Ï- ãÍãÏ ÇáÚæÝí
12-03-2004, 02:02 PM
HI ALL
WITH RESPECTION TO MY BEST FRIEND CARDIAC ARREST...THIS IS MY NOTE I HOPE U INJOY IT..REPRESENT DR. SAMI LECTURE..U CAN USE IT AS SUMMERY BUT ALSO GO TO UR BOOKS...AND PRAY 4 ME...
DR.MEEMO
----
ANTI-ARRHYTHMIC DRUGS
PHARMACOLOGY- 4TH YEAR-FACULTY OF MED IN UQU
LECTURE NOTES
DONE BY : ...... DR.MEEMO
CONTENETS :
• NORMAL PHYSIOLOGY OF CARDIAC RHYTHM.
• MECHANISM OF ARRHYTHMIAS.
• ANTI-ARRYTHMIC AGENTS.
FIRST : NORMAL PHYSIOLOGY OF CARDIAC RHYTHM.
ARRHYHTMIA : abnormal rhythmicity
PACEMAKER : area of heart that has the greatest conductivity and depolarization and act to control the pump activity of the heart
ACTION POTENTIAL PHASES OF THE HEART :
PHASE 0 : Na influx
PHASE 1 : Na-K exchange ( IN 0-1, NO RESPONSE TO OTHER IMPULSE )
PHASE 2 : K entry (platue)
PHASE 3 : Rapid drop of depolarization ( IN 2-3, MIGHT RSPONSE TO OTHER IMPULSE)
PHASE 4 : Repolarization
N.B.
If the AP is incomplete, another impulse may comes and initiate a new AP, BUT if we can make the AP complete, no chance to form a new one. by the way, we can control the hear rate.
SECOND : MECHANISM OF ARRYHTMIA
CAUSES OF ARRYTHMIAS :
1- abnormal pacemaker activity (either increase or decrease or both at time and decrease the automaticity )
2- abnormal conductivity
3- Originating ftom abnormal site
4- Travelling to extra pathways
N.B.
ARRYTHMIAS MAY CAUSE THE HEART TO BEAT AS(bradycardia,tachycardia)
MECHANISM OF ARRYTHMIA :
(I) ABNORMAL AUTOMATICITY
S.A. node shows the fasteset rate of depolarization of phase 4 . so S.A node dominate. However, if something enhancing, faster than S.A. node, and it will be the dominant.
Ischemia, infartion, .. etc >> pacemaker is abnormal >> abnormal automaticity due to decrease blood or K imbalance
EFFECT OF DRUGS ON AUTOMATICITY
1- To make more (-ve) discharge
2- To make more (+ve) discharge( +5 instead of -50>> threshold level)
3- To change the slope
4- To elongate the AP
So, each of the above cause elongate of AP1 & AP2
(II) ABNORMAL IMPULSE CONDUCTION
Once there is area of infarction in the way of imupse, or due to prolonged refractory period, that lead to abnormal conduction pathway, results in abnormal rhythm.
EFFECT OF DRUGS ON CONDUCTION :
To change the unidirectional block into bidirectional block ( though they will be slow – synchronicity )
If the abnormal refractory period =10 sec, we change the normal to 10 instead of 5 sec.
Impulse generate or impulse conductivity.(These are the main common line of treatment of arrhythmias.
So anti-arrythmic drugs are life saving. However, some are lethal proarrythmogenic.
THIRD : ANTI-ARRYHTMIC AGENTS
First, take a look in this diagram it may help to understand the site of action of each class of anti-arrhythmic agents.
PACEMAKER CURRENT (+ve) B-agonist, (-ve) class II
↓ (PHASE4)
Delay after depolarization→→→ FAST Na CURRENT (-ve) class I
↑ ↓ (PHASE0) ↑
↑ SLOW Ca CURRENT ↑RE-ENTRY(↑↑RP) class III
↑ ↓ (PHASE2) ↑
Transient inward current←←← INTRACELLULAR Ca (+ve) B-agonist,(-ve) class IV
↓
CONTRACTION
Class I : Na- channel blockers
i.e. local anesthetic action
they r subdivided according to their effecs on
1) action potential duration
2) kinetics of their interaction with cardiac Na-channel
class I A
include ( quinidine , procainamide, disopyramide)
1) lengthen the duration of AP
2) intermediate intervention with Na-channel
class I B
include ( lidocaine, phenytoin, tocainide, mexiletine )
N.B.
