Pharmacokinetics overveiw

Question 1

What is pharmacokinetics?

Answer 1

What the body does to a drug
Rate/ extent to which drugs are absorbed in the body and distributed to body tissues
Rate/ pathways in which drugs are eliminated from body by metabolism/ excretion
Relationship between time and plasma drug conc

Question 2

What are the 4 phases of pharmacokinetics?

Answer 2

Absorption
Distribution
Metabolism
Excretion

Question 3

How can drug residence in the body be represented?

Answer 3

Plot proportion of drug following single dose in 4 phases against time, subcutaneous injection of drug sufficient water-soluble to be excreted unchanged but also undergoes liver metabolism

Question 4

What are the routes of drug absorption?

Answer 4

• Enteral (small bowel)= oral, sublingual, rectal (buccal)
• Parenteral (avoid GI, blood circulation)= intravenous, intramuscular, subcutaneous, inhaled
• Topical application- eyes, skin

Question 5

How must a drug be successful after oral admission?

Answer 5

swallowed, survive gastric acid, avoid unacceptable food binding, absorbed across the gastrointestinal mucosa (lipid-soluble), survive hepatic first pass metabolism and enterohepatic circulation

Question 6

Contrast oral and IV routes

Answer 6

• Oral= convenient, simple, can be easily self-administered, long-term treatments for less acute illness
• IV= no concerns about absorption, rapidly achieves high drug conc, no first pass effect, rapid certain effects critical to outcome in severe illness

Question 7

Describe the intramuscular route

Answer 7

Injections simple to administer, unpredictable rate of absorption, painful (vaccination)
Cardiac arrest- poor circulation- unsuitable route

Question 8

Describe the subcutaneous route

Answer 8

Administered parenterally (insulin, heparin), absorbed well by subcutaneous fat (lipid-soluble), patients can inject themselves

Question 9

Describe the inhaled route

Answer 9

Inhaled to target airways in lung, salbutamol and beclomethasone
Bronchodilation drugs, droplets in airways, not too small to go into alveoli, Droplets deposit in bronchioles

Question 10

What factors are involved in distribution of drug?

Answer 10

(Plasma) protein binding (albumin)

Water/ lipid-solubility (ionisation)- dependence of ion transporters? Cross cell membranes?

Question 11

Where are drugs usually not wanted to go?

Answer 11

Brain, across placenta, breast milk

Question 12

How are drugs distributed?

Answer 12

Passive diffusion (some active), speed and efficiency depends on molecular size, lipid-solubility and protein binding. Free drug concentration
Continues until equilibrium achieved, reverse distribution towards plasma commences unless further doses administered

Question 13

What are the proportions of free drugs in body fluid compartments?

Answer 13

• Plasma= 5% (4L) (highly protein bound and water-soluble)
• Interstitial fluid= 15% (12L)
• Intracellular fluid= 35% (32L)
• Intracellular fat= 20% (highly lipid soluble)

Question 14

What is the apparent volume of distribution?

Answer 14

The volume of the dose that appears to be distributed into shortly after IV injection based on the plasma drug concentration
Initial plasma conc= Amount of drug given/ volume of distribution
Lower plasma conc= more absorption= higher Vd

Question 15

Where are drugs metabolised?

Answer 15

Liver- reduces biological activity, increases water-solubility for excretion

Question 16

What are the phases of metabolism?

Answer 16

1= deactivate/ reduce biological activity
oxidation in microsomal mixed function oxidase system
Enzyme induction/ inhibition
2= excretion, conjugation by either acetylation or glucuronidaton
Increased metabolism= faster elimination, shorter half-life, reduced activity, potential for increased exposure to toxic metabolites

Question 17

What are hepatic drug interactions?

Answer 17

Presence of one drug may influence metabolism of another
- Induce metabolism= stimulate liver to produce more enzymes
- Inhibit metabolism= competing
Warfarin, anti-epileptics and oral contraception= stable needed, statins withheld

Question 18

What is first-pass metabolism?

Answer 18

Occurs in gut wall and liver, determinant of peak plasma drug conc and drug response
Molecules absorbed pass through portal venous system and liver sinusoids before systematic circulation
Biotransformation of unchanged active drug to inactive metabolite reduce response, active metabolite no change, inactive to active= increase

Question 19

What are the main routes of drug excretion?

Answer 19

Renal, biliary, faeces, breast milk, sweat

Question 20

What is excretion?

Answer 20

The process by which drug and metabolites are removed from the body and may involve fluids (urine and bile), solids (faeces) and gases (expired air)

Question 21

What is urinary excretion?

Answer 21

Main route for low molecular weight drugs/ metabolites that are sufficiently water-soluble to avoid reabsorption
Drugs bound to plasma proteins not filtered
pH of urine more acidic than plasma so can affect pH partitioning (aspirin)
Some drugs actively secreted from tubular capillaries into tubules

Question 22

What is biliary excretion?

Answer 22

Faecal route preferred for large molecular weight (conjugated with glucuronide in liver)- drug molecules/ metabolites enter bile after liver metabolism carried into intestinal lumen and excreted in faeces
Lipid soluble= reabsorbed and renter portal vein

Question 23

What is entero-hepatic circulation?

Answer 23

Recycling between liver, bile, gut and portal vein
Reduces rate drugs eliminated from body, prolongs residence times
Gut flora can split off group- glucuronidaton hydrolysed
Broad spectrum antibiotics reduce reabsorption

Question 24

What is drug clearance?

Answer 24

Volume of plasma that is completely cleared of drug per unit time
Volume divided by time (mL/min, L/hr)

Question 25

What is clearance caused by?

Answer 25

Metabolism in liver, excretion in kidney

Mathematically related to pharmacokinetic descriptors like drug half-life- high rate of clearance= short half life

Question 26

What is bioavailability?

Answer 26

Oral bioavailability is area under curve oral/ area under curve IV for the plasma-concentration time graph expressed as a percentage

Question 27

What does oral bioavailability depend on?

Answer 27

• Gastric acid destruction (insulin, benzylpenicillin)
• Formulation (enteric coated, slow release)
• First-pass metabolism (lidocaine, morphine)
• Solubility, ionisation, food, diarrhoea

Question 28

What are the factors influencing pharmacokinetics?

Answer 28

Age (glomerular filtration rate- renal and organ function)
Sex (equivalent body mass- lipid soluble females)
Body weight/ impaired organ function/ genetic variation/ environmental factors/ food/ drug interactions