Introduction to clinical pharmacy L-11

Clinical pharmacokinetics

Presented by:

Kholod Hamad

Clinical Pharmacy- NUSU

Learning outcomes

• Rationalized the indication of the drug.

• Initiate drug regimen for the individual patient.

• Take useful blood sample for analysis and interpretation.

• Adjust the therapy regimen to suit the patient individual needs.

• Monitor the disease progression and drug side effects.

What is clinical pharmacokinetics?

• Concern about ADME, how to adjust the dosage regimen to suit the patient’s ADME characteristics and concentration vs. time profile following the therapeutic planning.

• The service known as Therapeutic Drug Monitoring (TDM) or Clinical Pharmacokinetic Services

Drug journey..

Tablet GIT

A mucosal

D blood

E kidney/liver

M liver

Metabolite

Receptor tissue

BIOPHARMACEUTICS PHARMACOKINETICS PHARMACODYNAMICS

Elimination

1 3 2

Absorption

• Must be able to get medications into the patient’s body

• Drug characteristics that affect absorption: – Molecular weight, ionization, solubility, &

formulation

• Factors affecting drug absorption related to patients: – Route of administration, gastric pH, contents of GI

tract

Bioavailability (F)

• The percentage of the administered dose that reaches the systemic circulation.

Absorption Rate (Ka)

• The speed of input into the systemic circulation.

Time to Peak Concentration

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0 5 10 20 30 60 120 180

minutes

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IV

Oral

Rectal

Distribution

• Membrane permeability

– cross membranes to site of action

• Plasma protein binding

– bound drugs do not cross membranes

– malnutrition = albumin = free drug

• Lipophilicity of drug

– lipophilic drugs accumulate in adipose tissue

• Volume of distribution (Vd) Vd = dose C0 • The apparent volume into which the drug distributes

within the body.

One compartmental model

Two compartmental model e.g Digoxin

Metabolism

• Drugs and toxins are seen as foreign to patients bodies

• Drugs can undergo metabolism in the lungs, bile, and liver

• Body works to convert drugs to less active forms and increase water solubility to enhance elimination

Metabolism

• Liver - primary route of drug metabolism

• Liver may be used to convert pro-drugs (inactive) to an active state

• Types of reactions

– Phase I (Cytochrome P450 system)

– Phase II

Phase I reactions

• Cytochrome P450 system

• Located within the endoplasmic reticulum of hepatocytes

• Through electron transport chain, a drug bound to the CYP450 system undergoes oxidation or reduction

• Enzyme induction

• Drug interactions

Phase II reactions

• Polar group is conjugated to the drug

• Results in increased polarity of the drug

• Types of reactions

– Glycine conjugation

– Glucuronide conjugation

– Sulfate conjugation

Elimination

• Pulmonary = expired in the air

• Bile = excreted in feces

– enterohepatic circulation

• Renal

– glomerular filtration

– tubular reabsorption

– tubular secretion

Clearance (CL)

• The volume of drug cleared per unit time.

Elimination Rate Constant (Ke)

• The proportion of drug in the body eliminated per unit time.

Elimination Half-life (t½)

• The time taken for the concentration to fall to half the previous value.

Concentration Vs. time profile for oral drugs

Cp

t

A

A+D D+E

E

Ka

Ke

Ke

Concentration Vs. time profile for parenteral drugs

Cp

D+E

E

Ke

Ke

Concentration Vs. time profile for continues infusion

Cp

Input > Output

Input = output

CONCENTRATION VS TIME PROFILE (AUC, Cmax, tmax)

Cp

Cmax

AUC

Concentration Vs Time Profile (Formulation, onset, duration of action)

Cp

t

Therapeutic

Range

Rapid absorbing

Slow absorbing

Sustained-release

Loading Doses

• Loading doses allow rapid achievement of therapeutic serum levels

• Same loading dose used regardless of metabolism/elimination dysfunction

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w/ bolus

w/o

bolus

Linear Pharmacokinetics

• Linear = rate of elimination is proportional to amount of drug present

• Dosage increases result in proportional increase in plasma drug levels

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Nonlinear Pharmacokinetics

• Nonlinear = rate of elimination is constant regardless of amount of drug present

• Dosage increases saturate binding sites and result in non- proportional increase/decrease in drug levels

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Drug plasma concentration monitoring is helpful for drugs:

• that have a low therapeutic index

• that are not metabolized to active metabolites

• whose concentration is not predictable from the dose

• that are often taken in overdose

Therapeutic Ranges for Commonly Used Drugs

For which specific drugs is drug concentration monitoring helpful?

The important drugs are: • Aminoglycoside antibiotics • Ciclosporin • Digoxin • Lithium • Phenytoin • Theophylline • Paracetamol and salicylate (overdose)

Other drugs are sometimes measured: • anticonvulsants other than phenytoin (eg carbamazepine,

valproate) • tricyclic antidepressants (especially nortriptyline) • anti-arrhythmic drugs (eg amiodarone).

Management of Drug Therapy

• “Target-effect” strategy

– Pre-determined efficacy endpoint

– Titrate drug to desired effect

• Monitor for efficacy – If plateau occurs, may need to add additional drug or choose

alternative agent

• Monitor for toxicity – May require decrease in dose or alternative agent

Management of Drug Therapy

• “Target-concentration” strategy

– Pre-determined concentration goal

• Based on population-based PK

• Target concentration based on efficacy or toxicity

– Know the PK of the drug you are prescribing

• Presence of an active metabolite?

• Should the level of the active metabolite be measured?

• Zero-order or first-order kinetics?

– Does it change with increasing serum concentrations?

Management of Drug Therapy

• Critical aspects of “target-concentration” therapy

• Know indications for monitoring serum concentrations – AND when you do not need to monitor levels

• Know the appropriate time to measure the concentration

• If the serum concentration is low, know how to safely achieve the desired level

• Be sure the level is not drawn from the same line in which the drug is administered

• Be sure drug is administered over the appropriate time

• AND Treat the patient, not the drug level

REMEMBER

No drug produces a single effect!!!

Case 1

• JB is a 5 years child with pneumonia. He has a history of renal insufficiency and is followed by the nephrology service. His sputum gram stain shows gram negative rods. He needs to be started on an aminoglycoside.

• What you should do for this patient??

Case 2

• MJ is a 33 years female with a history of congenital heart disease. She is maintained on digoxin 10 mcg/kg/day divided bid. She has a dysrhythmia and is started on amiodarone.

• What is your intervention??

Case 3

• JD is a 10 years male on phenytoin NG bid (10 mg/kg/day) for post-traumatic seizures but continues to have seizures. He is on continuous NG feeds. His phenytoin level is 6 mcg/ml.

• What is your response ??