Principles of pharmacology

Question 1

What is the difference between pharmacology and therapeutics?

Answer 1

• pharmacology is more focused on the ‘drugs’

- therapeutics is concerned with drug prescribing and the treatment of disease…more focused on the ‘patient’

Question 2

What is the difference between pharmacodynamics and pharmacokinetics?

Answer 2

pharmacodynamics deals with ‘what the drug does to the body’, whereas pharmacokinetics deals with ‘what the body does to the drug’

Question 3

What are the four classes of drug target proteins?

Answer 3

• receptors
• enzymes
• ion channels
• transport proteins

Question 4

What is the drug target of aspirin?

Answer 4

• enzyme cyclooxygenase

- blocks production of prostaglandins

Question 5

What is the drug target of local anaesthetics?

Answer 5

they block sodium ion channels, thus preventing nerve conduction

Question 6

What is the drug target of anti-depressant Prozac?

Answer 6

block serotonin carrier proteins, preventing serotonin from being removed from the synapse

Question 7

What is the drug target of nicotine?

Answer 7

it binds to and activates the nicotinic acetylcholine receptor

Question 8

How does dose affect the selectivity/specificity of a drug?

Answer 8

at a low dose, the effect is more specific, due to the fact that the drug will only interact w/ 1 target…but as the dose increases, the effect becomes less specific, as the drug starts to interact w/ other drug targets–> producing unwanted side effects

Question 9

What types of chemical interactions can be involved in drug-receptor interactions?

Answer 9

• electrostatic interactions: most common; includes H-bonds and vdw forces
• hydrophobic interactions: most important for lipid soluble drugs
• covalent bonds: least common, as irreversible
• stereospecific interactions: many drugs exist as stereoisomers

Question 10

What is the difference between agonists and antagonists?

Answer 10

• both can bind to receptors, but only agonists bind and ACTIVATE receptors
• antagonists bind and BLOCK receptors

Question 11

What is meant by the affinity of a drug?

Answer 11

the strength of binding of the drug to the receptor–> strength of each drug-receptor complex–> increased likelihood of receptor occupancy

Question 12

What is meant by efficacy?

Answer 12

the ability of an individual drug molecule to produce an effect once bound to a receptor
e.g. no response, partial response or complete response… antagonists, partial agonists and full agonists

Question 13

What is meant by potency?

Answer 13

• the concentration/dose of a drug required to produce a defined effect (THE LESS DRUG YOU REQUIRE FOR EFFECT, THE MORE POTENT IT IS)
• OR standard measure of potency= conc./dose required to produce 50% tissue response (EC50/ED50)

Question 14

What is the difference between EC50 and ED50?

Answer 14

EC50:

• for in vitro experiments
• specific concentrations of drug added to test effectiveness
• EC50= the conc. that produced a 50% response

ED50:

• for clinical trials
• specific dose of drug given to individuals
• ED50= dose that produced desired effect in 50% of individuals tested

Question 15

What is the clinical relevance of the difference between potency and efficacy?

Answer 15

efficacy is more important, as you want to know if drug can induce maximal response…potency simply determines dose needed to produce response
*if you have 2 drugs w/ equal efficacy, it doesn’t matter which is more potent, as you can still produce maximal response w/ the less potent drug (you just need to give a slightly higher conc.)

Question 16

What is meant by absorption in pharmacokinetics?

Answer 16

the passage of a drug from the site of administration into the plasma

Question 17

What is meant by bioavailability in pharmacokinetics?

Answer 17

the fraction of the initial dose that gains access to the systemic circulation

Question 18

What are some common forms of drug administration?

Answer 18

• intravenous (bulk flow transfer in bloodstream)
• oral
• dermal (percutaneous)
• inhalation
• intranasal

Question 19

What is pinocytosis?

Answer 19

when a small part of the cell membrane envelops a chemical molecules and forms a vesicle containing the drug, which then releases the chemical on the other side of the membrane

Question 20

Why is diffusion across aqueous pores not a major route for movement of drugs?

Answer 20

because most pores <0.5nm in diameter and there are very few drugs this small

Question 21

How do most drugs move across membranes?

Answer 21

by diffusing across lipid membranes (need to be lipid soluble) or by carrier mediated transport, involving a transmembrane protein that binds drug molecules on 1 side of membrane and transfers them across to other side

Question 22

Why are most drugs water soluble, not lipid soluble?

Answer 22

if given orally, need to be water soluble to dissolve in the aqueous environment of the GI tract and so be available for absorption

N.B. most drugs are either weak acids or bases, so exist ionised and unionised

Question 23

What two things determine whether a drug is ionised or not?

Answer 23

1. the dissociation constant (pKa)

2. the pH in that part of the body

Question 24

If pKa of a drug= pH of the tissue are equal, then what % of the drug is ionised?

Answer 24

the drug will be equally dissociated–> 50% ionised and 50% unionised

N.B. a weak acid will be more unionised in areas of low pH like the stomach and a weak base will be more unionised in areas of high pH like blood and urine

Question 25

Where are the most important carrier systems responsible for drug access in the body?

Answer 25

• renal tubule (excretion of drugs)
• biliary tract
• GI tract (absorption allowing drug access to bloodstream)
• blood brain barrier (absorption across)

Question 26

What 4 factors influence tissue distribution of drugs?

