Principles Of Pharmacology

Question 1

Pharmacodynamics vs pharmacokinetic

Answer 1

What the drug does to the body vs what the body does to the drug

Question 2

Pharmacodynamics qs

Answer 2

Where is the effect
What is the target
What is the response
Eg with cocaine effect is in the nucleus accumbens,target is dopaminergic neurones and response is cocaine with block the dopamine reuptake

Question 3

Drug targets

Answer 3

Receptors eg nicotine activates nach
Enzymes eg aspirin binds to cyclooxygenase and blocks prostaglandins production
Ion channels eg local anaesthetics block sodium ion channels
Transport proteins eg anti depressants block seratonin from, being removed

Question 4

Drug dose and selectively

Answer 4

Drugs can be selective for certain receptors but also be able to bind to other receptors eg

Question 5

Drug interactions

Answer 5

Electrostatic interactions - this is the most common mechanism and includes hydrogen bonds and Van der Waals forces.
Hydrophobic interactions - this is important for lipid soluble drugs.
Covalent bonds - these are the least common as the interactions tend to be irreversible
Stereospecific interactions - a great many drugs exist as stereoisomers and interact stereospecifically with receptors.

Question 6

Affinity and efficacy

Answer 6

Agonists and antagonists bind to receptors but only agonists can bind and activate receptors
Affinity of drug determines strength of binding of drug to the receptors. Thus affinity strongly linked to receptor occupancy.

Efficacy is the ability for the individual drug molecule to produce and effect once bound to a receptor

Question 7

Potency

Answer 7

Potency refers to the concentration or dose of a drug required to produce a defined effect.
The standard measure is to determine to concentration or dose required to produce a 50 % tissue response

The standard nomenclature for this measure is the EC50 (Half maximal effective concentration or the ED50 (Half maximal effective dose)

Question 8

The difference between EC50 and ED50

Answer 8

EC50 is where your testing concentrates on in vitro preparation

Ed50 is where you look for the dose of drug that produced desired effect in 50% of individuals tested

Question 9

Pharmacokinetics factors

Answer 9

Absorption
Distribution
Metabolism
Excretion

Question 10

Absorption and Bioavailability

Answer 10

absorption can be defined as the passage of a drug from the site of administration into the plasma.
Bioavailability is the fraction of the initial dose that gains access to the systemic circulation.

Absorption deals with process for drug transfer into systemic circulation and bioavailability deals with outcome of drug transfer into systemic circulation

Question 11

What derermines absorption and bioavailability

Answer 11

Site of administration
Eg intravenous injection
Oral
Inhalation
Dermal
Intra nasal
Bioavailability would be less than 100% as diffusioanl transfer occurs for most whereas for injection bulk flow transfer into the bloodstream occurs

Question 12

Diffusion

Answer 12

-pinocytosis: involves a small part of the cell membrane enveloping the chemical molecule and forming a vesicle containing the drug. The vesicle can then release the chemical on the other side of the membrane
-diffusion across aqueous pores (less common as pores are too small)
Simple diffusion,carrier mediated,diffusing across lipids

Question 13

Lipid solubility

Answer 13

Most drugs are more water soluble than lipid to allow dissolving in GI tract
Most drugs are weak acids and bases so can be ionized or unionized.
In the unionized form the drug retains lipid solubility.

Question 14

What does drug ionization depend on

Answer 14

1. Dissociation constant (pka)- if the pka of the drug and ph are equal of this tissue the drug will equally dissociate

2.the ph in that part of the body-eg aspirin is a weak acids and bases with pka 3.5 (3-5) so when ph is 3.5 it will equally dissociate. For weak acids if ph decreases unionized form dominates. Morphine is a weak base pka 8-10 for this when ph decreases ionized form dominates
As a result weak acid is more unionized in low ph like stomach and weak base is more unionized in high ph like blood and urine

Question 15

Why aren’t weak bases trapped in the stomach and weak acids trapped in blood

Answer 15

A weak base will indeed be poorly absorbed from the stomach due to the low pH leading to a high drug ionisation. However, once the drug eventually reaches the small intestine, it will be able to access a huge number of transport proteins that will enable absorption from the gastrointestinal tract.
A weak acid could potentially be absorbed from the stomach in its unionised state. However, it would then become more ionised at physiological pH and potentially become ‘trapped’ in the blood. Once again, however, most tissues possess transport proteins that could potentially move the ionised drug from the blood into the tissue.

Carrier systems-renal tubule,biliary tract,blood brain barrier,GI tract

Question 16

What is distribution affected by

Answer 16

Regional blood flow
Plasma protein binding
Capillary permeability
Tissue localisation

Question 17

Regional blood flow

Answer 17

Different tissues receive different amounts of blood. At rest this would be
Liver – 27%

Heart– 4%
Brain – 14%
Kidneys – 22%
Muscles – 20%

More drug distributed to tissues which receive the most blood flow

Question 18

Plasma protein binding

Answer 18

Drugs often bind to plasma proteins once in circulation most commonly albumin which binds acidic drugs well.
Amount of drug bound depends on :
1.free drug concentration
2.affinity for protein binding site
3.plasma protein’s concentration
Only free drug can diffuse out of blood and access tissues,other drugs cannot leave blood until it dissociates from the protein

Question 19

Capillary permeability

Answer 19

Majority of capillaries have continuous structure . If drugs less soluble they need to be transported via carrier proteins. . Brain is most difficult to access as it has a continuous structure with tight junctions
Discontinuous-eg liver where majority of drugs are metabolized
Fenestrated-eg glomerulus involved in excretion of chemicals. Allows small molecular weight substances to pass

