Principles of Pharmacology

Question 1

Contrast pharmacology and therapeutics

Answer 1

Pharmacology is the study of drug action. Therapeutics is concerned with drug prescribing and the treatment of disease.

Question 2

What are the 3 questions pharmacodynamics is concerned with?

Answer 2

Where is this effect produced?
What is the target for the drug?
What is the response that is produced after interaction with this target?

Question 3

Describe pharmacodynamics of cocaine

Answer 3

Acts on: dopaminergic neurons of nucleus accumbens
Target: dopamine reuptake protein on the pre-synaptic terminal (point at which drug binds)
Response: Cocaine will BLOCK the dopamine reuptake protein. This means that dopamine is not removed from the synapse as quickly, and is thus more available to bind to the dopamine (D1) receptor. Activation of this receptor is what causes euphoria.

Question 4

What are the 4 drug targets?

Answer 4

1. Receptors
2. Enzymes
3. Ion channels
4. Transport proteins

Question 5

What must a drug do in order to be effective?

Answer 5

For a drug to be an effective therapeutic agent it must show a high degree of selectivity for a particular drug target. Structural similarity between chemicals reduces this selectivity.

Question 6

What are the 4 ways drugs can interact with their receptors?

Answer 6

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

Question 7

What is the difference between agonists and antagonists?

Answer 7

Both agonists and antagonists possess the ability to bind to receptors, but only agonists can bind and activate receptors.

Question 8

Define affinity

Answer 8

The affinity of a drug determines strength of binding of the drug to the receptor. The strength of each drug-receptor complex is determined by the affinity of the drug. As a result, affinity is strongly linked to receptor occupancy.

Question 9

Define efficacy

Answer 9

Efficacy refers to the ability of an individual drug molecule to produce an effect once bound to a receptor.

Question 10

Define antagonists in terms of affinity and efficacy

Answer 10

A receptor agonist essentially has affinity but no efficacy. When bound to the receptor, it is effectively ‘blocking’ that receptor and preventing an agonist from binding to the receptor and inducing activation.

Question 11

Define partial-agonists in terms of affinity and efficacy

Answer 11

A partial agonist has affinity for receptor and sub-maximal efficacy. When bound to the receptor, it can produce a partial response, but cannot induce the maximal response from that receptor.

Question 12

Define agonists in terms of affinity and efficacy

Answer 12

A receptor agonist has affinity for the receptor and maximal efficacy. When bound to the receptor, it can produce the maximal response expected from that receptor.

Question 13

Define potency

Answer 13

Potency refers to the concentration or dose of a drug required to produce a defined effect.

Question 14

How is potency actually defined?

Answer 14

As a result, the standard measure of potency is to determine the concentration or dose of a drug required to produce a 50% tissue response.

Question 15

What is EC50 and ED50?

Answer 15

EC50 (Half maximal effective concentration) or the ED50 (Half maximal effective dose). EC50 is the concentration that produced a 50% response, usually determined in the in vitro stage of experimentation. ED50 is the dose of drug that produced the desired effect in 50% or the individuals tested.

Question 16

Contrast potency and efficacy

Answer 16

A highly potent drug produces a large response at relatively low concentrations.
A highly efficacious drug can produce a maximal response and this effect is not particularly related to drug concentration.

Question 17

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

Answer 17

Efficacy is more important as need to know if drug given can induce a maximal response. The potency simply determines the dose that you will need to administer to produce a response.

Question 18

How is absorption defined in pharmacokinetics?

Answer 18

Absorption can be defined as the passage of a drug from the site of administration into the plasma.

Question 19

Define bioavailability

Answer 19

Bioavailability is the fraction of the initial dose that gains access to the systemic circulation.

Question 20

What is a large determinant of absorption and bioavailability?

Answer 20

Site of administration (underlined in the definition of absorption) is a huge determinant of absorption and bioavailability. The process for drug passage is injecting the full dose straight into the circulation. The outcome if the full dose is administered straight into the circulation is that the bioavailability must be 100%.

Question 21

What are the forms of drug administration?

Answer 21

Oral
Inhalational
Dermal (Percutaneous)
Intra-nasal
Injecting

Question 22

Why is bioavailability usually less than 100%?

Answer 22

Drugs can move around the body either through bulk transfer (bloodstream) or diffusional transfer (molecule by molecule across short distances). Unless injected into bloodstream, drugs need to move across at least one lipid membrane before entering bloodstream which will take it to its intended site of action.

Question 23

What are the 4 form of diffusional transport?

Answer 23

Simple diffusion, Diffusion across aqueous pores, Carrier mediated transport and Electrochemical gradients.

Question 24

Define pinocytosis

Answer 24

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. Insulin accesses brain this way. Not a regular method of transport.

Question 25

Is the aqueous route a regular method of trasnport?

Answer 25

Diffusion across aqueous pores i.e. the gaps between epithelial/endothelial cells that make up the membrane, is also not a major route for movement of drugs across membranes. Most pores are less than 0.5nm in diameter, and since there are very few drugs this small, there is little movement of drugs across this aqueous route.

Question 26

When do weak acids and weak bases have greater lipid solubility?

Answer 26

The unionised form of the drug retains more lipid solubility and is more likely to diffuse across plasma membranes.

Question 27

What does the ionisation status of a drug depend on?

Answer 27

Whether the drug is unionised or not is going to depend on two things - 1. the dissociation constant (pKa) for that drug and 2. the pH in that particular part of the body.

Question 28

How do weak acids act in different environments?

