Pharmacokinetics Flashcards
What is pharmacokinetics?
The effect that the body has on the drug
What are some ways in which drugs can be removed from the body?
Urine
Faeces
Milk
Sweat
Expired air
What are some ways that drugs can enter the body?
Oral - mouth
Rectal - anus
Percutaneous - skin
Intravenous - blood plasma
Intramuscular - muscle
Intrathecal - cerebrospinal fluid
Inhalation - lungs
What is the LOAEL?
Lowest Observed Adverse Effect Level
What is the NOAEL?
No Observed Adverse Effect Level
What are the 4 Stages of pharmacokinetics?
ADME:
A - Absorption
D - Distribution
M - Metabolism
E - Excretion
What are the main ways in which drugs move around the body?
Bulk flow - Via the circulatory system
Diffusion over short distances
Diffusion across lipid bilayers in membranes
What are the 4 main ways in which small molecules can pass through cell membranes?
Passive diffusion
Facilitated diffusion
Active transport
Endocytosis (Pinocytosis)
What occurs during facilitated diffusion?
Molecules move via specialised carrier proteins.The molecule binds to one side of the carrier protein, causing a conformational change that allows release of the molecule on the other side
What are saturation kinetics?
Only a finite number of molecules can move through a transport protein in a given time
What occurs during active transport?
Molecules move via specialised carrier proteins. The ATP hydrolysis allows the movement of the molecule through the carrier protein
Where are some principal sites of facilitated diffusion and active transport?
Blood brain barrier
Gastrointestinal tract
Placenta
Renal tubule
Biliary tract
What are the 2 forms of weak acidic or basic drugs?
Ionised and unionised
What does the pKa show?
The pH at which 50% of the drug is ionised and 50% is unionised
How is aspirin trapped in the gastric mucosa?
In the stomach, the pH is 1.5
This increases [H+]
This shifts equilibrium to favour the reverse reaction to form unionised aspirin
This can move easily through the gastric mucosal barrier
In the plasma, the pH is 7.4
This decreases [H+]
This shifts equilibrium to favour the forwards reaction to form ionised aspirin
This can’t move easily through the gastric mucosal barrier
Where do weak bases accumulate?
In compartments with low pH
Where do weak acids accumulate?
In compartments with high pH
Why does most oral route drug absorption occur in the small intestine?
It has a very large surface area
What are the main body compartments in which drugs can move into?
Total body water - small, hydrophilic drugs
Extracellular water - large, hydrophilic drugs
Blood plasma - plasma protein bound drugs
Adipose tissue - lipid soluble molecules
Done and teeth - certain ions
What is the apparent volume of distribution?
The extent to which a drug partitions between the plasma and tissue
What is the formula for Volume of distribution (Vd)?
Dose ÷ [Drug]p
What is the body’s total volume of water?
41L
What is meant by a lower Vd?
More drug in plasma, so less in tissue
What is meant by a higher Vd?
More drug in tissue, so less in plasma
What is the most abundant plasma protein?
Albumin
How do some drugs bind with low affinity to albumin?
Via electrostatic forces and hydrophobic forces
What is the effect of protein binding on drug distribution?
Plasma protein binding reduces the availability of the drug for diffusion into the target organ and may also reduce the transport of the drug to non-vascular compartments
What effect does plasma protein binding have on Vd?
It decreases Vd
What is meant by drug metabolism?
The enzymatic conversion of one drug to another chemical entity
Which organ is the most important drug-metabolising organ?
The liver
What is bioavailability?
The amount of a drug that eventually reaches systemic circulation and is therefore available for action
What is the formula for availability (F)
F = quantity reaching plasma/quantity administered
What is the formula for comparing bioavailability of an administration method with an IV bolus?
F= drug plasma conc (Oral) x Dose IV
—————————————————
drug plasma conc (IV) x dose Oral
What allows the liver to perform stage I and stage II metabolism?
Drug-metabolising enzymes embedded into the SER of liver hepatocytes
What are the 3 main processes that make up the phase I metabolism reactions?
Oxidation
Reduction
Hydrolysis
What class of enzymes perform oxidation in stage I metabolism reactions?
Cytochrome P450 enzymes, which are microsomal haem proteins
What occurs during oxidation in stage I metabolism reactions?
One atom of O2 is used to form a hydroxyl group on the drug
What 2 types of bonds are most susceptible to hydrolysis?
Ester bonds
Amide bonds
What is usually formed as a result of stage I metabolic reactions?
Chemically reactive metabolites which can be active and/or toxic
How can paracetamol cause liver damage in overdose?
P450 proteins convert paracetamol into NAPQI
In normal amounts, this is all detoxified by stage II reactions, in which a glutathione molecule is added
In overdose, it becomes subject to saturation kinetics, so all of the detoxifying enzymes are fully saturated
The excess NAPQI instead binds to liver hepatocytes, causing damage
Which of the cytochrome P450 enzymes are involved in drug metabolism in the liver?
CYP1, CYP2 and CYP3
What is the usual result of phase II metabolic reactions?
Conjugation, binding a group to the reactive group produced in the phase I metabolic reactions
This usually terminates all biological activity and allows excretion
What co-factor is added during glucuronidation?
uridine diphosphate-glucuronic acid
What enzyme allows for glucuronidation?
Uridine diphosphate-glucuronosyltransferases
What are some examples of phase II metabolism mechanisms?
Glucuronidation
Glutathione conjugation
Glycine conjugation
Methylation
Sulphation
Acetylation
What are the 3 active metabolites of codeine?
Morphine
Normorphine
Norcodeine
What are the 3 metabolites of codeine formed from glucuronidation?
Codeine-6-glucuronide
Morephine-6-glucuronide
Morphine-3-glucuronide
What is the principle organ for drug elimination?
The kidneys during renal filtration
Why are drugs not reabsorbed in the kidneys?
They are usually rendered polar by phase II metabolism, so are not reabsorbed
What is clearance?
The volume of blood cleared of the drug per unit of time
What are the 4 symbols of clearance?
CLr - Renal clearance
CLh - Hepatic clearance
CLo - Other clearance
CLt - Total clearance
What is the formula for clearance?
CL = Rate of drug elimination
————————————
[Drug]plasma
What is meant by first order kinetics?
The rate of drug elimination increases as plasma drug concentration increases
What is meant by zero order kinetics?
The rate of drug elimination stays constant as [drug]plasma increases
What is meant by steady state?
The level of drug that is maintained in the body, when rate of administration is equal to rate of elimination
What is the elimination half-life?
The time taken for half of a drug to be cleared from the body
What is the formula for half life?
t1/2 = Ln(2) x Vd
—————–
CL
What is the administration half life?
The time taken to increase the [Drug]plasma levels by 50%
How many half lives are usually required to reach steady state?
5
How many half lives are usually required to clear a drug from the system?
5
What are some examples of factors that can effect the volume of distribution?
Ageing => Decrease in muscle mass = decrease in Vd
Obesity => Increase in adipose tissue = Increase in Vd
Fluid build up in tissue = Increase in Vd
What are some examples of factors that can effect clearance?
Increased Cytochrome P450 = increased clearance
Decreased Cytochrome P450 = decreased clearance
Cardiac failure = Decreased clearance
Hepatic failure = Decreased clearance
Renal failure = decreased clearance