Lidocaine goes undergo zero order kinetic
1) shorten duration of AP
2) rapid intervention with Na-channel
class I C
include mainly flecainide, (+/-) propafenol….why?
b/cos propafenol has high pro-arrhythmogenic effect
1) no effect/ minimal effect on AP
2) interact steadily with Na-channel
N.B.
Drugs like ( propafenol, mexilitine ) are not readily fit these simplified definition..in other way it doesn’t follow the same class…but we but it here artebaryãÌÇÒíÇ
Class II : beta blocker
Consider as sympatholytic agents
Include (esmolol, praopranolol )
All of them act to prolong the action potential
Class III : K-channel blocker
Its action is prolongation of action potential duration by reducing outword ( as in K-channel blocker ) or augmentation inword currents. This in turn, prolong the effect of resting potential.
Include (amiodraone, sotalol,bretylium)
Class IV : Ca- channel blocker
Include ( verapamil, diltiazem)….go and read about in details from ex. lectures
QUINIDINE
As class I A
Dextro-isomer of Q. both are cimchona-alkaloids which have the following actions
1- anti-malarial
2- anti-pyretic
3- oxitoxic effect
4- depressant effect on cardiac & skeletal muscle
MECHANISM OF ACTION :
Q. binds to open A and inactivated I sodium channels & prevent sodium influx, thus slowing the rapid up during phase 0
Decrease the slope of phase 4 spontaneous depolarization
PHARMACOLOGICAL ACTIONS :
Cardiac action :
1- depression of excitability & automaticity
2- prolongation of the resting potential in all the heart except the A.V. node & bundle of HIS
3- depression of speed of conduction in all the heart except the A.V. & bundle of HIS
4- (-ve) inotropic action, particularly following large dose or I.V.INFUSION but this is rare
5- Peripheral V.D. of arterioles via direct action
Effect on ECG :
1- prolong Q_T
2- widening QRS complex( if more than 30% u should stop it)
3- prolong P_R
other actions :
1- anti-malarial
2- anti-pyretic
3- curariform action on smooth muscle ( relaxation )
4- stimulation of CNS that lead to depolarization
PHARMACOKINETICS :
1- rapid absorb thru GIT
2- 80 % bound in plasma albumin
3- Elimination by hepatic metabolism
PREPARATION ;
Oral mainly
THERAPEUTIC ACTION :
1- atrial fibrillation( 1ST CHOICE )
2- atrial flutter
HOW TO USE IT ??
1 tablet/2hrs or 1 tablet/ 4hrs ( if minor)
After 3 days if no effect :
2 tablet/2hrs >> until arrhythmia stopped
BUT…. Once side effect appear>> stop using
N.B.
-Avoid night dose to avoid hypotension
-digitalis usually given before Q. in atrial fibrillation with or without CHF to avoid sudden acceleration of the heart ( paroxysmal Tachycardia )
TOXICITY :
1- cinchonism >> headache , dizziness , rashes
2- idiosyncrasy and or hypersensitivity >> rarely
3- cardiovascular side effect
A- may lead to heart block in various degree that may reach to fatal cardiac arrest
B- extrasystole , fatal vent. Tachycardia
C- embolism>> due to lodgment of thrombi from the stagent auricular appendages when normal sinus rhythm is resumed in long standing atrial fibrillation ( usually Q. can be used if the case is acute and recent but no more for old and chronic pt)
D- hypotension due to (-ve) inotropic action and the vasodilatation induced by Q.
4- GIT disturbances
DRUG INTERCATIONS :
1- decrease t1/2 of some drugs
2- increase plasma concentration of digoxin
3- increase anti-coagulant effect
4- increase plasma K level>> accentuate cardiac actions
5- alkalinization of urine leading to decrease its excretion
CONTRAINDICATIONS :
1- H.F.
2- Digitalis induced arrhythmia
3- Idiosyncrasy and/or hypersensitivity
4- Complete A.V. block idioventricular or A.V. nodal rhythm
5- Old standing atrial fibrillation (more than 6 months )
PROCAINAMIDE
As class I A
Similar to Q. , it is procaine derivatives but has less CNS effect.