Answer 28

For weak acids, as the pH decreases, the unionised form starts to dominate. As the pH increases, the ionised form starts to dominate.

Question 29

How do weak bases act in different environments?

Answer 29

For weak bases, as the pH decreases, the ionised form starts to dominate. As the pH increases, the unionised form starts to dominate.

Question 30

Where are the most important carrier systems related to drug action found in the body?

Answer 30

1) Renal tubule
2) Biliary tract
3) Blood brain barrier
4) Gastrointestinal tract

Question 31

What are the 4 factors influencing tissue distribution?

Answer 31

1. Regional blood flow
2. Plasma protein binding
3. Capillary permeability
4. Tissue localisation

Question 32

Why is regional blood flow important?

Answer 32

More drug will be distributed to those tissues that receive most blood flow. However, blood flow to various locations can change e.g. greater amount of blood to muscles during exercise or a greater amount of blood to digestive system after a meal.

Question 33

Why is plasma protein binding important?

Answer 33

Once drugs reach the systemic circulation, it is very common for them to bind to plasma proteins. Amount of drug that binds depends on:

1. The free drug concentration
2. The affinity for the protein binding sites
3. The plasma protein concentration

Question 34

Why is the binding capacity of albumin important?

Answer 34

The concentration of albumin in the blood is approximately 0.6mmol/l. Each albumin protein has two binding sites. As a result the binding capacity of albumin alone is 1.2mmol/l. The plasma concentration required for a clinical effect for nearly all drugs is considerably less than 1.2mmol/l plasma proteins are NEVER saturated with drugs.

Question 35

Why is the lipid solubility of drugs important?

Answer 35

Most of the capillaries in the body have a continuous structure with endothelial cells aligned in single file with small gap junctions between the cells. If drugs are very lipid soluble then they can diffuse across the endothelial cell and access the tissue.

Question 36

Why is the liver easier to access for drugs?

Answer 36

A discontinuous capillary structure (big gaps between capillary endothelial cells) allows for drugs to easily diffuse out of the bloodstream and access the liver tissue.

Question 37

Why is the kidney easier to access for drugs?

Answer 37

Fenestrations are circular windows within endothelial cells that allow for passage of small molecular weight substances including some drugs. This allows for some small drugs to pass from blood to kidney tubules which will enhance excretion of these drugs.

Question 38

How does tissue localisation affect distribution?

Answer 38

Drug will be retained in location where it dissolves more easily. Therefore, must have a contents mirroring the makeup of the location in which it needs to be retained.

Question 39

What quality should drugs have for optimal metabolism?

Answer 39

The process of metabolism involves the conversion of drugs to metabolites that are as water soluble as possible and easier to excrete.

Question 40

Where does the major amount of drug metabolism occur?

Answer 40

The major metabolic tissue is the liver. Within the liver, it is mainly cytochrome P450 enzymes that are responsible for drug metabolism. Drug metabolism involves two kinds of biochemical reaction:
1. Introduce reactive group to drug
2. Conjugate reactive group
This reduces lipid solubility and makes drug easier to excrete.

Question 41

What are the types of phase 1 reactions that can occur?

Answer 41

Oxidation, reduction and hydrolysis. The most common form of Phase 1 metabolism is oxidation. However, all oxidation reactions start with a hydroxylation step utilizing the cytochrome P450 system. The aim is to incorporate oxygen into non-activated hydrocarbons.

Question 42

What are pro-drugs?

Answer 42

When the parent drug has no activity of its own, and will only produce an effect once it has been metabolized to the respective metabolite - this result is known as a pro-drug.

Question 43

What enzymes drive phase 2?

Answer 43

Whereas the phase 1 enzymes are predominantly part of the cytochrome p450 family, the phase 2 enzymes are predominantly transferases to transfer the substituent group onto the phase 1 metabolite.

Question 44

What is first pass hepatic metabolism?

Answer 44

Orally administered drugs are predominantly absorbed from the small intestine and enter the hepatic portal blood supply where they will first pass through the liver before they reach the systemic circulation. At this point, the drug can be heavily metabolized and as a result, little active drug will reach the systemic circulation.

Question 45

What is the solution to first pass hepatic metabolism and a consequent problem?

Answer 45

Solution – administer a larger dose of drug to ensure enough drug reaches the systemic circulation.

Problem – the extent of first pass metabolism varies amongst individuals, and therefore the amount of drug reaching the systemic circulation also varies. As a result, drug effects and side effects are difficult to predict.

Question 46

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

Answer 46

1. Glomerular filtration
2. Active tubular secretion (or reabsorption)
3. Passive diffusion across tubular epithelium

Question 47

What kind of drugs can be expelled via glomerular filtration?

Answer 47

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.

Question 48

Why is active tubular secretion the most important method for drug excretion in the kidney?

Answer 48

More drug is delivered to the proximal tubule than the glomerulus since only 20% of renal plasma is filtered at glomerulus. The proximal tubule capillary endothelial cells have two active transport carrier systems - one for basic drugs and another for acidic and both capable or transporting actively.

Question 49

What factors influence extent of drug reabsorption via passive diffusion in the kidney?

Answer 49

If very lipid soluble, will most likely be reabsorbed into blood.

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 50

What is biliary excretion particularly useful for?

Answer 50

Particularly effective at removing phase 2 glucuronide metabolites. Drugs transported to the bile are then excreted into the intestines and will be eliminated in the faeces.

Question 51

How does enterohepatic recycling work?

Answer 51

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.