General Principles Of Pharmacokinetics Flashcards
Knowledge of pharmockinetic data about a drag tells us
What does to give
How often to give it
How to change the dose in medical conditions
How some drug interactions occur
Design of new drugs
Effective concentration is a function of
Dose
Absorption
Distribution
Elimination (metabolism and excretion)
Absorption from where to where
Extravascular to systemic circulation
Distribution from where to where
Bloodstream to body tissues
Metabolism occur in
Liver
gastrointestinal tract wall
Lung
Blood
Excretion occur in
Kidney
Bile
Expired air
Pharmokinetic parameters
Absorption- Bioavailability (F)
Distribution- Volume of Distribution
Metabolism- Elimination and Clearence
Excretion
Factors effecting drug absorption
Chemical and physical properties of the drug
ROA
Patients physiological variables
Drug-drug or food interactions
Drug and drug delivery
Mechanism of transport
Physiological properties that effect the drug absorption
Age
Sex
Genetic
Malabsorptive states
Lack of specific receptors needed for absorption
GI motility
Area of absorbing surface
Compliance of patient
Drug interactions
Site of drug administration
Blood flow at the absorption site
PH at the absorption site
Inactivation of drug in gut or liver
Food
Which properties effect drug absorption as a chemical and physical substance
Solubility— Partition coefficient
What is Partition Coefficient
Solubility of the molecule in a lipid solvent relative to its solubility in water or physiologic buffer
Higher PC— HIGHER DIFFUSION RATE
What is an Ion-trap?
At equilibrium, the total concentration of the drug will be different in each compartment.
Trap the toxins in its ionized form in the urine where it can be excreted.
Which type of drugs absorbed best?
Lips-soluble
Non-ionized
Small molecular weight
Why do we need to take the drugs with the water?
Accelerate gastric emptying providing exposure to the upper intestine with a higher pH and much larger surface area
What is the first pass metabolism
Drugs absorbed from GI tract pass into the blood stream-portal circulation
Blood travels immediately to the liver
Some drugs are intensively inactivated at the first time they pass through the liver.
What happens if the first-pass losses are high
Larger doses of the drug must be given to achieve a given plasma concentration
Bioavailability
Fraction of unchanged drug reaching the systemic circulation after administration by any route
Bioavailability affected by
ROA
Dosage form
Stability of the drug in the GI tract
Presence of food/ drugs in GI tract
Volume of distribution
Vd is an apparent, theoretical volume
Reflection of the amount left in the blood stream after all the drug has been absorbed and distributed
What does low Vd and high Vd mean?
A low Vd= drug mainly confined to blood and body water— Very little has overflowed into the tissues.
A high Vd tells us that the drug is widely distributed to the tissues— A lot has overflowed into the tissues.
What is the importance of Volume of distribution
Calculation of the dose needed to achieve a critical plasma concentration
What are the factors that affecting the drug distribution
Lips solubility
Membrane permeability
Blood flow
Plasma protein binding
Disease
Active transport
Drugs
Sequestration
Redistribution
How does the binding of plasma protein affects the drug absorption?
High protein binding— less free drug circulating in the plasma and highest drug concentrations usually found in blood
Only which drugs can act at receptor site?
Free drugs
What is the aim of drug metabolism?
More water-soluble
More polar
Inactive metabolites
In some cases some drugs become pharmacologically active after?
Being metabolized
What happens in the first phase of metabolism?
Phase 1 = microsomal oxidation, nonmicrobial oxidation, reduction, hydrolysis, dehalogenation, provide a more chemically reactive group to increase polarity of the drug molecule and a site for phase 2
What happens in the second phase of drug metabolism?
Phase 2= conjugation or synthetic reactions.
In phase 1 of drug metabolism which molecules take place?
Cytochrome P450 mono-oxygenase system.— CYP3A4,CYP2D6,CYP2C.
Alcohol dehydrogenase and CYP2E1
6-mercaptpuyrine—Xantine oxidase
Noradrenalinityramine— MonoAminoOxidase
What are the important enzymes of phase 2 of drug metabolism
UGT,UDP-glucuronosyltransferase
NAT, N-acetyltransferase
What reactions occur in the phase 2 conjugation step in the drug metabolism?
Glucuronidation
Acetylation
Methylation
Sulfate addition
What are the features of the metabolizing enzymes in drug metabolism?
Have broad substrate specifity
Multiple forms
İNTERİNDİVİDUAL DIFFERENCES in genetic expresssion
Constitutive or Inducible
May be induced or inhibited by food,alcohol,other drugs.
What are the features of the enzyme inducing drugs
Enhance the liver enzymes which break down drugs
Faster rate of drug breakdown
Larger dose of affected drug is needed to get the same clinical effect
Increased amount of metabolites
Enzyme inducing drugs
Phenytoin
Phenobarbitone
Carbamazepine
Rifampicin
Griseofulvin
Chronic alcohol intake
Smoking
Features of enzyme inhibiting drugs
Inhibit the enzyme itself or the production of enzymes which break down drugs
Decreased rate of drug breakdown— increased plasma concentration
Reduce the dose of affected drug to produce the same clinical effect.
Enzyme inhibitors
Erythromycin
Ciprofloxacin
Metronidazole
Ketoconazole
Oral contraceptives
Sodium valproate
Calcium channel blockers
What are the steps of clearance in the kidney?
1- Excretion— glomerular filtration, passive diffusion, active tubular reabsorption/ secretion.
2- metabolism
What are the steps of clearance in the liver
1- metabolism
2- biliary secretion— ENTEROHEPATİC CIRCULATION
Importance of Entero-hepatic circulation
If a drug enters this circulation that means it has a long half-life.
Only what type of drug is filtered
Unbound drug
In which type of intrinsic clearance drug is highly affected by hepatic blood flow
High intrinsic clearance
In which type of intrinsic clearance the drug clearance is depends on the metabolic capacity of the liver?
Low intrinsic clearance
The actual quantity of drug removed depends on what?
Clearance
Concentration
How many half-lives it should be passed in order to the drug is completely removed from the circulation?
4-5 half-lives.
90%
Half life formulation?
T1/2 = 0.7xVd /. Cl
What half-life does not depend on?
Dose
Dosage interval
Plasma concentration
In which conditions an accumulation of drug is seen?
If dosing interval is shorter than excretion accumulation will be seen.
With repeated drug doses, a drug will accumulate in the body until dosing stops.
How do you change the plasma concentrations?
Change the dose
Change the dosage interval
What is the first-order process?
Constant fraction
Half-life
Removal rate of the drug is proportional to its concentration in the plasma
What is zero-order process?
Constant amount
Rate of elimination does not change
No half-life
Maintenance dose
MD= Cl x Css x T
