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ANTI-ARRHYTHMICS (Adenosine: (Pharmacokinetics (Rapid deamination in…
ANTI-ARRHYTHMICS
Adenosine:
Uses:
terminate re-entrant tachyarrhythmias (SVT)
differentiate AF and flutter by slowing rate for analysis
diffferentiate SVT (rate slows) from VT (doesn't slow)
Presentation: colourless solution 3mg/ml
Chemical: purine nucleoside
Action:
binds Adenosine receptors (A1) on SAN/AVN
Gi protein coupled receptor
opens K+ channels → membrane hyper-polarisation
reduces cAMP
result: AVN conduction delayed and negative chronotropy
Dose: 6/12/12mg boluses
Onset: Rapid
Route: IV (Large vein!)
Side effects:
CVS:
risk AF/flutter (↓ atrial refractory period)
Other:
flushing, bronchospasm, sense impending doom, chest discomfort
Extras:
Contraindicated if 2nd/3rd degree AV block or SSS
effect enhanced if dipyridamole (blocks its uptake!)
Pharmacokinetics
Rapid deamination in plasma by RBCs
Half life <10s
Amiodarone
Action:
class 3 antiarrhythmic (blocks K+ channels)
prolongs repolarisation → ↑ AP duration & ↑ RP
Dose:
IV: loading 300mg then 900mg/24° infusion
PO: 200mg TDS week 1, BD for week 2, OD week 3.
Presentation:
Tablet: 100-200 mg
solution: clear, 150mg per ampoule, dilute in 5% dextrose
Route: IV/PO
Uses: Terminate both SVT and VT, WPW syndrome
Onset: relatively rapid
Chemical: benzofuran derivative
Side effects:
RS: pneumonitis, fibrosis, 10% affected after 3 years and 10% mortality
ENDO: hypo/hyperthyroidism, prevents conversion T4 to T3 (active)
CNS: corneal deposits (halos, blurred vision), peripheral neuropathy
GI: metallic taste, GI upset, hepatitis/cirrhosis (MONITOR LFTS)
DERM: slate grey skin, photosensitivity
CVS: bradycardia, hypotension, prolonged QT
Extras:
high protein binding (can displace or be displaced → risk toxicity e.g. digoxin)
avoid with QT prolonging drugs
caution with AVN blockers → risk complete heart block
Pharmacokinetics
Distribution: >95% protein binding, Vd 2-70 L/kg
Metabolism: Hepatic
Absorption: poor from gut, loral BA 50%
Excretion:
via bile, skin, lacrimal glands
elimination half-life 20-100 days!!
Digoxin
Side effects:
CV- PVCs, bigeminy, AV block
ECG signs - prolonged PR, ST depression, T wave flattening, shorten QT
Non-CVS: anorexia, nausea, vomiting, visual red-green disturbance, rash, gynaecomastia
Presentation:
Tablets 62.5-250 mcg
Colourless solution for injection: 100-250mcg/ml
Uses:
Rate control AF, flutter
positive inotrope in sedentary patients
Action:
binds and inhibits Na/K ATPase → ↑intracellular Na+ → ↓ efflux Ca2+ via the Na/Ca exchanger
↑ intracellular Ca2+ → ↑ contractility (positive inotropy)
↓ Intracellular K+ → ↓ conduction SAN/AVN → slows conduction (negative chronotropy)
increases vagal tone (decrease slope phase 4) → slows AV conduction time
Chemical: Glycoside extracted from foxglove
Route: IV/PO.
IM avoided - variable absorption, pain, tissue necrosis
Dose:
LOADING: 500mcg stat → 250-500mcg 6 hrs later
MAINTENANCE: 62.5- 500mcg per day
levels of therapeutic range is 1-2 mcg/L
toxicity
Features:
Bradycardia → atropine or pacing
ventricular arrhythmia → lidocaine, or phenytoin
hyperkalamia
Treatment:
Activated charcoal if ingestion <1 hr
Treat bradycardia and ventricular arrhythmia as abovd
Digibind (IgG antibody fragments against Digoxin → form complex → renal excretion)
Levels: >2.5 mcg/L. (Inevitably fatal if >30 mcg/L)
Pharmacokinetics:
Distribution:
25% protein binding
Vd 5-10 l/kg (high)
Metabolism:
minimal hepatic
Absorption:
variable from gut (oral BA >70%)
Excretion:
mostly excreted unchanged in urine
glomerular filtration and active tubular secretion
elimination half-life 35hrs but ↑↑↑ if renal failure
VAUGHN-WILLIAMS CLASSIFICATION
Class 1
Block fast Na+ in cardiac myocytes (not nodal tissue!)
Prolongs time to reach threshold potential
decrease gradient of phase 0 in myocytes
decreases conduction velocity
Subtypes
1a: INCREASE refractory period
Diisopyramide
Quinidine
Procainamide
1b: DECREASE refractory period
Lignocaine
Mexiletine
Phenytoin
1c: NO EFFECT on refractory period
Flecainide
Propafenone
Class 2
β-adrenoceptor blockade:
decrease gradient of phase 4.
reduces Ca2+ influx (via GPCR)
nodal, conducting and myocardial cells
Result:
Negative chronotropy
Negative inotropy
Atenolol
propanolol
esmolol
Class 3:
K+ channel antagonists:
reduces K efflux
delays repolarisation (nodal & myocytes)
decreases slope phase 3
prolongs refractory period
Amiodarone
sotalol
bretylium
Class 4
Ca2+ channel antagonists:
block L-TYPE
decrease slope of phase 0 of pacemaker cells →prolongs conduction → negative chronotropy
prolongs phase 2 of myocytes → increase refractory period
some effect as coronary artery vasodilator and negative inotropy
Verapamil
Diltiazem
Classification by uses
SVT
Digoxin
β-blockers (class 2)
Adenosine
Verapamil
VT:
Class 1b: (Lidocaine, mexeletine)
Both SVT & VT
Class 1a (diisopyramide, quinidine, procainamide)
Class 1c (flecanide, propafenone)
Sotalol. (Has class 2 and 3 action)
Phases of action potentials
Cardiac myocyte
Phase 4: RMP
Na+/K+ ATPase restore ionic gradient
RMP is -90mV
Phase 0:
VG Na+ channels (Na+ Influx)
Rapid depolarisation to + 20mV
Phase 1:
Early repolarisation
K+ opens (causes efflux)
Na+ closes
Phase 2:
Plateau phase
VG L-type Ca2+ open
Ca2+ Influx, offsets K+ Efflux
Absolute refractory period
Phase 3
Rapid repolarisation
L-type Ca2+ close
Continued K+ efflux
Relative refractory period
Pacemaker cell
Phase 3
Repolarisation
L-type Ca2+ close, K+ channel open (efflux)
Phase 4
hyperpolarisation followed by spontaneous drift (no RMP)
Threshold potential (-40mV)
Due to 'funny' Na+ channels, T-type Ca2+ channels, Na+/Ca2+ ATPase
gradient of slope altered by symapthetic/parasympathetic
Phase 0
depolarisation slower than myocyte
L-type Ca2+ channels open (influx)