25. Antiarrhythmic Drugs Flashcards
Describe the classification of antiarrhythmic drugs.
Fig. 25.1 Cardiac myocyte action potential
Diagram Fig. 25.1 Cardiac myocyte action potential Phase 0 Fast depolarisation −Na+ in
Phase 1
Early repolarisation
− K+ out, Cl− in
Phase 2
Voltage gated L-type Ca2+ channels open
Phase 3
Rapid repolarisation
− K+ out
Phase 4
Resting membrane potential
Fig. 25.1 Cardiac myocyte action potential
Phase 4
Resting membrane potential
Phase 0
Fast depolarisation
−Na+ in
Phase 1
Early repolarisation
− K+ out, Cl− in
Phase 2
Voltage gated L-type Ca2+ channels open
Phase 3
Rapid repolarisation
− K+ out
Page 103
Table 25.1 Vaughn-Williams classification of antiarrhythmics
IA
Class Mechanism Drug
Ia
Blocks fast Na+ channels in cardiac myocytes.
Quinidine, procainamide, disopyramide
↑ Refractory period
IB
Ib
Blocks fast Na+ channels in cardiac myocytes.
Lignocaine, phenytoin, mexiletine
↓ Refractory period
Ic
Ic
Blocks fast Na+ channels in cardiac myocytes.
Flecainide, propafenone
No effect on refractory period
II
II β-adrenoreceptor blockade
Atenolol, propranolol, esmolol
III
III
K+ channel blockade
Amiodarone, sotalol,
bretylium
IV
IV
Ca2+ channel blockade
Verapamil, diltiazem
How do class I drugs exert their effects?
Refer to the cardiac myocyte AP graph (Figure 25.1):
The sodium channel blockers
exert their effects by blocking fast Na+ channels,
therefore reducing the
influx of Na+ into cardiac myocytes
and
increasing the time it takes
the cell to reach threshold potential.
By doing this they decrease the slope
of Phase 0 of the AP
and
decrease cardiac conduction velocity.
For this reason,
they are effective at
abolishing reentrant
arrhythmias.
These fast Na+ channels are
not found in nodal tissue,
where
Phase 0 depolarisation results
from the influx of Ca2+ ions.
Class I drugs are
further sub-classified according to their effects on the refractory period (RP) of the myocyte.
Class I drugs may prolong or decrease
the time taken for repolarisation,
and therefore the RP,
by their action on the
K+ channels responsible
for Phase 3 of the AP
How do class II drugs exert their effects?
Refer to the sinoatrial node AP graph (Figure 25.2):
β-blockers are antagonists
at β adrenoceptors
and so
decrease sympathetic
tone on the heart,
which reduces the slope of Phase 4 of the AP.
β-adrenoceptors are found in nodal, conducting and myocardial tissues and are coupled,
via G proteins, to Ca2+ channels
that open when the
receptor is activated.
In the cardiac tissues there are relatively more
β1 than β2 adrenoceptors, and the
newer generations of β-blockers are much more
cardioselective,
(β1 > β2).
Blocking β adrenoceptors causes a decrease in Ca2+ flux into cells and so reduces the slope of Phase 0 of the AP.
A decrease in
Ca2+ influx causes:
> Decrease in heart rate (chronotropy)
> Decrease in contractility (inotropy)
as less Ca2+ is available
to the sarcomeres
in the myocytes
β-blockers also inhibit the action of myosin light chain kinase
and so they
decrease the heart’s relaxation rate (lusitropy).
How do class III drugs exert their effects?
Refer to the sinoatrial node AP graph (Figure 25.2):
Class III antiarrhythmics
block K+ channels,
decreasing K+ flux out of
the cells,
which delays repolarisation both in
nodal tissue
and
in the cardiac myocytes.
This decreases the slope of Phase 3 of the AP,
which leads to an increase
in the cells’ refractory period and hence reduces its
arrhythmogenicity.
How do class IV drugs exert their effects?
Refer to the sinoatrial nodal AP graph (Figure 25.2):
Class IV antiarrhythmics
block L-type Ca2+ channels, while leaving
T-, N- and P-type channels unaffected.
L-type channels are widespread throughout
the cardiovascular system.
T-type are
structurally similar to L and are present in the cardiac cells that have
T-tubule systems, e.g. SA node and some vascular tissues.
N-type are found in nerve cells and P in the Purkinje
fibres.
L-type Ca2+ channels are responsible for the
plateau phase of the
cardiac action potential.
