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Pharmacokinetics
(what the body does to the drug) deals with dose concentration effects TERM 2
Pharmacodynamics
DEFINITION 2 (what the drug does to the body) deals with maximum response and magnitude of the effect at a particular dose. TERM 3
Fundamental hypothesis
DEFINITION 3 drug efficacy and toxicity correlate withplasma drug levels (Cp). TERM 4
Standard pharmacokinetics
DEFINITION 4 (drug dose that induces little to no toxicity) is determined in non-diseased healthy volunteers (FDA Clinical Trial Phase I). Disease, old age, co-administered other drugs will (often) alters these standard doses. TERM 5
Volume of Distribution (Vd)
DEFINITION 5 Vd = amount of drug in the body Cp digoxin Vd = 500 L/Kgpenetration into deep tissues (muscles etc) furosemide Vd = 7 L/Kg found mostly in the blood plasma
volume of distribution example question
Patient presents to the emergency room with a drug overdose. The drugtaken is known. How much drug (dose) is in the whole body. Call the lab,get a Cp level, look up the Vd for the drug (Google, drug product insertetc), calculate the total amount of drug in the patients body. This is aperfect exam questio n. TERM 7
Clearance (Cl)
DEFINITION 7 Cl = rate of elimination Cp Two major routes of elimination are kidney and liver. Creatinine clearance (kidney) and clearance of a drug will be on the exam TERM 8
Two types of elimination -Capacity limited
eliminated
DEFINITION 8 (phenytoin, ethanol, aspirin ) a fixed amount of drug is eliminated per unit of time no matter how much ethanol has been consumed the body can only eliminate a fixed amount per unit time. Helps explain why it takes so long to sober up Capacity limited also called saturable elimination Capacity limited also called zero order elimination TERM 9
Two types of elimination -Flow dependent
elimination
DEFINITION 9 (all other drugs) The more drug in the plasma the more drug that is eliminated per unit of time. Also called firstorder elimination. TERM 10
Half-life
DEFINITION 10 t1/2 = time required to eliminate half of the drug in the body t1/2 = 0.7 (Vd) Cl Another great exam question
Extraction Ratio (ER) & The First Pass
Effect
ER = CLliver QWhere Q = hepatic blood flow, about 90 L/h in a 70 Kg person.Drug dose lost in high ER often are given at higher doses (po) toovercome high ER and thus maintain correct therapeuticblood levels.Problem with this is that many drugs produce potentially toxicmetabolites which are higher when dose is higher. TERM 17
Alternative Routes of
Administration
DEFINITION 17 F values iv = 100 im = 75 sc = 75 po = 5 to 100 rectal = 30 100 inhalation = 5 100 transdermal = 80 100 Avoid high first pass effects with transdermal, rectal and sublingual. TERM 18
The Time Course of Drug Effect
DEFINITION 18 Drug effect is related to drug concentration (Cp) in the blood however therelationship is non-linear TERM 19
Time course of drug effect -
Example
DEFINITION 19 Enalapril is an ACE inhibitor. T1/2 is about 3 hoursFollowing a singe oral dose of 10 mg po the peak blood level (average)is 64 ng/mL at 3 hours following this dose. Drug is given once per day. Seven half lives will lapse from the time of peak blood level ( ng/mL) to the end of the dosing interval.Seven half lives = 7 x 3 h = 21 hours + 3 h that took to reach the peak blood level = 24 h, so, single dose per day TERM 20
Delayed Drug Effects
DEFINITION 20 Changes in drug effect delayed in relation to changes in plasmaconcentration. The drug effect only takes place after the drug leaves the blood and enters the tissue where it is intended to work (movement from blood into CNS for example).
Delayed drug effect -Example
Warfarin is another example of delayed effect. drug inhibits the enzyme vitamin K epoxidase in the liver enzyme inhibition correlates with drug blood levels enzyme inhibition decreases synthesis of prothrombin clottingfactors these clotting factors have a long half life of about 14 hours. a dose adjustment of warfarin will take over 14 hours to manifest itself because of this half-life of the target. TERM 22
Cumulative Effects
DEFINITION 22 Example of use to avoid toxicity Aminoglycosides ( gentamicin ) given iv, accumulation leads to toxicity, damage to the renal cortex cells and renal failure. Administer drug in high dose pulse iv, saturate the transport cells in the cortex, slow down (prevent) accumulation in the renal cortex. TERM 23
Rationale Dosage Regimen
DEFINITION 23 The right dose at the right time for the right period Assumes that there is a target drug concentration that results in maximum efficacy and safety Digoxin for atrial fibrillation target Cp = 2 ng/mL Digoxin for heart failure target Cp = 1 ng/mL TERM 24
Maintenance Dose
DEFINITION 24 Give dose that replaces what has been removed from the body Dose to achieve steady state blood levels Drug dose rate in must equal drug dose rate out. TERM 25
Maintenance Dose -example
DEFINITION 25 Maintenance dose calculation Theophylline Cp desired = 10 mg/L CL for theophylline = 2.8 L/h/70 Kg (from Google, product insert etc) Plan to give drug iv so F = 1 (or 100%) Calculate dosing rateNote: Cp = concentration in plasma = TC = target concentration = target blood level Dosing rate = CL (Cp) 2. L/h/70 Kg (10 mg/L) 28 mg/h/70 Kg
Pharmacokinetic Variables
(a) Maximum Effect: the state in which increasing the dose causes no increase (or change) in biological response. The flat part of the dose-response curve. More drug in this condition can lead to toxicity due to ADRs. Measure blood levels to confirm that max has been achieved. (b) Sensitivity : hyperkalemia diminishes response to digoxin. Measure blood levels to ensure therapeutic values have been achieved. TERM 32
Clearance and TDM
DEFINITION 32 Factors that effect clearance (a) dose (b) organ blood flow (c) liver and/or kidney function TERM 33
Protein binding
DEFINITION 33 All (most) drugs are carried by a protein (albumin). From 0 to 99% of the total drug in the body can be bound to albumin Only the free unbound drug is active TERM 34
Factors affecting protein binding
DEFINITION 34 (a) Albumin concentration: poor liver function and nutritional state reduce albumin levels. Typical blood levels (Reference Interval) is about 3.5 to 5.0 g/dL. Reduced levels means less protein to hold the drug.(b) Aplha1acid glycoprotein binds quinidine, lidocaine and propranolol.Inflammatory disorders increase this proteins blood levels whichincreases the load of drug in the body.(c) Capacity limited protein binding: amount of drug that can be bound to proteins is limited. If drug dose exceeds capacity to bind drug then free (bioactive) levels will increase. toxicity.
