Pharmacokinetics 4

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  • Created by: LBCW0502
  • Created on: 30-01-18 16:46
What is metabolism?
Irreversible biotransformation of drugs in the body (lipophilic nature benefits absorption and distribution but not elimination). Process involves changing lipophilic compounds into hydrophilic products. Biochemical process is usually enzymatic
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Outline the general features of metabolism
Major mechanism for bringing an end to the pharmacological activity of a drug. Few drugs remain unchanged in the body. Most common pathways are oxidation and reduction (phase I). Conjugation takes place in phase II. Drug made more polar for excretion
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Drug metabolism via the liver depends on what?
Blood flow to the liver and activity of the enzyme in the liver
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What are metabolites?
Formed when liver enzymes chemically alter the drug. They are inactive or equally/more reactive than the parent drug e.g. allopurinol (treatment of gout) - active metabolite oxipurinol
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What is first pass metabolism?
A portion of an orally administered drug dose is inactivated by the liver before reaching systemic circulation (and target organ)
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Time curve after bolus IV injection
See lecture slide
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Describe features of bolus IV injection
Only distribution and elimination. Drug immediately available (F = 100% at t=0). Other routes required absorption
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IV administration (the fate of the drug) mainly depends on what?
Rate of elimination and rate of metabolism (assumptions - when Ke and Km are large the drug is rapidly cleared, when Ke and Km are small the drug is slowly cleared)
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Describe single oral administration
When drug is administered t=0 no drug is present in systemic circulation
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What is a time lag?
Period of time before drug begins to appear in the systemic circulation
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Rate of absorption (Ka) and rate of elimination (Ke) follow which type of kinetics?
First order kinetics - depends on concentration of drug at absorption site and in blood circulation
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Plasma concentration time curve after single oral administration
See lecture slide
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What does Ka not being equal to 0 at the elimination phase indicate?
Absorption continues after peak drug concentration reached
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What does Ka not being equal to 0 at absorptive phase indicate?
Metabolism and elimination occur before the blood level peaks
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What is TD?
Toxic concentration
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What is ED?
Minimum effective concentration
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Therapeutic window lies between which two levels?
TD and ED (level where blood drug concentration should be)
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What are the important parameters for the plasma concentration time curve after single oral administration?
Time to onset of action, time to reach peak concentration (Tmax), peak concentration (Cmax), intensity, duration of action
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What changes would be made in the parameters for e.g. migraine, arthritis?
Short onset of action is desirable, rapid onset is not critical
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What is the elimination rate constant (Kelim)?
Rate of metabolism in liver and the rate of elimination from the kidney
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Most metabolism and elimination processes operate by which order processes?
First order processes - the rate depends on concentration of drugs present (important to use drug concentration at specific time/any time) - measure plasma samples at regular intervals
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What is the decay equation?
Cp = Cp e^-kt (convert linear plot using natural log and plot Cp vs time)
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How do you calculate elimination half lfie?
0.693 / k
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How many half lives does it take for a drug to be eliminated from the body?
5-7 half lives (half life - 0.693 x (V/CL))
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What are the drug half lives for salicylic acid, paracetamol, levodopa, salbutamol, penicillin G and methadone?
3, 1-4h, 50 mins, 2.7h, 0.4-0.9h, 36h
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What are the major areas where drugs are eliminated from the body?
Kidneys and liver
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What are the minor areas where drugs are eliminated from the body?
Lungs and other (e.g. sweat, saliva, mother's milk)
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What is clearance?
Volume per unit time (blood/plasma) that would be completely freed of drug to account for elimination (most drugs follow 1st order kinetics, some follow 0 order/saturation)
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Is clearance additive?
Yes (CL systemic = CL renal + CL hepatic + CL other)
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What are the two most important sites for drug elimination?
Kidneys and liver
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Why is clearance usually constant over the therapeutic concentration range?
Drug elimination systems are not saturated (absolute rate of elimination is a linear function of drug plasma concentration) - important to ensure long-term drug dosing (steady state)
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What is renal clearance?
Clearance of unchanged drug and metabolites (water soluble compounds undergo more efficient renal excretion compared to lipid soluble compounds)
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How do you calculate extraction ratio?
(a)/(a+b), CL = ER x Q
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What are the equations for clearance?
CL = rate of elimination /c, CL = Vd x kelim, CL = Vd x ln2/t (1/2), CL = CLR + CLH, CL = QR.ERR + QH.ERH (t0.5 = ln2 x Vd/QR.ERR + QH.ERH)
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What is an extraction ratio (ER)?
Fraction of drug presented to eliminating organ which is cleared after a single pass through organ (some drugs mostly efficiently removed, proteins act as transport system/CL depends on blood flow). ER decreases when blood flow increases
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Describe features of a high extraction ratio
High enzyme activity, plasma bound drug stripped off during transit through organ, use of intrinsic function enzyme, blood flow limits process (EH>0.7)
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Describe features of a low extraction ratio
Enzyme metabolises drug at slow rate compared to blood flow. Enzyme remains attached to protein. Extent binding involved (EH
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Give examples of drugs with high, medium and low extraction ratios (hepatic)
Propanolol, codeine and diazepam
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Give examples of drugs with high, medium and low extraction ratios (renal)
Glucuronides, procainamide, digoxin
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What is QH altered by?
Increased by bed rest/isoprenaline and decreased by exercise/heart failure/propranolol
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CLu int is altered by what?
Increased by induction (smoking/drugs), decreased by inhibition (drugs)/liver cirrhosis
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Which factors alter clearance?
Body weight and body SA, plasma protein binding, high ER, renal function, hepatic function, decrease CO
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How does a lipophilic drug affect an underweight patient?
Drug cleared quickly
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What type of cells in the liver converts a drug into metabolites using enzymes?
Hepatocytes
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Describe features of plasma protein binding
Fraction of free drug doesn't vary with drug concentration because binding sites far exceeds number of drug molecules (controlled by binding affinity of drug) - plasma protein concentration
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Describe features of displacement drug from plasma binding sites
Alone will only lead to temporary and modest increase in free drug concentration and effect. Significant interactions can be explained by inhibition of drug metabolism
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Which factors allow a drug to most likely have an increased effect?
>90% bound, low Vd (
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What does the time to steady state depend on?
Half life (takes ~5 half lives to achieve a steady state concentration)
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Which factors affect how much drug accumulates between the first dose and a dose at steady state?
Elimination constant/half life (can't control half life) and dosing interval (can be adjusted to suite patient needs)
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What is the aim of drug therapy?
To ensure a steady state concentration within the therapeutic range
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Describe features of dosing interval
Dosing interval < drug half life (** higher than concentration after first dose), dose interval = half (** twice as high as concentration after first dose, dosing interval > half life (** similar to concentration after first dose/drug washed out)
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Describe features of multiple drug dosing
Drug levels maintained within limits to achieve maximum effectivene**, limit toxicity and minimise toxic concentration (need to consider drug accumulation, time to reach ** is a function of drug accumulation)
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Describe features of a loading dose
Given when there is an urgent need. Used for narrow therapeutic drugs. E.g. lidocaine requires fast loading dose to treat life-threatening arrthymias (C onboard included for patients already taking drug)
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Describe features of maintenance dose
Estimate of CL used to calculate rate of administration/maintenance dose to produce desired average plasma concentration at **
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How do you calculate maintenance dose?
(CL L/Hr)(Cpss ave) / (S)(F)
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