 |
Web Hosting by Netfirms | Free Domain Names by Netfirms |
|
|
|
|
CLINICAL PHARMACOKINETICS OF LIGNOCAINE |
 |
1. Introduction:
- Most frequently used drug for the initial parenteral therapy of acute ventricular arrhythmias, eg. prevention of VF after AMI.
- IV bolus followed by IV infusion
Poor oral bioavailability
High EH
Short duration of action
2. Pharmacokinetic Overview:
(a) Absorption:
- 60-70% of oral dose is metabolised by liver on “first pass”.
- Lignocaine plasma levels with oral administration are usually too low to be effective.
- Toxicity from metabolites produced by first-pass metabolism is possible.
- Drug is primarily used for acute effect.
(b) Distribution:
- Described best by a two-compartment model.
Vi(Vc)
0.5 L/kg
Total Vd (Vc + V
)
- About 50-80% protein bound (
- acid glycoprotein = AAG).
Extent of binding is closely related to AAG concentration.
(c) Elimination:
- < 5% renally cleared.
- Principal metabolites (MEGX and GX) have anti-arrhythmic activity and some convulsant activity (probably contribute to the toxic convulsant effects of Lignocaine).
- E
Normal Cl
Terminal t½
3. Factors Affecting Lignocaine Pharmacokinetics:
-
Lignocaine has a high E
changes in liver blood flow will produce the
most profound effects on disposition.
Eg. AMI or CCF
C.O. -
Table: Factors Affecting Lidocaine Elimination
1.
Decreased hepatic blood flow associated with decreased cardiac output (eg. congestive heart failure, myocardial infarction, age, shock).
2.
Portal-systemic and intrahepatic shunts in liver disease.
3.
Hepatocellular liver disease.
4.
Drugs which decrease hepatic blood flow (Propranolol, Anaesthetics, Norepinephrine).
-
Although the drug has a high E, changes in hepatic metabolism can also
affect Lignocaine disposition (eg. cirrhosis).
- Effect on Cl:
Eg. in CCF or cirrhosis, Cl
- Effect on t½:
0.693 X Vd t½ = ___________
Cl Cirrhosis: Vd
and Cl
But CCF: Vd
4. Plasma Level Monitoring:
-
Therapeutic levels approx 1.5 - 5.0 
g/ml.
- Inter-patient variability occurs.
-
Some patients require levels > 5 g/ml to control thin arrhythmias.
- Levels correlate well with CNS toxicity.
- Metabolites may contribute to activity/toxicity.
- May be preferable to measure free drug levels. There is evidence that Lignocaine toxicity is better related to free levels than total levels. However, no rapid and reliable method to measure free drug levels is presently available for basic drugs.
- General guidelines for interpreting Lignocaine plasma levels:-
|
Table: Lidocaine Plasma¶ Concentrations and Effects |
||
|
Concentration |
Antiarrhythmic Effect |
Toxicity§ |
|
< 1.5 |
Rarely effective |
Idiosyncratic |
|
1.5 - 4.0 |
Usually effective |
Mild CNS and cardiovascular effects in few patients. |
|
4 - 6.0 |
May be needed for major arrhythmias |
Mild CNS effects common; cardiovascular in those with concomitant heart disease. |
|
6 - 8 |
Acceptable only if alternative therapy not possible. |
Significant risk of CNS and cardiovascular depression. |
|
> 8 |
Seizures, obtundation, decreased cardiac output common. |
|
|
¶
Plasma and serum
measurements are similar. Whole blood concentrations may be 10 to 30%
lower. |
||
5. Clinical Application of Pharmacokinetic Data : Lignocaine Dosage Regimens:
(a) Loading dose:
- Terminal t½
- Loading dose bolus is given slowly (over 2-3 mins) to avoid high peak levels and toxicity.
L.D. = Vc x C
Condition Approx Vc (L/kg) Normal 0.5 CHF 0.3 Cirrhosis 0.6 Eg. A 30 year old (70kg) man admitted for an abdominal stab wound has become hypotensive from excessive blood loss. His ECG shows multifocal PVC’s. Lignocaine is ordered. What loading dose should be given to achieve a plasma level of 3mg/ml?
- Additional boluses of one-half the original amount may be administered if the arrhythmia reappears within 10-30 minutes.
(b) Maintenance infusion:
Rinf = Css X Cl
Condition Approx Lignocaine (Cl (ml/min/kg) Normal 10 CHF/Cirrhosis 6 Pulmonary oedema/cardiogenic shock 2 In general it can be assumed that each 10mg/kg/min of infusion will produce a level of 1mg/ml in normal patients (ie. to produce a level of 3mg/ml, use an infusion of 30mg/kg/min).
6. Empirical Approach to Lignocaine Dosing:
LD of 1 - 1.5 mg/kg (reduce by 30-50% in CCF).
Maintenance infusion of 2mg/min (reduce by 30-50% in CCF and chronic liver disease).
7. Clinical Examples:
(a) A 65 year old male was admitted to the coronary care unit with a 3 hour history of severe, crushing substernal chest pain radiating down both arms and an electrocardiogram consistent with an anterior myocardial infarction. Frequent multifocal ventricular ectopics and a short run of ventricular tachycardia were documented shortly after admission. The patient has moderate CCR, and weighs 58kg. Lidocaine was ordered and a dosage regimen was calculated to achieve a plasma concentration of 3.0mg/ml.
Calculate the appropriate loading dose and maintenance infusion rate of Lignocaine, using:-
(i) Pharmacokinetic, and
(ii) empirical approaches to dosing.
Ten minutes after the end of the loading dose of Lignocaine, another short run of VT occurred. What should be done?
(b) BP, a 65 year old patient weighing 70kg was admitted for hepatic encephalopathy and cirrhosis. On the fourth hospital day he developed ventricular arrhythmias and Lidocaine was ordered. Calculate a loading dose and a maintenance infusion which will achieve a steady state Lidocaine level of 2mcg/ml (mg/L).
8. Conclusions:
- Lignocaine dosage regimens can be either estimated empirically or calculated by using population averages for pharmacokinetic constants.
- TDM can be used to individualise dosage and (especially) to reduce the risk of toxicity.
- Clinical monitoring should be the principal basis for altering dosage. Warning signs of toxicity include paraesthesia tremor, drowsiness, and tinnitus.
- Monitoring free drug levels may emerge as a useful guide to Lignocaine therapy.
   |