Class IV drugs decrease
the slope of Phase 0 of the
nodal AP,
decreasing heart rate.
These channels are
also found in cardiac
myocytes and blood vessels and
decreasing Ca2+ flux reduces
cardiac conduction velocity and contractility
What are the main differences
between verapamil and
nifedipine?
Verapamil is a racemic mixture
whose L isomer
has a high affinity for the
L-type Ca2+
channels at the
SA and AV nodes.
This results in slowing of conduction through the pacemaker cells, a decrease in heart rate and an increase in the RP.
Verapamil’s effect on cardiac contractility and vascular tone is less marked
though it does cause some coronary artery vasodilation.
Nifedipine has little effect on the SA or AV nodes
but causes a marked
decrease in arterial tone.
For this reason it is used for arterial spasm in coronary angiography, Raynaud’s phenomenon, hypertension and angina.
svts
vts
SVTs VTs
Ia Ia
Ic Ib
III (but not bretylium) Ic
IV III
QUINIDINE
type
moa
uses
QUINIDINE
Class 1a antiarrhythmic
MOA
• Class 1a antiarrhythmic
• Blocks fast Na+ channels
- Prolongs phase 0 of action potential
- Increases refractory period
- ↓ Vagal tone
USES • Termination of SVTs including AF/Flutter • Termination of ventricular arrhythmias
QUINIDINE
adme
METABOLISM
AND EXCRETION
- Hepatic metabolism
- Excreted in urine
ABSORPTION/
DISTRIBUTION
• Oral bioavailability 75%
- Protein binding ~90%
- t½ 5–9 hours
EFFECTS
CVS
Can cause: • Other arrhythmias, e.g. heart block, sinus tachycardia & ventricular arrhythmias
• Hypotension
ECG • Long PR • Wide QRS • Long QT and torsardes de pointes
CNS • Cinchonism, i.e. tinnitus, blurred vision, hearing loss, headache, confusion
CAUTION!
• Displaces digoxin from
binding sites causing toxicity
• Vagolytic effects can ↑ SA
nodal rate and
increase AV
nodal conduction.
In AF/Flutter this can allow more impulses to reach the ventricles. Hence, preload with b -blocker/Ca2+ channel antagonist before treatment
Lignocaine
LIGNOCAINE
Amide local anaesthetic
and
Class 1b antiarrhythmic
• Routes of administration:
topical/infiltration/intrathecally/
epidurally
• 1/2% clear colourless solution
+/– 1:200 000 adrenaline
- Gel: 21.4 mg/mL
- Ointment: 5%
• Spray: 10%
• Aqueous solution: 4%
• EMLA cream: 2.5% lignocaine
+ 2.5% prilocaine
MAX DOSE
• IV 3 mg/kg or 7 mg/kg if
in combination with adrenaline
MOA
- Class 1b antiarrhythmic
- Blocks fast Na+ channels
• ↓ Slope of Phase 0
action potential
• ↓ Refractory period
• ↓ Vagal tone
USES
• Local anaesthetic
• Termination of VTs
CHEMICAL PROPERTIES
• Nil
Lignocaine
admes
effects
METABOLISM
AND EXCRETION
• Hepatic metabolism
• Excreted in urine
(<10% unchanged)
ABSORPTION/
DISTRIBUTION
- 33% ionised in blood
- Protein binding 64%
- VD 0.7–1.5 L/kg
- t½ 90–110 min
EFFECTS TOXICITY! Signs of toxicity: > 4 μg/mL • Perioral tingling • Dizziness • Tinnitus • Parasthesia > 5 μg/mL • Altered consciousness • Coma • Seizures > 10 μg/mL • AV block • Refractory hypotension • Cardiac arrest Allergy is rare
Flecainide
type prep
dose
FLECAINIDE Amide local anaesthetic Class 1c antiarrhythmic • Tablets: 50/100 mg • Solution: 10 mg/mL
DOSE
• Oral: 100–200 mg BD IV
• Loading:
2 mg/kg over 30 min (max 150 mg)
• Maintenance:
1.5 mg/kg/hr for first hour
then 250 μg/kg/hr for 24 hours
MOA
- Class Ic antiarrhythmic
- Blocks fast Na+ channels
- Prolongs phase 0 of action potential
• No effect on
refractory period
USES • Termination of • SVT • VT • WPW
FLECAINIDE
adme
METABOLISM
AND EXCRETION
• Hepatic metabolism
• Active metabolites and unchanged drug excreted in urine