Question 20

Tissue localization

Answer 20

THC (cannabis) will diffuse out of the blood down its concentration gradient into the brain reaching equilibrium
A water soluble drug will do the same
The position if equilibrium will differ as the Braun has the higher fat content whereas the blood has higher water content so THC would be weighted towards brain and water soluble drug towards plasma

Question 21

Drug metabolism

Answer 21

Drug needs to be partially lipid soluble so it can access tissues to produce effect but should be converted into water soluble metabolites to ease excretion
P450 in liver is the major group which works by :phase 1 introducing a reactive group to the drug and phase 2 adding a conjugated to the reactive group
This decreases lipid solubility

Question 22

Phase 1 metabolism

Answer 22

The aim of phase 1 metabolism is to introduce reactive polar groups into their substrates
Done via oxidation reduction and hydrolysis
Common form is oxidation
Often added to OH,COOH,SH,NH2 group

Question 23

Pro drugs

Answer 23

Parent drug has no activity of its own only producing an effect once metabolized to respective metabolite
Metabolism would be required for the pharmalogical affect

Question 24

Phase 2 metabolism

Answer 24

Adds a substitute T group and the resulting metabolite in nearly always inactive and less lipid soluble than phase 1 metabolite
This allows excretion in urine or bile

Question 25

Common phase 1 and 2 conjugated

Answer 25

Oxidation->electrophile formation->gluthathione conjugation

Reduction->nucleophile->glucuronidation,acetylation,sulfation

Phase 2 predominantly transferases to transfer group to phase 1 metabolite

Question 26

First pass (presystemic) metabolism

Answer 26

Orally administered drugs are absorbed from the small intestine and ensure the hepatic portal blood supply where they pass the liver before reaching systemic circulation
At this point the drug can be heavily metabolized so little active drug reaches systemic circulation
Solution-administer larger dose of drug to ensure enough reaches

Problem-the extent of first pass metabolism varies and thus amount of drug reaching systemic circulation varies

Question 27

Excretion

Answer 27

Lots of routes
Eg via lungs (alcohol breath test measures this)
Breast milk (careful that drugs excreted don’t affect baby)
Commonly via urine or bile

Question 28

Kidney excretion

Answer 28

1. Glomerular filtration (depends on size)
2. Active tubular secretion (or reabsorption) (depends on available transporters)
3. Passive diffusion across tubular epithelium (depends on urine ph and extent of drug metabolism)

Question 29

Glomerular filtration

Answer 29

Glomerular filtration allows drug molecules of molecular weight less than 20,000 to diffuse into the glomerular filtrate. This obviously means that drugs with a molecular weight less than 20,000 have an additional route for excretion (glomerular filtration) compared with larger drugs – as a result, this should result in a quicker rate of excretion.

Question 30

Active tubular secretion

Answer 30

Active tubular secretion is the most important method for drug excretion in the kidney. Firstly, whereas only 20% of the renal plasma is filtered at the glomerulus, the remaining 80% of the renal plasma passes onto the blood supply to the proximal tubule. Therefore, more drug is delivered to the proximal tubule than the glomerulus. Secondly, within the proximal tubule capillary endothelial cells are two active transport carrier systems. One is very effective at transporting acidic drugs and one is very effective at transporting basic drugs. Both are quite capable of transporting drugs against a concentration gradient.

Question 31

Passive diffusion

Answer 31

Passive diffusion generally leads to reabsorption from the kidney tubule. As glomerular filtrate moves through the kidney, most of the water filtered (99%) is reabsorbed. If drugs are particularly lipid soluble, then they will also be reabsorbed, passively diffusing across the tubule back into the blood. The factors that will influence the extend of reabsorption;
1. Drug metabolism – phase 2 metabolites tend to be considerably more water soluble than the parent drug and are therefore less well reabsorbed.
2. Urine pH – this can vary from 4.5-8. Based on the pH partition hypothesis mentioned previously, acidic drugs will be better reabsorbed at lower pH and basic drugs will be better reabsorbed at higher pH.

Question 32

Biliary excretion:

Answer 32

Second major route is via bile
Liver cells transport some drugs from plasma to bile via transporters similar to those in the kidney. These are excreted into intestine and eliminated via faeces
Very affective in removing phase 2 metabolites glucoronide

Question 33

What process elongates drug effect and give an example

Answer 33

Enterohepatic recycling

1. A glucuronide metabolite is transported into the bile.
2. The metabolite is excreted into the small intestine, where it is hydrolysed by gut bacteria releasing the glucuronide conjugate.
3. Loss of the glucuronide conjugate increases the lipid solubility of the molecule.
4. Increased lipid solubility allows for greater reabsorption from small intestine back into the hepatic portal blood system for return to the liver.
5. The molecule returns to the liver where a proportion will be re-metabolised, but a proportion may escape into the systemic circulation to continue to have effects on the body.

Question 34

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

Answer 34

Efficacy is more important. You want to know if the drug you are giving can induce a maximal response. The potency simply determines the dose that you will need to administer to produce a response. If you have two drugs that have equal efficacy, then it doesn’t really matter if one is more potent than the other, since you can still produce the maximal response with the less potent drug – you just need to administer a slightly higher concentration.

Question 35

You are taking Drug A as an analgesic – it is a weak acid. The urine pH suddenly increases from 6.5 to 8. Will the drug effect be prolonged or reduced over the next few hours?

Answer 35

Drug A is a weak acid. If the urine pH increases to 8, then Drug A will become more ionized in the alkaline environment. This will decrease the lipid solubility of Drug A. As a result, less of the drug will be reabsorbed in the kidney tubule, and more will be excreted. The drug effect will be reduced due to this more effective excretion.