Transcript Lithium - Learnblock

Clinical Pharmacokinetics of Lithium and
Therapeutic Drug Monitoring
Michael Dolton, B.Pharm (Hons)
At the completion of this lecture you will
 understand the importance of monitoring
lithium concentrations due to variability in
pharmacokinetics and narrow safety margin
 appreciate the importance of lithium drug
interactions
 understand the PK-PD rationale for TDM and
dose adjustment
Lithium
First discovered in 1817
Indications
Acute treatment and prevention of mania
in bipolar disorder
Augmentation for treatment-resistant
depression
Available as 250mg (Lithicarb) and 450mg SR
(Quilonum SR) tablets
Lithium in Bipolar disorder
1st line therapy in acute mania and
prophylaxis in bipolar disorder
Some second generation antipsychotics
and anticonvulsants are also considered
1st line for these indications
Don’t stop Lithium abruptly or treat
intermittently unless toxicity present
Lithium Case History
Ms Ursla Down, 58 year exam supervisor, has been
taking lithium for bipolar disorder. Her serum
levels have ranged from 0.5 to 0.8 mM.
After developing peripheral oedema and is treated
with hydrochlorothiazide 100 mg mane.
One week later Ursla is admitted to hospital with
delirium and her serum lithium level was measured
at 2.5 mM.
Basic Concepts
Drug
Dose
Concentration
in plasma
PHARMACOKINETICS
Concentration
at effect site
Pharmacological
effect
PHARMACODYNAMICS
Pharmacokinetics
 what the body does to the drug
Pharmacodynamics
 what the drug does to the
body
Lithium Pharmacokinetics
J Clin Pharmacol 1994;34:280-285.
Renal Excretion
Renal Clearance (CLR) = filtration + secretion - reabsorption
Filtration
http://www.health.bcu.ac.uk/physiology/renalsystem.htm
Lithium Renal Excretion
Excreted in a similar way to sodium
Lithium CL = 26 mL/min
GFR = 120 mL/min
CLR < GFR
indicates both filtration and reabsorption
Not secreted
Lithium CL = filtration - reabsorption
Lithium unwanted effects
Antagonises antidiuretic hormone in
kidney producing diuresis
impairs thyroid function
cause weight gain
hand tremor
inverted T-wave of ECG
Lithium Toxicity
Grade
I
II
III
Manifestations
tremor, nausea, vomiting, sedation, ataxia
impaired consciousness, tremor, twitching
semi-coma, convulsions
sequelae - renal impairment, cerebral damage
Lithium Toxicity - conc vs effect
Therapeutic
prophylaxis
treatment
Toxicity
Grade I
Grade II
Grade III
mM
0.4 – 1.0
0.5 - 1.2
1.5 - 2.4
2.5 - 3.4
> 3.5
12 h post dose sample
AMH 2010
Lithium Toxicity - Treatment
Sufficient IV fluid replacement to
ensure diuresis
Haemodialysis increases lithium
clearance
Indicated if GFR < 60mL/min, lithium > 2.5,
delirium, seizures, coma, persistent clinical
effects in spite of fluids
Lithium concentration (mmol/L)
Lithium
Post-distribution sample
Flat concentration-time profile
after 12 h after the conventional
or sustained release dose forms
tablet
12
Time (h)
24
Lithium – When to monitor
When staring lithium (once SS achieved)
Prophylaxis: Every 3-6 months
Dose changes, interacting medications
started / ceased
Clinical signs of toxicity, or of lack of
efficacy
Dehydration, or changes in salt intake
Clinical status
The clinical status of the patient can
increase the risk of toxicity such as
renal impairment or dysfunction
dehydration related to fever, vomiting,
diarrhoea, heavy sweating and low salt
diet
Drug interactions with lithium
Decreases Lithium clearance
Diuretics - sodium depleting (e.g. thiazide)
NSAID -renal PG effects
ACE inhibitors, A2RA’s
Pharmacodynamic interactions
effects with no change in lithium
concentration
anticonvulsants, SSRIs, calcium channel blockers
Lithium vs. Sodium
80% of the filtered load of lithium is
reabsorbed in tandem with sodium
Part of Nephron
Lithium
Sodium
Proximal Tubule
✓
✓
Distal Tubule
✗
✓
Loop of Henle
✗
✓
Collecting Tubules
✗
✓
Lithium + Thiazide diuretics
Thiazide diuretics decrease sodium
reabsorption in the distal tubule
This creates a relative sodium deficit
Leads to a compensatory increase in
proximal tubule sodium and lithium
reabsorption ( Lithium in blood)
Lithium Case History II
Lithium and the diuretic were both
withdrawn.
36 h later Ms Down experiences a manic
episode and lithium at the previous dose is
restarted.
Oedema was found to be related to lithium
concentrations and safely treated with
amiloride.
