Drug regimes Flashcards
What are the key determinants of a dosage regimen?
Activity/toxicity (therapeutic window, side effects, dose-response relationships)
Clinical factors (state of patient, compliance, convenience)
Pharmacokinetics (dose, onset, loading dose, maintenance dose, time to steady-state)
Other factors (dosage form, route of administration, drug interactions).
Define dosage
The administration of medicine in prescribed amounts over time
What factors influence the onset of drug action
Route of administration
Bioavailability and first-pass metabolism
Clinical situations (pathologies, blood perfusion, changes in pH, etc.)
Chemical structure and formulation.
Describe the main routes of drug administration & elimination
What pharmacokinetic factors influence drug regimens?
Dose: potency and efficacy
Onset: Absorption & distribution
Loading dose: Vd
Maintenance dose: clearance
Time to steady-state: half-life
What factors affect the dosage of a drug given?
potency
absorption
Bioavailability and 1st pass metabolism
Distribution
What factors influence the onset of action of a drug?
Route of administration
Chemical structure and formulation (slow or fast release)
Clinical situations (pH change, shock, tissue blood perfusion)
If a drug is given orally what factors affect onset of action?
Polypharmacy (other drugs)
Gut content
Splanchnic blood flow
What is loading dose and how is it calculated
An initial higher dose to enable therapeutic concentrations sooner
Dose = Vd x plasma conc
What is a maintenance dose?
The dose given to maintain drug conc at therapeutic conc
= clearance (CL) x steady state conc (Css)
How can steady state concentrations be maintained?
Constant IV infusion (impractical)
Increased dose frequency (beware of owner compliance)
What is saturation kinetics?
At high doses, increases in drug concentration result in disproportionate rises in steady-state levels due to enzyme saturation (e.g., phenytoin).
How does “normal” kinetics differ from saturation kinetics?
In normal kinetics, plasma concentrations increase proportionally with dose
What is plasma protein binding?
Only free drugs are active, distributed, metabolized, or excreted
Drugs bind to plasma albumin (acidic drugs) or β-globulin (basic drugs)
Extensive binding slows drug elimination.
What happens in cases of saturable binding?
At high drug concentrations, binding sites may saturate, leading to non-linear drug concentration increases.
What drug-related factors affect absorption?
High absorption for lipid-soluble drugs.
Low absorption for drugs with molecular weight > 1000 Da or high ionization.
Formulation can improve absorption
What body-related factors affect absorption?
Increased absorption with larger absorptive surface area.
Altered by pH, GI motility, absorptive surface integrity, and diseases
What drug-related factors affect distribution?
High for lipid-soluble and weak base drugs.
Low for water-soluble and weak acid drugs
What body-related factors affect distribution?
Higher body fat increases 𝑉𝑑 for lipid-soluble drugs.
Higher body water increases 𝑉𝑑 for water-soluble drugs.
Low for drugs highly bound to plasma proteins.
What drug-related factors affect metabolism?
High metabolism for lipid-soluble drugs.
Protective chemical groups (e.g., F, CN) can reduce metabolism.
CYP inhibition reduces clearance, and CYP induction increases clearance
What body-related factors affect metabolism?
Enzyme quantity (e.g., P450 enzymes).
Polymorphisms in metabolizing enzymes.
Decreased blood flow to metabolizing organs reduces clearance.
Diseases
What drug-related factors affect excretion?
High for water-soluble and ionizable drugs
Low for lipid-soluble drugs.
Inhibitory drug-drug interactions reduce excretion
Drug with low plasma protein binding have increased clearance
What body-related factors affect excretion?
Drug transporter quantity.
Blood flow and GFR in kidneys.
Diseases affecting excretory organs
How does absorption in neonates differ from adults?
How does distribution in neonates differ from adults?
How does metabolism in neonates differ from adults?
How does excretion in neonates differ from adults?
What dosing adjustments are needed for neonates?
Usually lower doses to prevent toxicity.
- Adult doses may result in accumulation due to differences in distribution
- Blood brain barrier not fully complete – risk of undesired CNS penetration
Avoid drugs like fluoroquinolones and tetracyclines
How does absorption in geriatrics differ from adults?
How does distribution in geriatrics differ from adults?
How does metabolism in geriatrics differ from adults?
How does excretion in geriatrics differ from adults?
What dosing adjustments are needed for geriatrics for drugs mainly eliminated by kidney?
- Reduce dose or dosing frequency (increase dosing interval)
- Use alternative drug that is predominantly metabolised in liver
What dosing adjustments are needed for geriatrics for lipid-soluble drugs
Average adult dosing regimens may result in accumulation due to increased fat distribution - more likely to produce “hang over effect” and toxicity
Reduce dose or dosing frequency (increase dosing interval)
What dosing adjustments are needed for geriatrics for water-soluble drugs
Rarely change dosing regimen as reduction in Vd and therefore half-life tends to be small
How does chronic cardiovascular disease affect drug PK? What changes would you make to dosing regimen?
Decreased blood flow: lower clearance for highly cleared drugs (eg anesthetics)
Avoid drugs with high clearance or reduce dose
How does respiratory disease affect drug PK? What changes would you make to dosing regimen?
Altered serum pH and protein binding
Adjust dose down for intravenous anaesthetics
How does liver disease affect drug PK? What changes would you make to dosing regimen?
Content and activity of phase I/II reactions is decreased
Little effect on drug metabolism until 80% functional loss
No adequate functional tests
Most antimicrobials are well tolerated
Rarely an issue but reduce dose if necessary for severe cases or use a drug that is primarily renally cleared
How does renal disease affect drug PK? What changes would you make to dosing regimen?
Potentially most profound changes in PK
gradual loss of urine concentrating ability & ability to acidify
Altered drug distribution patterns
Change in acid base balance
Uraemia: chronic acidosis, reduced albumin binding of drug, less hepatic metabolism
Avoid renally cleared drugs?
Adjust dose down for changes in GFR?
What is therapeutic index?
comparison of amount of therapeutic agent that causes therapeutic effect to amount that causes toxic effects
Ideal drug has high therapeutic index
Name some drugs with a high therapeutic index
NSAIDs - aspirin, tylenol, ibuprofen
Sedatives - benzodiazepines
Most antibiotics
beta-blockers
Name some drugs with a low therapeutic index
Neuroleptics - phenytoin, phenobarbital
Lithium
Some antibiotics - vancomycin
Digoxin
Immunosuppressives
Drugs with low therapeutic indexes used in chronic therapy may require therapeutic monitoring for altered physiological states
What is therapeutic monitoring?
Measure plasma drug concentrations to:
- Detect changes in pharmacokinetics
- Optimize dose/therapeutic response
- Monitor compliance
- Avert toxicity
When should blood samples be taken?
At steady-state levels (after 5 half-lives)
Peak concentration (Cmax) for toxicity monitoring
Trough concentration (Cmin) for efficacy monitoring.
