Pharmacokinetics Flashcards
What are the major routes by which drugs may be administered?
Dermal Subcutaneous Intramuscular Intraperitoneal Inhalation Ingestion Intravenous
What happens to a drug after it is absorbed?
Drug enters GIT and is absorbed
Travels to liver via hepatic portal system
Enters systemic circulation
What factors determine drug distribution?
- Regional blood flow (higher [drug] affects CG)
- Extracellular binding (plasma proteins)
- Capillary permeability
- Localisation in tissues (lipophilic drugs localise in fatty tissue)
What are the principle routes of drug excretion?
- Eliminated through kidneys - converted into something water-soluble and excreted in urine
- Liver - drugs concentrated in bile and bile excreted into intestines - large molecular weight drugs
Also lungs, skin, GI secretions, saliva, sweat, milk, genital secretions
What is drug metabolism a potential point of?
Interaction between drugs
What is enterohepatic circulation?
Once excreted into the gut via bile, the drug (or metabolite) may be reabsorbed
Circulation of biliary acids, bilirubin, drugs, etc. from liver –> bile –> SI –> absorption by enterocyte and transport back to liver
Drug trapped in cycling process persists in body for longer than expected
What is biological half-life?
Time taken for concentration of drug in the blood/plasma to fall to half its original value
What is apparent volume of distribution?
The theoretical volume needed to contain the total amount of drug in the body if the drug was evenly distributed throughout the body and in the same concentration as the site of sample collection, e.g. peripheral venous plasma
What is bioavailability?
Proportion of administered drug that is available within the body to exert its pharmcological effect
= post-hepatic concentration
Amount that leaves the liver and enters systemic circulation
What is drug clearance?
- The volume of plasma/blood cleared of a drug per unit time
- Related to volume in which the drug is dissolved and rate at which drug is eliminated
- Incorporates excretion through bile, kidneys and all other routes
How do compartments and barriers differ? Examples
Compartments are aqueous, e.g. blood, lymph, ECF
Barriers are lipid, e.g. cell membranes
Why do drugs exist in a dynamic equilibrium of their ionised and non-ionised forms?
Most drugs are weak acids or weak bases
What does the ratio of ionised to non-ionised drug depend on?
pH of environment
pKa of molecules
How are drugs excreted by the kidney?
- Majority of drug excreted enters urine via active secretion rather than UF
- At glomerulus, drug-protein complexes are not filtered (too large)
- At proximal tubule - active secretion of acids and bases
- At proximal and distal tubules - lipid soluble drugs reabsorbed (can prolong life of drug)
How are drugs excreted by the liver?
Biliary excretion allows conc of lipophilic, large molecular weight molecules
Drugs hitch a ride on active tranport systems geared for transport of bile acids and glucuronides into bile
Drugs can do this bc they are non-polar and large MW
What are the advantages and disadvantages of oral administration?
Advantages:
- Permits self-medication
- Doesn’t require rigorously sterile preparations
- Incidence of anaphylactic shock is lower than IV
- Capacity to prevent complete absorption (vomiting, lavage)
Disadvantages:
- Inappropriate for drugs which: a) are labile in acid pH of stomach or o/w degraded, b) undergo extensive first pass metabolism
- Requires patient compliance
What are the advantages and disadvantages of intravenous administration?
Advantages:
- Rapid onset of action
- Systemic exposure
- Avoids poor absorption from, and destruction within, GIT
- Permits careful control of blood levels
Disadvantages:
- Slow injection necessary (to avoid toxic bolus)
- Higher incidence of anaphylactic shock
- Trained personnel required
- Complications possible: embolism, phlebitis, pain
What are the advantages and disadvantages of administration by inhalation?
Advantages:
- Ideal for small molecules, particles, gases, volatile liquids, aerosols
- Enormous SA presented by alveolar membranes
- Simple diffusion
- Phagocytic cells clear particles
Disadvantage:
- Possible localised effect within lung (unless desired)
What are the advantages and disadvantages of intramuscular administration?
Advantages:
- Relatively high blood flow, increased during exercise
- Enables DEPOT therapy
Disadvantage:
- Possible infection and nerve damage (especially in gluteal region)
What are the advantages and disadvantages of subcutaneous administration?
Advantages:
- Local administration
- Dissemination can be minimised for local effect
- Enables DEPOT therapy
Disadvantages:
- Pain, abscess, tissue necrosis
What are the advantages and disadvantages of dermal administration?
Advantages:
- Local application and action
- Lipid soluble compounds diffuse rapidly
Disadvantages:
- Local irritation and skin reactions
- Alteration of skin structure
How can drug action be terminated?
- Metabolism of drug to inactive metabolites
- Excretion
How can transfer of substances across membranes occur?
- Passive diffusion
- Facilitated diffusion
- Active transport
- Pinocytosis
- Filtration (small water soluble molecules)
- Paracellular transport
How do you measure bioavailability
Area under concentration vs. time curves (AUC)
What are first-order kinetics?
The rate of elimination of a drug where the amount of drug decreases at a rate that is proportional to the concentration of drug remaining in the body
Applies to most drugs in clinical use
X=time, Y=log plasma [drug]
On what does first-order kinetics depend?
[Drug] at any given time
What are zero-order kinetics?
- A constant amount of drug is removed per unit time
- Usually, something is going on that is saturating the system
- E.g. alcohol dehydrogenase
- Once enzymes are saturated, rate of removal of drug peaks and remains constant
- X=time, Y=[drug]
How do you calculate volume of distribution from a log plasma [drug] time graph?
Vd= dose/C0 C0 = initial concentration of drug in plasma - extrapolate line backwards to see where it crosses y axis