PHARMACOLOGICAL ACTIONS :
CARDIAC :
Same as with Q. but has less effect as (-ve) inotropic
ANS :
Vagolytic action, with no affect on alpha-receptor (not blocker)
OTHER :
DISTRIUTION :
Only 20% bind to plasma, t1/2 = 3-4 hrs
ELEMINATION : renal
PREPARATION : orally, I.V., I.M.
THERAPEUTIC USES :
Like Q. but for long term therapy not useful b/cos of low safety index
ADVERSE EFFECT :
Cardiac >>> as Q.
Other>> systemic lupus like syndrome in 70 % of pt.
DISOPYRAMIDE :
As class I A
- not imp.
- Used for ventricular arrhythmia
- Toxicity>>atropine like
LIDOCAINE
- has high 1st pass effect so must be given I.V.
- mild side effect :
- accentuated ventricular arrhythmia in 10 %
- neurological disturbances ( paresthesia,tremor,nausea of cerebral origin, headache )
- if plasma level exceed 9>> seizure
- drug interaction :
- decrease hepatic flow>increase plasma conc. > increase toxicity.
- Used for emergency so shouldn’t exceed 5 μg/ml
PHENYTOIN OR DILANTIN
- class I B
- anti-epileptic>>mainly for major epilepsy
- mechanism :
- decrease automaticity via blockin Na-channel blocker
- used for :
- Vent-arrhythmia due to(digitalis, open cardiac surgery, M.I )
- Digitalis induced supra-vent-arrhythmia
- Paroxysmal atrial flutter & tachycardia
FLECENIDE
As class I C, no more used.
PROPAFENONE
As class I C
- one of the best anti-arrhythmic drugs
- similar in structure with propranolol
- elimination takes 5 hrs
- very beneficial for vent. Arrhythmia
- can be used for supra-vent
- mild side effect as metallic taste and conctipation.
AMIODARONE
Amidarone (cordarone): consider as class ( I, II , III )
CLINICAL USES AND ACTIONS :
Effective in most types of arrythmias and is considered the most efficacious of all anti- arrhythmic drugs, this may be because it has a broad spectrum; it block sodium, calcium, and potassium channels and beta adrenoceptors. Because of its toxicities, however, amiodarone is usually reserved for use in arrhythmias that are resistant to other drugs. Used for ttt of CHF and as anti-hypertensive too
ADVERSE EFFECTS :
Amiodarone causes microcrystalline deposits in the cornea and skin, thyroid dysfunction, paresthesias, tremor, visual disturbance, and pulmonary fibrosis (15-24% of pt), bronchospasm, nausea, chest pain, flushing headache and bradycardia.
PHARMACOLOGY :
amiodarone is high accumulative drugs. and long half life ( 13-103 days ) . so, 15-30 days need to reach loading dose.
N.B.
ONCE SIDE EFFECT START TO APPEAR WE JUST KNOW THAT THE EFFECT OF AMIODARONE IS STARTED
Amiodarone rarely cause new arrythmias,because it blocks calcium channel and beta receptors as well as sodium and potassium channels.
THERAPUETIC DOSE :
Used for both ventricular and supraventricular arrhythmias. 100-200mg/d can be used
MISCELLANEOUS ANTI-ARRYTHMIC DRUGS
ADENOSINE
A normal component of the body, but when it is given in high doses (6-12mg) as in I.V bolus the drug markedly shows conduction in an A.V node. By hyperpolarizing this tissue through increased K and by reducing calcium current. Adenosine is extremely effective in abolishing AV nodal arrhythmia. Adenosine has an extremely short duration of action ( 15 sec ). Toxicity includes flushing and hypotention, but because of their short duration theses effects don’t limit the use of the drug. Chest pain and dyspnea may also occur.
Drug of choice for supraventricular tachycardia,
Less effective in presence of adenosine receptor blockers like theophylline and caffeine. Potentiated by adenosine uptake inhibitors like dipyridamole.