ABSORPTION/
DISTRIBUTION
- Well absorbed orally
- Bioavailability 90%
- Protein binding 50%
EFFECTS CVS • May precipitate conduction disorders • Caution with sinoatrial and atrioventricular disease
• Negative inotrope – can
precipitate heart failure
OTHER
• Dizzyness
• Parasthesia
• Headache
AMIODARONE
type
preparation
dose
moa
AMIODARONE
Class III antiarrhythmic
• Tablets: 100/200 mg
• Solution: 150 mg clear
colourless – dilute in 5% dextrose
DOSE
• IV loading:
5 mg/kg over
1 hour, into large vein
• Maintenance: 15 mg/kg/day
infusion (usually patients
given 300 mg loading +
900 mg over 24 hours)
• Oral: 200 mg t.d.s. for
1 week, reducing to BD for
1 week, reducing to od there onwards
MOA
• Class III antiarrhythmic but also
has properties of I, II and IV
• Blocks K+ channels,
slows depolarisation,
AP duration + RP
CHEMICAL PROPERTIES
• Highly irritant, give into large vein
USES • Termination of SVT, VT, WPW (The ‘domestos’ of antiarrhythmics – ‘kills all known arrhythmias’)
DIGOXIN
dose
moa
toxicity
seen t what level
how rx
use
DIGOXIN
Glycoside extracted from
foxglove leaves (digitalis lanata)
- Tablets: 62.5–250 μg
- Colourless solution: 100–250 μg/mL
DOSE
• Loading: 500 μg followed by
500 μg or 250 μg 6 hours later
(depending on patient’s size)
- Maintenance: 62.5–500 μg/day
- Therapeutic range: 1–2 μg/L
MOA
• Binds to and inhibits Na+/K+ATPase pump.
This causes rise in intracellular [Na+].
This decreases extrusion of Ca2+
by Na+/Ca2+ exchange pump,
because this relies on high concentration gradient of
Na+ across cell membrane (which is reduced).
• ↑ intracellular Ca2+ causes ↑ contractility
• ↓ intracellular K+ causes
↓ conduction in SA & AV node,
slowing HR
• Increases vagal tone, so ↑ AV conduction time
TOXICITY
• TOXIC at [plasma]
> 2.5 μg/L serious effects
not usually seen at < 10 μg/L
- > 30 μg/L fatal
- Treat bradycardia with atropine or pacing
- Treat ventricular arrhythmias with phenytoin
• ‘Digibind’ antidote available
(IgG antibody fragments against digoxin, bind
and the complex is removed by kidneys),
but very expensive.
Use if > 20 μg/L,
life threatening arrhythmias,
uncontrolled hyperkalaemia
• Digibind can cause anaphylaxis
USES • To slow rate of AF and flutter • Inotrope in cardiac failure
Digoxin
ADME
effects
ecg appearance
other
levels increased decreased by
METABOLISM
AND EXCRETION
• Minimal hepatic metabolism
• Excreted unchanged in urine
ABSORPTION/ DISTRIBUTION • Oral bioavailability > 70% • Protein binding 25% • VD 5–10 L/kg • t½ 35 hours, ↑ ↑ ↑ in renal failure
EFFECTS
CVS
Arrhythmias and conduction abnormalities:
- Premature ventricular contraction
- Bigeminy
- AV block – all types
- Junctional rhythm
- Atrial/ventricular tachycardia
ECG
- Long PR (toxicity)
- ‘Inverted tick’ (toxicity)
- Flat T wave (at therapeutic level)
- Short QT (at therapeutic level)
OTHER • Anorexia • Nausea and vomiting • Diarrhoea • Headache • Lethargy • Visual disturbances of red-green perception • Rashes • Eosinophilia • Gynaecomastia
Plasma levels:
↑ by amiodarone, erythromycin, captopril
•↓ by antacids, phenytoin, metoclopramide
VERAPAMIL
DOSE
MOA
VERAPAMIL
Calcium channel antagonist
• Tablets: 40–240 mg
• Solution: 2.5 mg/mL
DOSE
• Oral: 240–480 mg /day in 3 divided doses
- IV: 5–10 mg over 30 s, titrate to effect
- Peak effect: 3–5 min
- Duration: 10–20 min
MOA
• Class IV antiarrhythmic
• Block L-type Ca2+ channels
so ↓ slope of nodal AP
• ↓ Ca2+ influx so
↓ conduction velocity and contractility
• Coronary artery dilation
USES
• Termination of SVT
(most common use),
AF and atrial flutter.
