tachycardia
• Bronchospasm but short Duration of action
ADENOSINE
• Carotid massage and vagal maneuvers first
• Rapid IV push 6mg – 12 mg – 12 mg
• Flush with 20ml N/S
• Record rhythm strip
• FLUSHING
• CHEST PAIN
• ASYSTOLE/BRADY
• VENTRICULAR ECTOPY
Adenosine- adverse effects
• Feeling of impending doom!
• Flushing, dyspnoea, chest pain, transient
arrhythmias
• Contraindicated in asthma, heart block
Digoxin
• Not in Vaughan Williams class
1. Atropine
• Atropine blocks the effects of acetylcholine.
• It elevates sinus rate and AV nodal and
sinoatrial (SA) conduction velocity, and it
decreases refractory period.
LCAT
Lipoprotein lipase Lipoprotein lipase
STATINS
Diet Biosynthesis
Conversion to
Bile Acids hormones within
cells or storage
Re- as granules
absorption
Intestine
Lipoprotein
BILE ACID catabolism
SEQUESTRANTS FIBRATES
Feces
Pharmacologic Classes and Agents:
Ex.
- Colestipol
- Cholestyramine
- Colesevelam
Chemistry :
- Large polymeric cationic exchange resins.
- Unsoluble in water.
- Bind bile acids prevent the absorption.
Mechanism of action :
But produce :
- Bloating
- Dyspepsia
- Lipid absorption menurun vit. ADEK
absorbtion also decrease bleeding.
- Warfarin & digoxin absorption menurun.
Cara Pemberian
- Diminum d.c.
INHIBITORS OF CHOLESTEROL ABSORPTION
Ex. Ezetimibe
- Rapidly absorbed by the enterocytes
and glucuronidated, recirculates
enterohepatically several times a day
in coordination with meals inhibit
cholesterol absorption (LDL).
- Little effect on HDL & triglycerides.
INHIBITORS OF CHOLESTEROL SYNTHESIS
HMG Co A
reductase is a rate
limiting enzyme in
cholesterol
synthesis
-Statins:
= Simvastatin
= Pravastatin
= Atorvastatin--
at dose of 80mg/day
----- TG <<<
“ 3-hydroxy-3-methyl-glutaryl-CoA”
Biosynthesis of Cholesterol
O CH3 O
CH3-C-SCoA -OOC-CH -C-CH -C-SCoA
2 2
OH
acetyl coenzyme A 3-hydroxy-3-methyl-glutaryl-CoA
HMG CoA
reductase
CH3
CH3 CH3
-OOC-CH -C-CH -CH -OH
CH3 2 2 2
CH3
CH3
OH
HO mevalonate
cholesterol
Effect lain dari statin
Pleiotropic effects
- reversal of endothelial dysfunction
- Decreased coagulation
- Decreased inflammation
- Improved plaque stability
Contoh : - Lovastatin
- Simvastatin CYP 450 3 A4
- Atorvastatin
- Fluvastatin CYP 450 2 C9
- Rosuvastatin
Fibric Acids derivatives
Fibrates bind to and activates PPAR
(Peroxisome Proliferator-Activated Receptor )
Pharmacodynamics
- Niacin inhibits VLDL secretion
Side-effects of niacin:
Dietary, Exercise & Lifestyle
Modifications