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PHARMACOKINETIC DESCRIPTION OF PLASMA LEVELS OF DRUGS

 

1. Clinical Pharmacology:

Overview

2. Pharmacokinetics:- 

ADME
Sources of pharmacokinetic variation.

3. Theophylline Formulations:

4. Clinical Application of Pharmacokinetic Data:

Dosing guidelines.

1. Clinical Pharmacology:

(a) Structure : Dimethylated xanthine:

(b) Principal actions:

- Bronchodilator:

Acute and chronic treatment of asthma (especially as an adjuvant to inhaled b-agonist therapy).

- Cardiac stimulant Eg. acute cardiac failure

- Diuretic

(c) Mode of Action in respiratory disease:

Theophylline produces increased levels of both cAMP (bronchodilator) and cGMP (bronchoconstrictor). In practice, Theophylline always seems to produce bronchodilatation.

(d) Dose/plasma level-response relationship:

- The most effective dose can vary almost ten-fold between patients (400-3200mg/day) because of pharmacokinetic variation (concept of "standard dose" is meaningless)

- The bronchodilator effect of Theophylline increases in proportion to the logarithm of the plasma concentration over a range of 5 to 20 g/ml, and an optimum range of plasma levels has been established : 10-20 g/ml (55-110 mol/l).

Plasma level-response relationship for Theophylline
g/ml			mol/l
40	Seizures Brain damage Cardiac arrhythmias Cardiac arrest	Serious toxicity possible	220
20	Nausea Vomiting Diarrhoea Headache Irritability Insomnia	Toxicity probable	110
10	Optimum range		55
5	Clinical improvement possible		27.5
0	Sub-therapeutic levels		0

 

2. Pharmacokinetics:

(a) Absorption - (i) Oral:

	Liquids and plain tablets	slow release tablets
Extent	~ 100%	80-100%
Rate	Rapid (absorption complete within 4-6 hours)	Delayed (complete absorption requires ~ 20 hours)
Consistency	Very consistent	Slightly more erratic

Absorption (ii) Rectal:

Slow and erratic absorption from suppositories. Therefore, only indicated when the patient is unable to take oral medication (eg. Vomiting).

 

(b) Distribution:

- Two-compartment model (bronchioles located in the tissues compartment).

- Rapid distribution into peripheral tissues other than fat.

- Volume of distribution ~ 0.45 l/Kg.

- Only ~ 60% plasma protein bound.

- readily crosses the placenta, and enters breast milk.

 

(c) Metabolism:

- Inactive metabolites formed from multiple pathways.

- Main pathways : formation of uric acid derivatives by hydroxylation and demethylation.

- Caffeine is a metabolite in neonates.

 

(d) Excretion:

- < 10% is excreted unchanged in the urine.

 

(e) Non-linear kinetics:

Theophylline may display non-linear kinetics (dosage changes frequently result in disproportionately large changes in plasma levels).

- Demethylating enzyme is saturable

metabolic clearance with high plasma levels.

- Urine flow and renal excretion up with high plasma levels (diuretic effect)

renal clearance with high plasma levels.

in different patients, total clearance may either remain approximately constant (first-order kinetics) or decline (zero-order kinetics) with increasing plasma levels of Theophylline.

 

(f) Clearance : the best index of elimination:

- "Average" ~ 0.04 l/hr/kg

- Varies greatly (~ 16-fold).

Causes of variation:

- Increased clearance:

Age: 1 - 16 years.

Diet: Low carbohydrate, high protein.

Habits: Cigarette, marijuana smoking (PAH).

Drugs: Phenobarbitone.

- Decreased clearance:

Age: Neonates and infants < 1 year.

Diet: High carbohydrate, low protein.

Excessive methylxanthines (eg. coffee).

Disease: Liver disease, Heart failure, Pneumonia, Severe airways obstruction, Fever.

Drugs: Cimetidine (not Ranitidine), Macrolide antibiotics (Erythromycin).

 

(g) Half-life:

	Approx. half-life (hr)
Adult non-smokers	8
Adult smokers	4
Neonates	20-30
Children	3

 

3. Formulations of Theophylline:

(a) Chemical Complexes:

Eg.

	% Theophylline
Aminophylline (Theophylline ethylenediamine)	80
Choline theophyllinate	65

- Salts formed between Theophylline and bases, to increase solubility or absorption.

- However, these salts readily dissociate at physiologic pHs (when Theophylline acts as a weak base)

little advantage over Theophylline alone.

 

(b) Slow release tablets (Theodur, Neulin SR):

- Theophylline absorption is very rapid from plain tablets and the drug has a short half-life.

frequent (six hourly) administration is necessary to avoid wide fluctuations in plasma levels.

- Slow release formulations - allow bd administration with acceptable plasma level fluctuation.

- compliance.

 

4. Clinical Application of Pharmacokinetic Data : Dosing Guidelines:

(a) Acute asthma:

- Widespread mucous plugging of small airways bronchial receptor sites may not be accessible to inhaled bronchodilators

use IV therapy.

- Loading dose (Aminophylline by slow, constant IV injection over 20 minutes):-

(i) Patient not receiving oral Theophylline:

LD = Vd x C

0.5l/kg x 10mg/l

= 5mg/kg (6mg/kg Aminophylline)

(ii) Patient receiving oral Theophylline:

Measure or estimate plasma level:-

LD = Vd x (desired C - current C).

- IV infusion:-

Patient Group	Average Aminophylline dosage (mg/kg/hour)
Children	0.8
Adult smokers	0.8
Adult non-smokers	0.5
Cardiac failure	0.2
Liver disease	0.2
NB: Monitor plasma levels

Total body weight (TBW) or ideal body weight (UBW)?

- Opinions differ on whether to use TBW or IBW.

- Recent evidence suggests that Theophylline does slowly enter fat tissue and TBW may therefore provide a better indication of the volume of distribution.

 

(b) Chronic oral therapy:

* measure peak levels, ie. 1-2 hours after regular Theophylline, 4-6 hours after slow release Theophylline.

 

(c) Aminophylline infusions for acute asthma:

Chiou method to optimise dosage:

Estimation of clearance before steady-state is achieved:

Cl	=	2 x Rinf	+	W (C - C)
		___________		________________
		C + C		(C + C)(t-t)

Where:

Cl = Clearance (l/hr)
Rinf = (Theophylline mg/hr)
W = Weight (kg)
C, C = Theophylline plasma levels at times t and t (mg/L)

 

Clinical Example:

A 17 year old female (50kg) presents with acute asthma. She was given an initial intravenous loading dose of 250mg Aminophylline and 15 minutes later an Aminophylline infusion (25mg/hr) was commenced. Plasma was taken for Theophylline assay at 1.167hrs and 5hrs, and the measured levels were 10.62 and 8.26mg/L, respectively:-

(a) What is the patient’s clearance of Theophylline?

(b) What is the predicted steady-state level?

(c) How long will it take to reach steady-state?

The patient is still not well controlled after one day in hospital:-

(a) Calculate a loading dose and new infusion rate to achieve and maintain a plasma Theophylline level of 13mg/L.

(b) What would be a suitable oral regimen for this patient?