- Prophylaxis of angina
- Hypertension
CHEMICAL PROPERTIES
• Nil
VERAPAMIL
ad
me
METABOLISM
AND EXCRETION
• Hepatic metabolism subject
to zero order kinetics
• Both active metabolites
and unchanged drug excreted in urine
ABSORPTION/
DISTRIBUTION
• Well absorbed (90%) but
extensive first-pass metabolism
- Oral bioavailability 25%
- Protein binding 90%
- VD 3–5 L/kg
- t½ 3–7 hours
EFFECTS
CVS
• May precipitate VF or VT in WPW
• CCF in patients with poor LV function
• Caution with b–blockers/digoxin/
halothane –
severe bradycardia
• Hypotension (may be desirable)
OTHER
• Cerebral vasodilatation
B Blockers
MOA
MOA
• All competitive antagonists at B adrenoceptor
- Some have intrinsic sympathomimetic activity
- Varying receptor affinity (see box below)
RECEPTOR SELECTIVITY
Aim to block B1 but not
B2 receptors.
‘Cardioselective’ drugs:
- Atenolol
- Esmolol (ultra-short acting)
- Metoprolol (short acting)
- Bisoprolol
• Carvedilol
NB all will act on b2 if dose high enough
USES • Hypertension • Angina and MI • Tachycardias • Obtund reflex hypertension during laryngoscopy, e.g. esmolol
- In phaeochromocytoma– pre-op stabilisation
- HOCM
- Anxiety
- Glaucoma
- Migraine prophylaxis
Beta blockers
ADME
ABSORPTION/
DISTRIBUTION
• Varying lipid solubility of different agents
• Low lipid solubility, e.g. atenolol = poorly
absorbed from gut
• Higher lipid solubility, e.g. metoprolol = well
absorbed, but cross BBB and CNS side-effects
• Variable protein binding
METABOLISM
AND EXCRETION
• Low lipid solubility = minimal hepatic
metabolism and excreted unchanged in urine
• High lipid solubility = hepatic metabolism
Beta blockers effects
EFFECTS
CVS
• Negative inotrope and chronotrope so:
• ↑ Time in diastole and coronary artery perfusion • ↓ Cardiac oxygen requirements BUT, may worsen performance of failing ventricle
• ↓ BP • ↓ HR and CO • ↓ Renin secretion by b1 inhibition at juxtaglomerular apparatus BUT: beware in peripheral vascular disease as inhibition of b2 receptors causes some constriction which may further compromise circulation in peripheries.
RS • Bronchospasm, worse in susceptible patients so give cardioselective drugs in asthma/COPD and give test dose of short acting drug, e.g. esmolol/metoprolol
CNS
- Cross BBB can cause:
- Hallucinations
- Nightmares
- Depression
- Fatigue
- ↓ Intra-ocular pressure
GI
• Dry mouth
• GI upset
METABOLIC
Non-selective agents can:
• ↑ Resting BM in diabetics
• Mask symptoms of
hypoglycaemia (sweating,
tachycardia, etc.)
• ↑ Triglycerides and ↓ HDL
ADENOSINE
Naturally occurring purine
nucleoside
• Colourless solution:
3 mg/mL
DOSE
• Give incremental doses at
1 min intervals until desired
effect achieved 6 mg/12 mg/
12 mg
• Give as fast bolus into largevein
MOA • Binds to adenosine (A1) receptors coupled with K+ channels that open, to hyperpolarised membrane
• A1 receptors only found in sinoatrial and atrioventricular nodes so adenosine selectively decreases conduction velocity in the nodes (negative dromotropic effect)
• Also decreases cAMP mediated catecholamine stimulation of ventricles (negative chronotropic effect) CHEMICAL PROPERTIES • Nil
USES
• To differentiate between SVT (rate slows)
and VT
(rate doesn’t slow)
• If tachyarrhythmia is re-entrant, it may terminate it
• To differentiate between atrial
fibrillation and flutter, by
slowing ECG trace for analysis
Adenosine
ABSORPTION/
DISTRIBUTION
• t½ < 10 s
METABOLISM
AND EXCRETION
• Deamination in plasma
and red blood cells
EFFECTS CVS • No clinically significant effects on BP when given as described
OTHER
• ↑ Pulmonary vascular
resistance
• SOB, flushing and
chest discomfort
• Bronchospasm in
asthmatics
• Sense of impending doom. (Patients genuinely feel like they’re going to die. Warn them of this and support them through the feeling. It only lasts a few seconds.)