MAGNESIUM
Used in digitalis –induced arrythmia
POTASSIUM
Suppress ectopic pacemaker
DIGITALIS
Slowing AV conduction
WITH RESPECTION TO MY BEST FRIEND CARDIAC ARREST...THIS IS MY NOTE I HOPE U INJOY IT..REPRESENT DR. SAMI LECTURE..U CAN USE IT AS SUMMERY BUT ALSO GO TO UR BOOKS...AND PRAY 4 ME...
DR.MEEMO
----
ANTI-ARRHYTHMIC DRUGS
PHARMACOLOGY- 4TH YEAR-FACULTY OF MED IN UQU
LECTURE NOTES
DONE BY : ...... DR.MEEMO
CONTENETS :
• NORMAL PHYSIOLOGY OF CARDIAC RHYTHM.
• MECHANISM OF ARRHYTHMIAS.
• ANTI-ARRYTHMIC AGENTS.
FIRST : NORMAL PHYSIOLOGY OF CARDIAC RHYTHM.
ARRHYHTMIA : abnormal rhythmicity
PACEMAKER : area of heart that has the greatest conductivity and depolarization and act to control the pump activity of the heart
ACTION POTENTIAL PHASES OF THE HEART :
PHASE 0 : Na influx
PHASE 1 : Na-K exchange ( IN 0-1, NO RESPONSE TO OTHER IMPULSE )
PHASE 2 : K entry (platue)
PHASE 3 : Rapid drop of depolarization ( IN 2-3, MIGHT RSPONSE TO OTHER IMPULSE)
PHASE 4 : Repolarization
N.B.
If the AP is incomplete, another impulse may comes and initiate a new AP, BUT if we can make the AP complete, no chance to form a new one. by the way, we can control the hear rate.
SECOND : MECHANISM OF ARRYHTMIA
CAUSES OF ARRYTHMIAS :
1- abnormal pacemaker activity (either increase or decrease or both at time and decrease the automaticity )
2- abnormal conductivity
3- Originating ftom abnormal site
4- Travelling to extra pathways
N.B.
ARRYTHMIAS MAY CAUSE THE HEART TO BEAT AS(bradycardia,tachycardia)
MECHANISM OF ARRYTHMIA :
(I) ABNORMAL AUTOMATICITY
S.A. node shows the fasteset rate of depolarization of phase 4 . so S.A node dominate. However, if something enhancing, faster than S.A. node, and it will be the dominant.
Ischemia, infartion, .. etc >> pacemaker is abnormal >> abnormal automaticity due to decrease blood or K imbalance
EFFECT OF DRUGS ON AUTOMATICITY
1- To make more (-ve) discharge
2- To make more (+ve) discharge( +5 instead of -50>> threshold level)
3- To change the slope
4- To elongate the AP
So, each of the above cause elongate of AP1 & AP2
(II) ABNORMAL IMPULSE CONDUCTION
Once there is area of infarction in the way of imupse, or due to prolonged refractory period, that lead to abnormal conduction pathway, results in abnormal rhythm.
EFFECT OF DRUGS ON CONDUCTION :
To change the unidirectional block into bidirectional block ( though they will be slow – synchronicity )
If the abnormal refractory period =10 sec, we change the normal to 10 instead of 5 sec.
Impulse generate or impulse conductivity.(These are the main common line of treatment of arrhythmias.
So anti-arrythmic drugs are life saving. However, some are lethal proarrythmogenic.
THIRD : ANTI-ARRYHTMIC AGENTS
First, take a look in this diagram it may help to understand the site of action of each class of anti-arrhythmic agents.
PACEMAKER CURRENT (+ve) B-agonist, (-ve) class II
↓ (PHASE4)
Delay after depolarization→→→ FAST Na CURRENT (-ve) class I
↑ ↓ (PHASE0) ↑
↑ SLOW Ca CURRENT ↑RE-ENTRY(↑↑RP) class III
↑ ↓ (PHASE2) ↑
Transient inward current←←← INTRACELLULAR Ca (+ve) B-agonist,(-ve) class IV
↓
CONTRACTION
Class I : Na- channel blockers
i.e. local anesthetic action
they r subdivided according to their effecs on
1) action potential duration
2) kinetics of their interaction with cardiac Na-channel
class I A
include ( quinidine , procainamide, disopyramide)
1) lengthen the duration of AP
2) intermediate intervention with Na-channel
class I B
include ( lidocaine, phenytoin, tocainide, mexiletine )
N.B.
