Lecture 4

Question 1

What happens after you administer a drug?

Answer 1

• drug needs to be absorbed and travel to reach its target
• over time the effects will wear off, as the drug is eliminated from body

Question 2

What is the therapeutic window?

Answer 2

conc range where drug will have its desired outcome

Question 3

What is the steady state?

Answer 3

• attained after 4 half-times
• time to steady state depends on the dosage

Question 4

What are steady state concentrations?

Answer 4

• proportional to dose/dosage interval
• proportional to F/CL (bioavailability)

Question 5

What are fluctuations

Answer 5

• proportional to dose interval/half-time
• blunted by slow absorption

Question 6

What are some important things to consider when thinking of routes of adminstration

Answer 6

• Convenience (easy to take medicine orally then injection)
• Bioavailability - different drugs are absorbed with different efficiency from the gut
• Processing - Hepatic portal circulation is a major consideration. drugs that are absorbed from the gut first encounter the liver before entering systemic circulation, so there can be significant processing

Question 7

What is first pass metabolism?

Answer 7

when drugs are ingested orally, drugs are absorbed in the gut then pass through the hepatic circulation before entering the systemic circulation
- strongly influences the bioavailability of many drugs

Question 8

What is the extraction ratio?

Answer 8

the amount of drug cleared from the liver divided by the amount of drug in the blood

Question 9

What are the different routes of administration?

Answer 9

• oral
• intravenous
• intramuscular
• inhalation
• sublingual
• transdermal

Question 10

What is the oral mode of administration

Answer 10

• most common route for drugs
• rate of absorption is slow and can be affected by food
• exposure is influenced by breakdown in the gut

Question 11

What is the intravenous mode of administration?

Answer 11

• rapid onset of action
• inconvenient and requires expertise
• high control over circulating level by controlling the rate of infusion, or amount injected

Question 12

What is the intramuscular mode of administration?

Answer 12

• injection to muscle
• rate of absorption depends on blood flow to site

Question 13

What is the inhalation mode of administration

Answer 13

absorption is through the epithelium in the lungs, and can be rapid

Question 14

What is the sublingual mode of administration

Answer 14

rapid absorption, also bypasses first pass despite oral delivery, rapid delivery

Question 15

What is the transdermal mode of administration

Answer 15

convenient, slow absorption and sustained exposure

Question 16

What is bioavailability?

Answer 16

fraction of unprocessed drug that reaches the systemic circulation after administration by a particular route

Question 17

What is distribution?

Answer 17

• refers to how a drug is partitioned into different body compartment after it is absorbed
• distribution can have a big influence on the effective concentration of a drug in the body, as well as the lifetime of the drug in the body

Question 18

What are the two key factors related to distribution?

Answer 18

• binding to plasma proteins
• drug accumulation in tissues

Question 19

What is drugs binding to plasma proteins

Answer 19

• drugs circulate in equilibrium between free and bound
• only the free fraction is pharmacologically active
• some drugs are highly bound (so small effect even if a lot is present in body)

Question 20

What is drug accumulation in tissues

Answer 20

• accumulation is favoured for drugs that are lipophilic.
• perfused tissues can accumulate a drug more readily than tissues with poor perfusion
• key parameter is volume of distribution

Question 21

What is the volume of distribution?

Answer 21

provides a relative comparison of how well different drugs are distributed into tissues
- drugs with a high volume of distribution are well distributed
- drugs with a low volume of distribution are poorly distributed
- volume of distribution = total amount of drug in the body/[drug]

Question 22

What is single compartment distribution?

Answer 22

• drug is contained within a single compartment
• if elimination pathway is present, drug concentration decreased with exponential decay kinetics (rate of elimination depends on concentration of drug)

Question 23

What is multiple compartment distribution

Answer 23

• after administration, drug distributes into multiple compartments
• elimination pathway is present, drug concentration in the blood determines the rate of elimination, but the reservoir of drug in the tissues can prolong the lifetime of the drug in the body

Question 24

How are drugs eliminated?

Answer 24

• metabolism in the liver (Biotransformation), and excretion (kidney, gut)
• metabolism in the liver involves Phase 1 and 2

Question 25

What is phase 1 of drug elimination?

Answer 25

mixed function oxidase system (CYP family enzymes) generates oxidative modifications of drugs

Question 26

What is phase 2 of drug elimination

Answer 26

conjugation of parent compound, or phase 1 product with large polar adducts to make product more prone to excretion

Question 27

What are some key points in drug elimination

Answer 27

• phase 1 and phase 2 don’t need to occur in sequence
• reactions happen in liver
• multiple CYP enzymes can metabolize a drug, often more than one pathway
• genetic variation in CYP enzymes lead to individual differences
• CYP3A4 is the most widely expressed CYP in liver
• toxic intermediates are formed, which can lead to hepatotoxicity

Question 28

What are the primary routes of drug excretion

Answer 28

Bile/Feces
- biotransformed drugs in the liver are incorporated into bile, and secreted into the gut
- modifications make the drug more polar and less prone to accumulate in tissue or reabsorbed in digestive tract
Urine
- drug passes from blood through glomerular filtration, or is actively secreted in to the renal tubule and excreted in urine