Understanding when drug therapeutic regimes might need changing

Question 1

What factors related to the drug affect drug absorption?

Answer 1

Highfor lipid soluble drugs
Low for Molecular size >1000da
Decreases for high degree of ionisation
Formulation can improve absorption

Question 2

What factors related to the body affect drug absorption (oral drugs)

Answer 2

Increases with surface area of absorptive surface
pH will affect extent of ionisation
GI motility (slow increases absorption, fast decreases)
Integrity of absorptive surface
Diseases

Question 3

What factors related to the drug affect drug distribution?

Answer 3

Highfor lipid-soluble drugs
High for weak base drugs

Low for water soluble drugs
Low for weak acid drugs

Question 4

What factors related to the body affect drug distribution?

Answer 4

Vd increases with high body fat content (lipid soluble drugs) - more space for drugs to be absorbed into
Vd increases with high body water content (water soluble drugs)
Low for drugs highly bound to plasma proteins

Question 5

What factors related to the drug affect drug metabolism/clearance?

Answer 5

Generally highfor lipid soluble drugs, but low for water soluble drugs
Protective chemical groups (eg F, CN) for lipid soluble drugs can reduce metabolism
Drug – drug interactions:
- CYP inhibition reduces clearance
- CYP induction increases clearance

Question 6

What factors related to the body affect drug metabolism/clearance?

Answer 6

Quantity of drug metabolising enzymes (eg P450 enzymes in liver)
Polymorphisms in metabolising enzymes (species-species and patient-patient differences)
Decreasing blood flow to metabolising organ will decrease drug clearance
Drug with low plasma protein binding have increased clearance
Diseases

Question 7

What factors related to the drug affect drug excretion/clearance?

Answer 7

Highfor water soluble drugs (straight through glomerulus into filtrate)
High for ionisable drugs

Low for lipid soluble drugs(reabsorbed)
Inhibitory drug – drug interactions

Question 8

What factors related to the body affect drug excretion/clearance?

Answer 8

Quantity of drug transporters present
Decreasing blood flow to excreting organ and GFR for the kidney will decrease drug clearance
Drug with low plasma protein binding have increased clearance
Diseases

Question 9

What is the difference in the absorption of drugs between neonates/pediatrics and normal adults?

Answer 9

Absorption is variable:
-Altered gastric emptying
-Irregular peristalsis
-Increased permeability of mucosa
-Rapid topical absorption due to immature percutaneous barrier

=> variable bioavailability

Question 10

What is the difference in the distribution of drugs between neonates/pediatrics and normal adults?

Answer 10

1. Increased for non-lipid drugs:
   - Greater water content
   - Decreased plasma protein binding
2. Decreased for lipid drugs:
   - Lower adipose content

Plasma levels affected so alterations to dose and dosing frequency needed

Question 11

What is the difference in the metabolism of drugs between neonates/pediatrics and normal adults?

Answer 11

Reduced hepatic function:
- Very species specific
- Biotransformation of drugs normal within days in foals
- 3-6 weeks in other domestic species

=> possible lower metabolic clearance

Question 12

What is the difference in the excretion of drugs between neonates/paediatrics and normal adults?

Answer 12

1. GFR normal (Within a few days)
2. Drug tubular secretion in nephron takes longer:
   - For many weak acid or basic drugs may take 3-4 weeks

=> possible lower excretion clearance

Question 13

What changes to dosing regimen may you need for a neonate/paedriatric patients?

Answer 13

Increasing dose is rare
Usually, dose needs reduction:
- Adult doses may result in accumulation due to differences in distribution - more likely to produce toxicity, adverse reactions
- Blood brain barrier not fully complete – risk of undesired CNS penetration
Sometimes, absolute contraindication (Fluroquinolones and tetracyclines)

Question 14

How is the absorption of drugs different in geriatric patients compared to a typical adult?

Answer 14

Absorption reduced:
- Gastric pH increased -altered drug ionisation
- Less microvilli
- Less mixing and dissolution
- Delayed disintegration of tablets

=> reduced bioavailability (lower Cmax and later Tmax)

Question 15

How is the distribution of drugs different in geriatric patients compared to a typical adult?

