Pharmokinetics Flashcards
Pharmokinetics
The study of the rate and extent to which drugs are absorbed into the body and distributed to the body tissues
The rate and pathways by which drugs are eliminated from the body by metabolism and excretion
The relationship between time and plasma drug concentration
‘What the body does to the drug’
Four main stages of pharmokinetics
Absorption, distribution, metabolism, excretion
Enteral routes for drug absorption
Oral, buccal(mucosal orally), sublingual (under the tongue), rectal
Parenteral routes of drug absorption
Intravenous, intramuscular, subcutaneous, inhaled
Topical application
Method of drug absorption
For a drug to be successful after oral administration it must
Be swallowed -> survive gastric acid -> avoid unacceptable food binding -> be lipid soluble so can be absorbed across the gastro-intestinal mucosa -> survive hepatic (liver enzymes) first-pass metabolism and the enterohepatic circulation
Benefits of oral routes
Convenient, simple, can be easily self administered, Better for long term treatments for less acute illnesses
Intravenous route
No concerns about absorption, rapidly achieves high drug concentrations, no ‘first pass’ effect -> better for very ill patients where rapid, certain effect is critical to outcome
Intramuscular route
Simple to administer, unpredictable rate of absorption, painful, drug only gets into bloodstream if there is good circulation
Subcutaneous route
Good for drugs that have to be administered parenterally, are absorbed well from subcutaneous fat (lipid soluble), that ideally can be injected by patients themselves
Inhaled route
For a drug to be successful after inhalation in must be inhaled into the target airways in the lung -> i.e. if drugs are too small they will only go to the alveoli not the small airway
Speed and efficiency of distribution into the body by passive diffusion depends on
Molecular size, lipid solubility and protein binding
Volume o fdistribution
The apparent volume of distribution is the volume that the dose appears to have distributed into shortly after intravenous injection based on the plasma drug concentration
Drugs with high volume distribution
Take long time for body to get rid of the drugs after it is stop being administered
Liver is a major site of drug metabolism it
Reduces biological activity (so its not a threat) and increases water-solubility (so they can get out of the body)
Phase 1 metabolism
Enzymes which cause oxidation in microsomal mixed function oxidase system -> Make molecules more polar so that they can be excreted through the urinary system
Phase 2 metabolism
No always needed -> conjugation by either acetylation or glucoronidation
Factors effecting drug metabolism
Genetics, age, gender, nutrition, disease, dose, drugs, route
Increased metabolism
Faster elimination,shorter half life, reduced activity, potential for increased exposure to toxic metabolites
Decreased metabolism
Slower elimination, longer half life, increased activity, potential drug accumulation and toxic effects
Hepatic drug interactions
Presence of one drug may influence the metabolism of another
The first drug may induce metabolism of the second by stimulating the liver to produce more metabolising enzymes - takes days/weeks
The first may inhibit metabolism of the second by competing for the metabolising enzyme - immediate
First pass metabolism
Occurs in the gut wall and liver -> is a major determinant of the peak plasma drug concentration and thus of drug response after an oral dose
Drug molecules undergoing first pass metabolism
QAre vulnerable to metabolism by enzymes in the intestinal wall and liver prior to entry into the systemic circulation
Portal vein and liver sinusoids
Drugs absorbed through the stomach or any part of the small intestine must pass through these before entering the systemic circulation
Bio transformation of unchanged drug to inactive metabolite
Reduces drug response
Bio transformation of active drug to active metabolite
Results in no change in drug response
Bio transformation of inactive drug(pro-drug) to active metabolite
Results in increased drug response
Potential routes of drug excretion
Renal excretion, biliary excretion, faeces, breast milk, sweat
Excretion
Process by which drugs and their metabolites are removed from the body and may involve fluid, solids or gases
Urinary excretion
Usual route for low-molecular weight drugs that are sufficiently water-soluble to absorb reabsorption from the tubule
lipid soluble molecules
Can cross the renal tubular membranes so are not lost renally so must be converted into water soluble
Drugs bound to plasma proteins
Are not filtered renally
Sodium bicarbonate
USed to make renal tubule more alkaline in the result of an overdose of lipid soluble molecules e.g. aspirin
Faecal excretion
The preferred route of elimination for large-molecular-weight drugs, including those that are conjugated with glucoronide in the liver
Molecules enter bile after liver metabolism are then carried into intestinal lumen and are excreted in the faeces
If molecules are still sufficiently lipid soluble in the faecal excretion route
They may be reabsorbed and re-enter the portal vein
Entero-hepatic circulation
The recycling between the liver, bile, gut and portal vein
Enterohepatic circulation
Prolongs the residence time of drugs in the body sustaining their effects
Bacterial flora
Have enzymes capable of hydrolysing conjugates which release the drug or active metabolite for reabsorption - allowing the recycling of glucoronide conjugates
Drugs that inactivate or kill micro-organisms e.g. broad spectrum antibiotics
Can reduce reabsorption and drug availability
Clearance
Volume of plasma which is completely cleared of drug per unit time
Clearance is caused predominantly by
either metabolism of the drug in the liver or excretion at the kidneys
Bioavailability (oral)
Area under the curve of drug given orally/ area under curve of drug give intravenously - for the plasma concentration-time graph expressed as a percentage
Ora bioavailability depends on
Gastric acid destruction, formulation, first-pass metabolism, solubility, ionisation, food, diarrhoea
Drugs must be … in order to be absorbed into the body
Lipid-soluble
Drugs must be more … in order to be eliminated in the urine or faeces
Water soluble
The conversion of lipid soluble to water soluble through
Metabolism
First order (exponential) kinetics
A constant fraction of drug is cleared in unit time
Zero-order (saturation) kinetics
A constant amount of drug is cleared in unit time
In first order kinetics rate of metabolism/elimination of a drug depends on
It’s concentration
i.e. as conc increases, rate increases -> as conc decreases rate decreases
Increasing drug dose in first order kinetics has a
predictable effect
In zero order kinetics
Elimination rate reaches a maximum0> so if a drug is administered at a rate faster than its clearance then it will progressively accumulate
Examples of zero order kinetics
Ethanol, phenytoin
Half life
The time taken for the plasma concentration of the drug to halve
Increasing drug dose in zero order kinetics has a
very unpredictable effect
Progressive accumulation
Repeated doses of a drug are given at a time when the previous doses have not been completely eliminates
Accumulation continues until
Steady rate is reached where the rate of elimination = the rate of administration
Steady state actually involves
Fluctuations in drug concentrations - with peaks just after administration and troughs just prior to the next administration
Long half life
Slow to reach steady state, loading dose may be needed, slow to be eliminated, requires less regular dosing
E.g. atenolol 8hrs
Short half life
Rapid steady state, not suitable orally, more regular dosing required
E.g dobutamine 2mins
Loading doses
Used for drugs with long half lives which will not reach a steady state concentration for Na long time -> an initial dose is given which is much larger than the maintenance dose in order to achieve a peak plasma concentration close to the plateau concentration which can then be maintained
Maintenance dose
Regular dose given to ensure a steady state of drug above therapeutic effects is maintained
Dose interval
A compromise between convenience for/adherence of patient and benefit of reduced fluctuation in plasma concentration
Therapeutic drug monitoring
Done too look for beneficial effects and avoid adverse effects
Can also be used to check for adherence