Lithium TDM
Lithium conc (mM)
Confused and anorexic
1.2 mM
0.4 mM
Manic episode
weeks
Lithium dosing
diuretic
Clinical Pharmacology
The Right drug
The Right patient
The Right dose
The Right time
The Right Response
The
Right
dose
Do we need to measure drug
concentration?
For example
INR or PT for warfarin
 serum cholesterol concentration
measurements for pravastatin
 serum urate concentration for
allopurinol
 blood pressure for metoprolol
Why measure blood levels?
Drug
Dose
Concentration
in plasma
Concentration
at effect site
Analytical
method
Hard to
measure
(invasive)
Pharmacological
effect
Surrogate
marker
Hard to
measure
(outcome)
What is Therapeutic Drug
Monitoring?
 using drug concentration data as a
"surrogate" of drug effect to
individualise drug therapy to ensure
maximum beneficial effects with
minimal adverse effects.
When is TDM appropriate?
pharmacological response is difficult
to quantify
e.g. cyclosporin  outcome has serious consequences
 concentrations used as a surrogate
indicator/predictor of outcome
When is TDM appropriate?
drugs used as prophylactic agents
(endpoint is the absence of an event)
e.g. anticonvulsants, antiarrythmics,
lithium
drugs with a narrow therapeutic range
(individualise therapy to maximise
benefits and minimise risks)
e.g. digoxin, anticonvulsants, cardiac
antiarrhythmics, immunosuppressants
When is TDM appropriate?
drug clearance changes rapidly
e.g. declining renal function, change in
renal function post-transplant,
examining drug interactions
Monitor patient compliance
e.g suspected poor compliance,
particularly for prophylactic medicine,
used in clinical trials
When is TDM appropriate?
investigate unexpected or unexplained
effects
diagnose adverse effects to define
patient management especially where
the adverse effects mimic the disease
state e.g. cardiac arrhythmias and
digoxin
When is TDM appropriate?
Management of overdose
 urine drug screen - identify potential
causes of coma
 assign cause and decide management
 e.g. paracetamol - decision on
administration of antidote
 warfarin overdose and unexplained INR
Commonly monitored drugs
 Antibiotics
 Aminoglycosides, Vancomycin
 Antifungals
 Flucytosine, Itraconazole, Voriconazole, Posaconazole
 Anticonvulsants
 Phenytoin, Carbamazepine, sodium valproate
 Immunosuppressants
 Cyclosporin, Tacrolimus, Sirolimus
 Antiarrhythmics
 Digoxin, perhexiline
Others - Theophylline
What is a therapeutic range?
 An optimal concentration range for a
DRUG is NOT the same as a "normal"
range defined for biochemical
parameters
Encompasses those recorded in patients
experiencing therapeutic benefit and
minimal toxicity
Concentration-effect relationship
SAFETY MARGIN
Probability
Effect
Toxicity
Drug Concentration
What is a therapeutic range?
optimal range has not been defined for
many drugs
optimal range should only be used as a
guide and should always be interpreted
with the clinical assessment of the
patient
Cyclosporin Target range?
First 3 months
Kidney
: 150-300
Liver
: 150-300
Heart
: 250-350
Heart-lung: 350-600
BMT
: 100-300
maintenance
100-200 ng/ml
100-200 ng/ml
150-250 ng/ml
200-300 ng/ml
100-300 ng/ml
Interpreting Drug level data
accurate dose history including dose
(with an assessment of compliance) and
duration of therapy
 time of dose administration and blood
sample withdrawal
 patient status including age, weight
and organ function (e.g. renal function
assessed using estimated creatinine
clearance)
Interpreting Drug level data
 biological fluid sampled (e.g. whole
blood, plasma or serum)
 clinical status of patient (e.g.
experiencing adverse effects)
 medication history (including drugs that
may potentially interact with the drug
of interest)
 What is the therapeutic range for
THIS patient?
TDM vs. TCI
Therapeutic Drug Monitoring (TDM)
Target Concentration Intervention
(TCI)
(Holford, 1996)
Target Concentration Intervention
(Holford and Tett)
Select target
concentration
Use population
PK and PD data
Estimate
dose
Refine estimates
on outcome
Measure a
blood level
Dose prediction methods
Empirical dose protocol
Nomogram using patient covariates
Bayesian Dose prediction
population pharmacokinetic approach
Example Nomogram - Tobramycin
Massie et al, 2006
Dose prediction methods
Bayesian Dose prediction
uses prior knowledge of the population
pharmacokinetic parameters
information about the patient
predict PK parameters
individualize the dose
computer aided
relies on knowledge of population
pharmacokinetics
Bayesian software - TCIWorks
TCIWorks – Dose prediction
Role of the pharmacist in TDM
Interpret relevant information
Treat the patient not the number
Use pharmacokinetic knowledge to make
rational dose recommendations
Questions?
[email protected]