Drug metabolism and excretion

Question 1

What is the main site of drug metabolism?

Answer 1

Liver

Question 2

What is the main site of drug excretion?

Answer 2

Kidney

Question 3

What are the two main processes of drug metabolism?

Answer 3

1. Molecule is made more lipophilic to reduce the possibility of reabsorption in the renal tubules
2. Conjugated to reduce its effects and aid excretion

Question 4

What is a prodrug?

Answer 4

Inactive form of drug that becomes active through conversion in the body

Question 5

Which reactions happen in phase I of metabolism?

Answer 5

Oxidation

Reduction

Hydrolysis

Glucyronidation

Glycosylation

Sulfanation

Methylation

Acetylation

Amino acid conjugation

Glutathione conjugation

Question 6

Which phase I reactions are the most important?

Answer 6

The ones by the P450 system

Question 7

What is required for reactions by the P450 system to take place?

Answer 7

Cytochrome P450 haem proteins

Molecular oxygen

cP450 reductase

NADPH

Question 8

What reaction does P450 catalyse?

Answer 8

NADPH + oxidised cyto + H+ -> reduced cyto + NADP+

Question 9

How can other drugs affect the P450 system?

Answer 9

Other drugs can increase/decrease the effect of P450

Some drugs can increase the effect of drugs through inhibiting the P450 system

Question 10

What processes are involved in renal excretion?

Answer 10

Filtration at the glomerulus

Active tubular secretion

Reabsorption from the tubule

Question 11

Describe how glomerular filtration helps to excrete drugs

Answer 11

Arterial blood pressure forces ultrafiltrate from the glomerular capillaries into Bowman’s capsule

Small drug molecules in both charged and uncharged states cross the glomerular membranes readily, achieving a concentration in the filtrate identical to their free concentration in plasma

Drug molecules bound to plasma proteins are not filtered

Question 12

Describe how active tubular secretion helps to excrete drugs

Answer 12

Occurs at the PCR

Low-specificity carriers in the basolateral membrane transport endogenous substances and drugs from the plasma into the tubular cells from where they pass into the filtrate by facilitated diffusion

Tubular secretion of one drug may be competitively inhibited by another

Question 13

Describe how reabsorption from the tubule affects drug excretion

Answer 13

Drugs within the tubules in the unionised and lipid form will be reabsorbed

A weak acid = more readily excreted in alkaline than acidic urine

Question 14

Self-renewal of bile

Answer 14

Bile is produced at a daily rate of 0.5-1 litre

Question 15

Describe the enterohepatic circulation and how that affects the bioavailability of drugs

Answer 15

Drugs may be reabsorbed from the bile back into the intestine to undergo further cycles of billiary excretion

This happens through active transport

This increases the drug’s half life

Question 16

What determines the course of drug action?

Answer 16

The concentration of the drug at the site

An important exception - drugs that bind irreversibly, since the effect outlives the concentration

Question 17

Describe the course of drug action in well and poorly perfused systems

Answer 17

Well perfused tissues can equilibrate with the plasma concentration quickly

Poorly perfused tissues will take up and release drugs slowly

Question 18

What are ways drugs can enter cells?

Answer 18

Direct diffusion through the lipid bilayer

Carrier-mediated transport

Diffusion through aqueous pores

Pinocytosis

Question 19

What determines the diffusion of a drug through membranes?

Answer 19

Concentration gradient

Diffusion coefficient

Question 20

What is the Henderson Hasselback equation?

Answer 20

Determines the fractional ionisation of weak acids and bases

For a weak acid: log10 ci/cu = ph-pKa
For a weak base: log10 ci/cu = pKa – ph

Question 21

What is lipid trapping?

Answer 21

In different pH, the level of ionisation is different

Lipid bilayer prevents the movement of ionised molecules

Therefore, we can say that lipid bilayers act as traps preventing the movement of ions

Question 22

What is the importance of carriers for nutrition?