Lidocaine goes undergo zero order kinetic
1) shorten duration of AP
2) rapid intervention with Na-channel
class I C
include mainly flecainide, (+/-) propafenol….why?
b/cos propafenol has high pro-arrhythmogenic effect
1) no effect/ minimal effect on AP
2) interact steadily with Na-channel
N.B.
Drugs like ( propafenol, mexilitine ) are not readily fit these simplified definition..in other way it doesn’t follow the same class…but we but it here artebaryãÌÇÒíÇ
Class II : beta blocker
Consider as sympatholytic agents
Include (esmolol, praopranolol )
All of them act to prolong the action potential
Class III : K-channel blocker
Its action is prolongation of action potential duration by reducing outword ( as in K-channel blocker ) or augmentation inword currents. This in turn, prolong the effect of resting potential.
Include (amiodraone, sotalol,bretylium)
Class IV : Ca- channel blocker
Include ( verapamil, diltiazem)….go and read about in details from ex. lectures
QUINIDINE
As class I A
Dextro-isomer of Q. both are cimchona-alkaloids which have the following actions
1- anti-malarial
2- anti-pyretic
3- oxitoxic effect
4- depressant effect on cardiac & skeletal muscle
MECHANISM OF ACTION :
Q. binds to open A and inactivated I sodium channels & prevent sodium influx, thus slowing the rapid up during phase 0
Decrease the slope of phase 4 spontaneous depolarization
PHARMACOLOGICAL ACTIONS :
Cardiac action :
1- depression of excitability & automaticity
2- prolongation of the resting potential in all the heart except the A.V. node & bundle of HIS
3- depression of speed of conduction in all the heart except the A.V. & bundle of HIS
4- (-ve) inotropic action, particularly following large dose or I.V.INFUSION but this is rare
5- Peripheral V.D. of arterioles via direct action
Effect on ECG :
1- prolong Q_T
2- widening QRS complex( if more than 30% u should stop it)
3- prolong P_R
other actions :
1- anti-malarial
2- anti-pyretic
3- curariform action on smooth muscle ( relaxation )
4- stimulation of CNS that lead to depolarization
PHARMACOKINETICS :
1- rapid absorb thru GIT
2- 80 % bound in plasma albumin
3- Elimination by hepatic metabolism
PREPARATION ;
Oral mainly
THERAPEUTIC ACTION :
1- atrial fibrillation( 1ST CHOICE )
2- atrial flutter
HOW TO USE IT ??
1 tablet/2hrs or 1 tablet/ 4hrs ( if minor)
After 3 days if no effect :
2 tablet/2hrs >> until arrhythmia stopped
BUT…. Once side effect appear>> stop using
N.B.
-Avoid night dose to avoid hypotension
-digitalis usually given before Q. in atrial fibrillation with or without CHF to avoid sudden acceleration of the heart ( paroxysmal Tachycardia )
TOXICITY :
1- cinchonism >> headache , dizziness , rashes
2- idiosyncrasy and or hypersensitivity >> rarely
3- cardiovascular side effect
A- may lead to heart block in various degree that may reach to fatal cardiac arrest
B- extrasystole , fatal vent. Tachycardia
C- embolism>> due to lodgment of thrombi from the stagent auricular appendages when normal sinus rhythm is resumed in long standing atrial fibrillation ( usually Q. can be used if the case is acute and recent but no more for old and chronic pt)
D- hypotension due to (-ve) inotropic action and the vasodilatation induced by Q.
4- GIT disturbances
DRUG INTERCATIONS :
1- decrease t1/2 of some drugs
2- increase plasma concentration of digoxin
3- increase anti-coagulant effect
4- increase plasma K level>> accentuate cardiac actions
5- alkalinization of urine leading to decrease its excretion
CONTRAINDICATIONS :
1- H.F.
2- Digitalis induced arrhythmia
3- Idiosyncrasy and/or hypersensitivity
4- Complete A.V. block idioventricular or A.V. nodal rhythm
5- Old standing atrial fibrillation (more than 6 months )
PROCAINAMIDE
As class I A
Similar to Q. , it is procaine derivatives but has less CNS effect.
