Drug Movement in the Body

Question 1

Fate of drugs in the body?

Answer 1

Absorption - process by which a drug enters the body from its site of administration (the lumen of GI tract is considered to be outside of the body)

Distribution - process by which a drug leaves the circulation and enters the tissues perfused by blood; once within a tissue, further, blood-independent distribution may occur by diffusion/carrier-mediated transport

Metabolism - process by which tissue enzymes (principally in the liver - hepatic metabolism catalyse the chemical conversion of a drug to a MORE POLAR FORM that is more readily excreted from the body)

Excretion - processes that remove the drug from the body (principally the kidneys - renal excretion)

Question 2

What is elimination?

Answer 2

Metabolism and excretion

Question 3

Overview of drug disposition?

Answer 3

Question 4

Where does most absorption occur?

Answer 4

In the small intestine, as there is a greater absorptive surface area

However, some substances, e.g: ethanol, are absorbed from the stomach

Question 5

Physiochemical factors controlling drug absorption?

Answer 5

1. Solubility
2. Chemical stability
3. Lipid to water partition coefficient
4. Degree of ionisation

Question 6

Why is solubility important in drug disposition?

Answer 6

Drug must dissolve (dissolution) in order to be absorbed

Question 7

Why is chemical stability important in drug disposition?

Answer 7

Some drugs are destroyed by acid in the stomach, or enzymes in the gastrointestinal tract

Question 8

Why is lipid to water partition coefficient important in drug disposition?

Answer 8

Absorption of a drug commonly occurs by simple diffusion across membranes (importantly, some agents are transported); for a given drug conc. gradient across a membrane, the rate of diffusion increases with the lipid solubility of the drug.

Drug MUST have a degree of lipid solubility (amphipathic)

Question 9

Why is degree of ionisation important in drug disposition?

Answer 9

Many drugs exist as weak acids or weak bases, existing in both ionised and unionised forms (dynamic equilibrium between the 2 forms)

ONLY UNIONISED FORMS READILY DIFFUSE ACROSS THE LIPID BILAYER

Question 10

What is an acid?

Answer 10

Donates protons (reaction driven to right by increasing pH)

Question 11

What is a base?

Answer 11

Accepts protons (reaction driven to left by decreasing pH)

Question 12

What does degree of ionisation depend upon?

Answer 12

pKa of the drug and local pH

pKa = pH at which 50% of drug is ionised and 50% is unionised

Question 13

How to calculate proportions of ionised and unionised drugs?

Answer 13

Henderson-Hasselbalch equation

Acid: pKa - pH = log (HA/A-)

Base: pKa - pH = log (BH+/B)

Question 14

Absorption of acids and bases?

Answer 14

Absorption of weak acids is facilitated by pH of stomach lumen; bases are not readily absorbed until they reach the small intestine

Majority of absorption (even weak acids) occurs in small intestine (large SA) Weak acids and weak bases are well absorbed, strong acids (pKa 10) are poorly absorbed

Question 15

What happens to acids and bases in different environments?

Answer 15

Acidic drugs become less ionised in an acid environment; basic drugs become less ionised in a basic environment

Question 16

Good pH for drug absorption?

Answer 16

pH 4.5 - 90% of drugs absorbed

Question 17

Factors affecting GI absorption?

Answer 17

GI motility - the rate of stomach emptying and movement through the intestines; modified by some drugs and presence of food

pH at absorption site (varies along GI tract)

Blood flow to stomach and intestines (increased by food)

Way in which the tablet, capsule etc is manufactured; can be customised to release drugs at different rates and sites, e.g. intestine vs stomach

Physicochemical interactions, e.g. the rate of absorption of some drugs is modified by calcium rich-rich foods

Presence of transporters in the membranes of epithelial cells of the GI tract which can facilitate drug absorption

Question 18

What is oral availability?

Answer 18

Fraction of drug that reaches the systemic circulation after oral ingestion, i.e. amount in systemic circulation / amount administered

Question 19

What is systemic availability?

Answer 19

Fraction that reaches the systemic circulation after absorption, i.e. amount in systemic circulation / amount absorbed

Drugs administered i.v. have 100% systemic availability

Question 20

Disadvantages of orally administered drugs?

Answer 20

Once absorbed, can be inactivated by enzymes in the gut wall and liver (FIRST-PASS or pre-systemic METABOLISM) before reaching the systemic circulation and body tissues in general

Question 21

What are common routes of drug administration?

Answer 21

Oral

Inhalational

Buccal/sublingual

Transdermal/subcutaneous

Intravenous

Rectal

Intramuscular

Question 22

Advantages and disadvantages of drugs administered orally?

Answer 22

Advantages - convenient, non-sterile route; good absorption for most drugs

Disadvantages - inactivation of some drugs by acid/enzymes; variable absorption; first pass metabolism; G.I. irritation

Question 23

Advantages and disadvantages of drugs administered sublingually?

Answer 23

Advantages - by-passes portal system and avoids first pass; avoids gastric acid

Disadvantages - infrequent route, few sublingual preparations available

Question 24

Advantages and disadvantages of drugs administered rectally?

Answer 24

Advantages - as for sublingual; used for noctural administration of some drugs

Disadvantages - infrequent route; variable absorption; aesthetically unacceptable (in UK)

Question 25

Advantages and disadvantages of drugs administered intravenously?

Answer 25

Advantages - rapid onset (emergency) route, continuous infusion; complete availability; route for drugs that cause local tissue damage

Disadvantages - sterile preparation required; risk of sepsis or embolism; high drug levels at the heart

Question 26

Advantages and disadvantages of drugs administered intramuscularly?

Answer 26

Advantages - rapid onset of lipid soluble drugs, depot injection for slow prolonged release possible

Disadvantages -painful; tissue damage with some drugs; absorption variable

Question 27

Advantages and disadvantages of drugs administered by inhalation?

Answer 27

Advantages - lungs ideally suited due to huge surface area; good for volatile agents (anaesthetic gases), aerosols etc. Ideal for local effect

Disadvantages - few disadvantages

Question 28

Advantages and disadvantages of drugs administered by topical?

Answer 28

Advantages - ideal for local effect

Disadvantages - few disadvantages

Question 29

Forms of a drug in relation to distribution to body fluid compartment?

Answer 29

Drugs within the systemic circulation can be distributed to one + body fluid compartments

Exist in BOUND or FREE forms within each compartment; only free drug can move between compartments:

1. Ionised and unionised drugs that are not bound to protein (e.g. albumin, α1-acid glycoprotein) can move freely by diffusion
2. Only unionised drugs move readily by diffusion

Question 30

What is the volume of distribution?

Answer 30

Vd - apparent volume in which a drug is dissolves, as drugs are not evenly distributed in the body

Question 31

Calculating Vd?

Answer 31

Vd = dose / plasma concentration

Question 32

What do different Vd values mean?

Answer 32

Vd of 15L indicates distribution throughout total body water (or concentration in certain tissues), e.g. highly lipid soluble drugs (ethanol)

Question 33

Difference between enteral and parenteral?

Answer 33

Enteral - via the GI tract, inc. oral, sublingual, rectal

Parenteral - not via the GI tract, inc. iv, intramuscular, inhalational, topical