Answer 22

Carriers are important for membrane transport of essential nutrients that have low lipid solubility

Question 23

Which transporters are effective for drug transport?

Answer 23

Transporters found in the kidney

Important in the elimination of drugs from the body

Question 24

Example of a kidney transporter involved in the removal of drugs

Answer 24

P-glycoprotein

Involved in the removal of chemotherapeutic agents

Question 25

What are features of activa transporters?

Answer 25

Uphill transport Finite number of transporters - leads to saturation

Question 26

What are the two main ways of drug administration?

Answer 26

Enteral administration Factors controlling oral absorption

Question 27

What is enteral administration?

Answer 27

Oral absorption from the stomach or gut following swallowing Most convenient/acceptable route

Question 28

What is an important consideration regarding enteral administration of drugs?

Answer 28

Oral absorption will deliver the drug directly to the liver, the major site of drug metabolism, via the portal circulation This will lead to substantial first-pass elimination

Question 29

What type of administration prevent first-pass metabolism from the liver?

Answer 29

Sublingual or buccal administration Lower rectal administration

Question 30

Example of drug given through the sublingual/buccal route

Answer 30

Glyceryl trinitrate absorbed quickly to relieve anginal pain

Question 31

Which factors control oral absorption of drugs?

Answer 31

Lipid solubility and ionisation Drug formulation Gastrointestinal motility Bioavailability

Question 32

How does lipid solubility and ionisation affect the absorption of drug?

Answer 32

Weak acids will be mostly absorbed in the more alkaline intestine Rapid passage of drug from the stomach to the intestine is likely to speed up drug absorption

Question 33

# Fill in the blank Ionised form of drugs are more -

Answer 33

Water soluble

Question 34

# Fill in the blank Unionised form of drugs are more -

Answer 34

Membrane permeable

Question 35

How does gastrointestinal motility affect drug absorption?

Answer 35

Stasis can slow oral absorption Diarrhoea may allow insufficient time for complete absorption

Question 36

Causes of low bioavailability

Answer 36

Incomplete release of the dosage form Destruction within the gut Poor absorption First-pass elimination

Question 37

What is bioavailability?

Answer 37

Proportion of the administered dose that reached the systemic circulation

Question 38

What are the uses of parenteral administration of drugs?

Answer 38

Rapid effects Drugs that are poorly absorbed from the gut Irritants Localisation of action

Question 39

Different types of parenteral administration

Answer 39

Intravenous Inhalation Intramuscular and subcutaneous Topical

Question 40

Advantage of intravenous administration

Answer 40

Most rapid route

Question 41

Advantage of intramuscular and subcutaneous drug administration

Answer 41

Utility in providing long-term therapy

Question 42

Describe the difference in drug distribution between small and large molecules

Answer 42

Large molecules cannot easily enter interstitial and intracellular spaces Smaller, lipid-soluble molecules can spread rapidly throughout the whole body

Question 43

What does volume of distribution mean?

Answer 43

The volume of fluid required to hold the amount of drug in the body at the measured plasma concentration

Question 44

What is the equation for volume of distribution?

Answer 44

Vd = dose/cp cp concentration of drug in the plasma after it has equilibrated in its distribution volume but before a significant fraction has been eliminated

Question 45

What are different ways drugs can interact with body tissues once administered?

Answer 45

Can bind in to proteins and other tissue components Can accumulate in lipids Can penetrate into the brain

Question 46

Which proteins bind to drugs?

Answer 46

Weak acids = albumin Weak bases = a-acid glycoprotein

Question 47

What is the consequence of protein binding?

Answer 47

The bound drug is usually inactivated The reduction in free drug concentraiton may reduce elimination or protein binding may serve to deliver the drug to the kidney and liver to enhance elimination One drug may prevent the binding of another, enahncing the pharmacological activity

Question 48

What two aspects of the brain prevent drug entry?

Answer 48

Blood brain barrier - tight juncitons Turnover of CSF - drugs that penetrate slowly will be removed by washout and achieve a steady-state concentration below the plasma concentration