PHARMACOLOGICAL ACTIONS :
CARDIAC :
Same as with Q. but has less effect as (-ve) inotropic
ANS :
Vagolytic action, with no affect on alpha-receptor (not blocker)
OTHER :
DISTRIUTION :
Only 20% bind to plasma, t1/2 = 3-4 hrs
ELEMINATION : renal
PREPARATION : orally, I.V., I.M.
THERAPEUTIC USES :
Like Q. but for long term therapy not useful b/cos of low safety index
ADVERSE EFFECT :
Cardiac >>> as Q.
Other>> systemic lupus like syndrome in 70 % of pt.
DISOPYRAMIDE :
As class I A
- not imp.
- Used for ventricular arrhythmia
- Toxicity>>atropine like
LIDOCAINE
- has high 1st pass effect so must be given I.V.
- mild side effect :
- accentuated ventricular arrhythmia in 10 %
- neurological disturbances ( paresthesia,tremor,nausea of cerebral origin, headache )
- if plasma level exceed 9>> seizure
- drug interaction :
- decrease hepatic flow>increase plasma conc. > increase toxicity.
- Used for emergency so shouldn’t exceed 5 μg/ml
PHENYTOIN OR DILANTIN
- class I B
- anti-epileptic>>mainly for major epilepsy
- mechanism :
- decrease automaticity via blockin Na-channel blocker
- used for :
- Vent-arrhythmia due to(digitalis, open cardiac surgery, M.I )
- Digitalis induced supra-vent-arrhythmia
- Paroxysmal atrial flutter & tachycardia
FLECENIDE
As class I C, no more used.
PROPAFENONE
As class I C
- one of the best anti-arrhythmic drugs
- similar in structure with propranolol
- elimination takes 5 hrs
- very beneficial for vent. Arrhythmia
- can be used for supra-vent
- mild side effect as metallic taste and conctipation.
AMIODARONE
Amidarone (cordarone): consider as class ( I, II , III )
CLINICAL USES AND ACTIONS :
Effective in most types of arrythmias and is considered the most efficacious of all anti- arrhythmic drugs, this may be because it has a broad spectrum; it block sodium, calcium, and potassium channels and beta adrenoceptors. Because of its toxicities, however, amiodarone is usually reserved for use in arrhythmias that are resistant to other drugs. Used for ttt of CHF and as anti-hypertensive too
ADVERSE EFFECTS :
Amiodarone causes microcrystalline deposits in the cornea and skin, thyroid dysfunction, paresthesias, tremor, visual disturbance, and pulmonary fibrosis (15-24% of pt), bronchospasm, nausea, chest pain, flushing headache and bradycardia.
PHARMACOLOGY :
amiodarone is high accumulative drugs. and long half life ( 13-103 days ) . so, 15-30 days need to reach loading dose.
N.B.
ONCE SIDE EFFECT START TO APPEAR WE JUST KNOW THAT THE EFFECT OF AMIODARONE IS STARTED
Amiodarone rarely cause new arrythmias,because it blocks calcium channel and beta receptors as well as sodium and potassium channels.
THERAPUETIC DOSE :
Used for both ventricular and supraventricular arrhythmias. 100-200mg/d can be used
MISCELLANEOUS ANTI-ARRYTHMIC DRUGS
ADENOSINE
A normal component of the body, but when it is given in high doses (6-12mg) as in I.V bolus the drug markedly shows conduction in an A.V node. By hyperpolarizing this tissue through increased K and by reducing calcium current. Adenosine is extremely effective in abolishing AV nodal arrhythmia. Adenosine has an extremely short duration of action ( 15 sec ). Toxicity includes flushing and hypotention, but because of their short duration theses effects don’t limit the use of the drug. Chest pain and dyspnea may also occur.
Drug of choice for supraventricular tachycardia,
Less effective in presence of adenosine receptor blockers like theophylline and caffeine. Potentiated by adenosine uptake inhibitors like dipyridamole.
MAGNESIUM
Used in digitalis –induced arrythmia
POTASSIUM
Suppress ectopic pacemaker
DIGITALIS
Slowing AV conduction