Pharmacokinetics Flashcards
What are some of the different methods of pharmaceutical process?
Oral Parenteral (IV, intramuscular, subcutaneous) Topical Rectal Transdermal (e.g. GTN, oestrogen) Inhalation Sublingual
Outline the steps of pharmacokinetics.
PHARMACEUTICAL PROCESS (how is drug getting to the patient?) Oral or parenteral (injection)
PHARMACOKINETIC PROCESS (how is drug getting to site of action?)
Oral: gut -> liver -> extracellular fluid
Parenteral: extracellular fluid
Eliminated by liver metabolism & renal excretion
PHARMACODYNAMIC PROCESS (is drug producing desired effect?) Pharmacological effect
THERAPEUTIC PROCESS (how is the pharmacodynamic process translated into a therapeutic effect?) Therapeutic effect
Define oral bioavailability. What does the rate and amount depend on?
Proportion of drug given orally (or any other way except IV) that reaches the circulation unchanged
Amount depends on first-pass metabolism and gut absorption
Rate depends on pharmaceutical factors and gut absorption
What is the therapeutic ratio? Give an example of a drug with a narrow therapeutic window, and an example of a drug with a wide therapeutic window.
Lethal dose in 50% (LD50)/Minimum effective dose in 50% (ED50)
Narrow therapeutic window e.g. warfarin (side-effects start occurring below the maximum dose) (small therapeutic index)
Wide therapeutic window e.g. penicillin (unwanted adverse effects occur way above the maximum dose)
What is the first pass effect?
Any drug in the portal circulation passes through and is metabolised by the liver.
This reduces the concentration of active drug before it reaches the systemic circulation
Applies to oral drugs (ileum -> venous blood -> hepatic portal vein), rectal drugs (enters systemic and portal circulation) but not parenteral drugs (enter systemic circulation immediately)
Define drug distribution.
The theoretical volume into which a drug has distributed, assuming that this occurs instantaneously.
Amount given/plasma concentration at time = 0s
Lipid soluble drugs have a high drug distribution, non-lipid soluble drugs have a low drug distribution
What is the difference between object drugs and precipitant drugs?
Object drugs (class I): used at dose lower than the number of albumin binding sites - low [free drug]
Precipitant drugs (class II): used at dose greater than the number of albumin binding sites - high [free drug] —–> displaces object drugs
note: elimination rate increases to restore steady state and reduce [free drug]
When are protein binding interactions particularly important? Give some examples.
Important when:
- drug is highly bound to albumin
- drug has a low volume of distribution
- drug has a low therapeutic index
OBJECT DRUG PRECIPITANT DRUG Warfarin Sulfonamides, aspirin, phenytoin Tolbutamide Sulfonamides, aspirin
Aspirin given to patients on warfarin -> causes temporary over anti-coagulation by increasing [free drug]
Describe the graphs of first order and zero order pharmacokinetics.
First order: rate of elimination proportional to drug level
- constant fraction of drug eliminated per unit time
- defined half life
- predictable therapeutic response to dose increases
Linear [drug]plasma: shallow downwards curve
Logarithmic [drug]plasma: straight downwards slant
Zero order: rate of elimination is a constant
- therapeutic response can suddenly escalate as elimination mechanisms saturate
- e.g. alcohol, phenytoin
Linear [drug]plasma: straight downwards slant
What does the overall rate of drug metabolism curve look like?
Low dose is first order
High dose is zero order
Hyperbolic curve
What is a loading dose? Why is it used?
LOADING DOSE = initial higher dose of drug given at beginning (determined by volume of distribution)
Then maintenance dose is given to maintain a high [free drug]
During repeated administration, a new steady state is achieved within 5 half lives (irrespective of dose or frequency of administration)
However, this will take too long to reach a high dose, hence why a loading dose is given first.
Outline how drugs are metabolised in the liver.
Phase I = oxidation/reduction & hydrolysis (drug usually inactivated)
Phase II = conjugation e.g. sulfation, glucuronidation (drug inactivated)
Some drugs go straight to phase II
Liver microsomal enzymes activate cytochrome P450 reductase (affinity for lipid soluble drugs)
Give some examples of drug interaction. When is it most important to consider drug interactions?
Phenobarbitone stimulates CP450 to reduce effects of warfarin and increase effects of phenytoin
Rifampicin stimulates CP450 to reduce effects of oral contraceptive
Tobacco stimulates CP450 to reduce effects of theophylline
Cimetidine inhibits CP450 to increase effects of warfarin
Important when:
- low therapeutic ratio
- used at minimum effective concentration
- zero order drug
Outline the excretion of drugs by the kidney.
Active secretion of molecules back into the proximal convoluted tubule
Passive reabsorption of lipid-soluble drugs out of the distal convoluted tubule (dependent on pH)
Non-lipid soluble drugs remain in urine
Weak acids e.g. aspirin HA —————–> H+ + A-
(lipid soluble) (lipid insoluble)
Reduce pH = more HA -> increase absorption
Increase pH = less HA -> reduce absorption (aspirin overdose: force alkaline diuresis)
Weak bases e.g. amphetamines BH —————> H+ + B
(lipid insoluble) (lipid soluble)
Reduce pH = less B -> reduce absorption
Increase pH = more B -> increase absorption
note: if a drug is excreted by the kidney, the half life is longer
(lower maintenance dose required)
What is receptor supersensitivity? Give an example, and how this can lead to problems.
“Cross-talk” between signalling pathways increases sensitivity of the cell to external stimulus
e.g. beta-adrenergic stimulation in the heart increases the heart rate and force of contraction by phosphorylation of calcium channels
Stop taking beta-blockers -> increased sympathetic activation of heart -> increases heart rate & force of contraction -> increased O2 consumption -> angina & MI