Answer 26

1. regional blood flow: more drug distributed to tissues that receive most blood flow
2. plasma protein binding: drugs can bind to plasma proteins once in systemic circulation
3. capillary permeability
4. tissue localisation: lipid soluble drugs will be ‘localised’ in fatty areas (e.g. brain) compared to water soluble drugs, which will be more in plasma (as blood has higher water content)

Question 27

What 3 factors determine the amount of drug that is bound to plasma proteins?

Answer 27

1. the free drug concentration
2. the affinity for the protein binding sites
3. the plasma protein concentration
   N.B. differences in the extent of plasma protein binding for individual drugs is largely due to the particular affinity for the protein binding sites for that particular drug (acidic drugs bind well to albumin)
   *only free drug can diffuse out of blood into tissues

Question 28

What type of capillary structure is found at the blood brain barrier?

Answer 28

continuous structure w/ tight junctions between endothelial cells
–> so most difficult tissue in body for drugs to access

Question 29

What is an example of a tissue with discontinuous capillary structure and why?

Answer 29

• liver
• bc key metabolic tissue, dealing w/ metabolism of a huge variety of chemicals, incl. most drugs
• big gaps between capillary endothelial cells allow for drugs to easily diffuse out of blood to liver tissue

Question 30

What is an example of a tissue with fenestrated capillary structure and why?

Answer 30

• glomerulus of kidney
• bc key excretion tissue (incl. drugs)
• fenestrations= circular windows within endothelial cells, allowing passage of small substances–> so some small drugs can pass from blood to kidney tubules for excretion

Question 31

Why does metabolism involve the conversion of drugs to water soluble metabolites?

Answer 31

so that they are easier to excrete, as more would be retained in the blood

Question 32

What enzymes in the liver are responsible for the majority of drug metabolism?

Answer 32

cytochrome P450 enzymes

Question 33

What 2 types of biochemical reaction does drug metabolism involve?

Answer 33

• phase 1: main aim is to introduce a reactive group to drug (OH, COOH, SH, NH2)
• phase 2: main aim is to add a conjugate to reactive group, making the metabolite inactive–> becomes even less lipid soluble than phase 1 metabolite

*both stages act together to dec. lipid solubility/inc. water solubility–> aids excretion and elimination

Question 34

What are ‘pro-drugs’?

Answer 34

parent drugs that have no activity and only produce an effect once they have been metabolised–> metabolism is required for the pharmacological effect

Question 35

What types of enzymes are predominantly involved in phase 1 and 2 of drug metabolism?

Answer 35

• phase 1 enzymes are mostly part of the cytochrome p450 family
• phase 2 enzymes are mostly transferases to transfer the substituent group onto phase 1 metabolite

Question 36

What is first pass (presystemic) metabolism?

Answer 36

• orally administered drugs are predominantly absorbed from the small intestine–> enter hepatic portal blood supply–> so pass through liver before reaching systemic circulation
• the drug can be heavily metabolised in liver, so little active drug reaches systemic circulation
• N.B. first pass metabolism= prerequisite for activity of prodrugs

Question 37

What is the solution to first pass metabolism of drugs and what is the problem?

Answer 37

• solution= give larger dose so enough drug reaches systemic circulation
• problem= extent of first pass metabolism varies amongst individuals (so amount of drug reaching systemic circulation also varies)–> drug effects and side effects are difficult to predict

Question 38

What are the most important routes of excretion?

Answer 38

• via kidney in urine

- via liver in bile

Question 39

What are the 3 major routes for drug excretion via the kidney?

Answer 39

1. glomerular filtration (dependent on size…small drugs)
2. active tubular secretion/reabsorption (dependent on available transporters…basic and acidic drugs)
3. passive diffusion across tubular epithelium (dependent on urine pH + extent of drug metabolism…lipid soluble drugs reabsorbed into blood)

Question 40

Why is more drug delivered to the proximal tubule than the glomerulus?

Answer 40

• only 20% of renal plasma is filtered at the glomerulus, whereas the other 80% passes on to the blood supply at the proximal tubule–> therefore more drug is delivered
• there are 2 active transport carrier systems (one each for acidic/basic drugs) within the proximal tubule capillary endothelial cells

Question 41

What 2 factors influence the extent of reabsorption of drugs from the kidney tubule?

Answer 41

1. drug metabolism: phase 2 metabolites tend to be more water soluble than the parent drug, so they are less well reabsorbed (as drugs that are particularly lipid soluble get reabsorbed)
2. urine pH: can vary from 4.5-8 (pH partition hypothesis states that acidic drugs will be better reabsorbed at lower pH and basic drugs at higher pH)

Question 42

What is the route of drugs from liver cells to the faeces?

Answer 42

• liver cells transport some drugs from plasma to bile via transporters (particularly effective at removing phase 2 glucuronide metabolites)
• drugs are then excreted from the bile into the intestines–> then eliminated in the faeces

Question 43

What is the process of enterohepatic drug recycling (use a glucuronide metabolite as an example)?

Answer 43

1. glucuronide metabolite transported into bile
2. metabolite is excreted into small intestine, where it is hydrolysed by gut bacteria–> releases glucuronide conjugate
3. loss of conjugate increases lipid solubility of molecule
4. inc. lipid solubility allows greater reabsorption from small intestine back into hepatic portal blood system for return to liver
5. molecule returns to liver where some will be re-metabolised, and some may escape into systemic circulation to continue to have effects on the body
   - -> PROLONGED DRUG EFFECT