Answer 15

Body mass decreases:
- Less water content
- Increased adipose tissue
- Increased Vd for fat soluble drugs-increases half life
- Lower Vd for water soluble drugs - decreases half life

=> affects plasma level (changes needed in dose and dosing frequency)

Question 16

How is the metabolism of drugs different in geriatric patients compared to a typical adult?

Answer 16

Minimal effects :
- Decreased plasma albumin
- less binding may lead to more free drug for metabolism but also increases Vd resulting in no change in half-life

=> little change

Question 17

How is the excretion of drugs different in geriatric patients compared to a typical adult?

Answer 17

Decreased renal elimination:
- Decreased renal mass, GFR and tubular secretion
- Very similar to animal with chronic renal disease

=> lower excretion/clearance

Question 18

What changes are often made to dosage regimes for geriatric patients - drugs eliminated by kidneys?

Answer 18

Reduce dose or dosing frequency (increase dosing interval)
Use alternative drug that is predominantly metabolised in liver

Question 19

What changes are often made to dosage regimes for geriatric patients - lipid-soluble drugs?

Answer 19

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)

Question 20

What changes are often made to dosage regimes for geriatric patients - water soluble drugs?

Answer 20

Rarely change dosing regimen as reduction in Vd and therefore half-life tends to be small

Question 21

How does chronic cardiovascular disease affect pharmacokinetics?

Answer 21

Decreased blood flow: lower clearance for highly cleared drugs (eg anesthetics)

Question 22

How does respiratory disease affect pharmacokinetics?

Answer 22

Altered serum pH and protein binding

Question 23

How does liver disease affect pharmacokinetics?

Answer 23

• 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

Question 24

How does renal disease affect pharmacokinetics?

Answer 24

• A gradual loss of urine concentrating ability and ability to acidify
• Also altered drug distribution patterns
• Change in acid base balance
• Uraemia => chronic acidosis, reduced albumin binding of drug, less hepatic metabolism

Question 25

What changes to dosage regimen with renal disease?

Answer 25

Avoid renally cleared drugs
Lower dose for changes in GFR

Question 26

What changes to dosage regimen in hepatic disease?

Answer 26

reduce dose if severe or use drug that is primarily renally cleared

Question 27

What changes to dosage regimen in chronic cardiovascular disease?

Answer 27

avoid drugs with high clearance or reduce dose

Question 28

What changes in dosage regimen in respiratory disease?

Answer 28

adjust dose down for IV anaesthetics

Question 29

How can the dosage regimen to monitored to ensure effectiveness?

Answer 29

monitor plasma concentrations

Question 30

What is the therapeutic index?

Answer 30

a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects
High therapeutic index is ideal

Question 31

Give examples of drugs with high therapeutic indexes

Answer 31

NSAIDs - aspirin, tylenol, ibuprofen
Sedatives - benzodiazepines
Most antibiotics
beta-blockers

Question 32

Give examples of drugs with low therapeutic indexes

Answer 32

Neuroleptics - phenytoin, phenobarbital
Lithium
Some antibiotics - vancomycin
Digoxin
Immunosuppressives

Question 33

describe the use of drugs with low therapeutic indexes in chronic therapy

Answer 33

may require therapeutic monitoring for altered physiological states

Question 34

What is therapeutic monitoring?

Answer 34

Measuring the plasma drug concentrations?

Question 35

What is the purpose of therapeutic monitoring?

Answer 35

Detect changes in pharmacokinetics
Optimize dose/therapeutic response
Monitor compliance
Avert toxicity

Question 36

When should therapeutic monitoring be done?

Answer 36

when concentrations get to steady-state levels (5 half-lives in absence of loading dose):
- Provides best correlation between plasma drug concentrations and clinical status
- For toxicity need to sample at peak concentration (Cmax)
- For efficacy need to sample at trough (Cmin) - just before next dose