Intro to Pharmacology

Question 1

What is the difference between Pharmacology and Therapeutics?

Answer 1

Pharmacology = drug action 
Therapeutics = drug prescribing and treatment (patient-focused)

Question 2

What is the difference between pharmacodynamics and pharmacokinetics?

Answer 2

Pharmacodynamics = what the drug does to the body 
Pharmacokinetics = what the body does to the drug

Question 3

What 3 questions can be asked about a drug to understand its pharmacodynamics?

e.g. what would you comment on the pharmacodynamics of cocaine?

Answer 3

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

Cocaine: effect = euphoria; target = dopamine reuptake protein on the pre-synaptic terminal; response = blocks dopamine reuptake

Question 4

Drug target sites tend to be proteins.

What are the 4 main drug target sites in the body? Give an example of a drug for each type of target site:

Answer 4

Receptors - nicotine
Enzymes - aspirin
Ion channels - local anaesthetis
Transport proteins - prozac (anti-depressant)

Question 5

What is selectivity?

Why do drugs require high levels of selectivity?

Why is it hard to achieve complete selectivity for drugs?

Answer 5

The degree to which a drug acts on a given site relative to other sites

To reduce the number of side effects

A lot of drugs and chemicals are structurally quite similar

Question 6

How does the selectivity of a drug affect the dosage given? e.g. if a drug is 50 times more selective for target A than target B?

Answer 6

A specific dosage of a drug will begin to show effects at its primary target site e.g. target A. If the drug is 50x more selective for target site A than B, then 50x that dosage will be required to start seeing effects at target B

Question 7

So why is it important to keep drug dosages as low as possible but still treating the issue?

Answer 7

At a low dose, the effect you see is more specific, due to the fact that the drug will only interact with one target. As the dose increases, the effect becomes less specific, because the drug starts to interact with other drug targets producing other unwanted effects

Question 8

Pergolide is a drug used to treat Parkinson’s.

What receptor does it primarily act on and what other receptors can it affect at higher doses?

Answer 8

Dopamine receptors primarily

Can also bind to serotonin receptors and adrenergic receptors

Question 9

What are the 4 different chemical interactions drugs can use to interact with target sites?
(HINT: think chemistry - bonding)

Answer 9

1. Electrostatic interactions - most common, includes hydrogen bonds and Van der Waals forces.
2. Hydrophobic interactions -lipid soluble drugs
3. Covalent bonds - least common, interactions tend to be irreversible
4. Stereospecific interactions - many drugs exist as stereoisomers and interact stereospecifically with receptors

Question 10

What is the equilibrium formed by drugs, receptors, and drug-receptor complexes?

How does an increase or decrease in drug affect this equilibrium?

Answer 10

Drugs + receptors –> drug-receptor complex

Increase in drugs shifts equilibrium to the right as more complexes are formed
Decrease in drugs shifts equilibrium to the left as more receptors are remain unoccupied

Question 11

What is the difference between agonists and antagonists?

Answer 11

Both fit the target site
Agonists = activate the target site
Antagonists = occupy the target site, so the true molecule cannot bind to the target site to activate it

Question 12

What is meant by the affinity of a drug?

Answer 12

Strength of binding of the drug to the receptor

Higher affinity = stronger bond

Question 13

What is meant by the efficacy of a drug?

Answer 13

Ability of an individual drug molecule to produce an effect once bound to a receptor
Higher efficacy = more complete response

Question 14

So how does efficacy of drugs relate to antagonist / agonist effects?

Answer 14

No response from drug binding to target site = antagonist
Partial response from drug binding to target site = partial agonist
Complete response from drug binding to target site = complete agonist

Question 15

What is meant by the potency of a drug?

So what is the standard measure of potency?

Answer 15

The concentration or dose of a drug required to produce a defined effect - higher potency = lower dosage required

Standard measure of potency is to determine the concentration (EC50) or dose (ED50) of a drug required to produce a 50% tissue response

Question 16

What is the difference between EC50 and ED50?

Answer 16

The concentration that produced a 50% response would be the EC50
When responses are vague e.g. reduction in breathlessness, the dose of drug that produced the desired effect in 50% of the individuals tested

Question 17

Why is only potency linked to dosage, but not efficacy?

Answer 17

Efficacy is to do with the response from the drug, so a more potent drug will require a smaller dosage for maximal response compared to a less potent drug. But both drugs still give a maximal response, just at different dosages

Question 18

What are the 4 major pharmacokenetic factors affect the amount of drug reaching the tissues?

Answer 18

1. Absorption
2. Distribution
3. Metabolism
4. Excretion

Question 19

What is meant by absorption in pharmacokenetics?

What is meant by bioavailability?

How are absorption and bioavailability different?

Answer 19

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

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

Absorption = process of drug getting into the system VS Bioavailability = how much drug gets into the system

Question 20

What are some common forms of drug administration?

Answer 20

1. Oral
2. Inhalational
3. Dermal (Percutaneous)
4. Intra-nasal

Question 21

What are the 2 main ways drugs can move around the body?

Answer 21

1. Bulk flow transfer (i.e. in the bloodstream)

2. Diffusional transfer (i.e. molecule by molecule across short distances)

Question 22

Other than intravenous administration, why do other forms of drug administrations not have 100% bioavailability?

Answer 22

With all other forms of administration, in order for the drug to reach the bloodstream it is first going to need to diffuse across at least one lipid membrane

Question 23

What are the 4 ways chemicals can diffuse across plasma membranes?

Which of these 2 ways are used by drugs and why not the other 2?

Answer 23

1. Pinocytosis - cell membrane envelopes drug into vesicle then releases the drug on other side of the membrane
2. Diffusion across aqueous pores - gaps between endo/epi-thelial cells
3. Diffusion across lipid membranes
4. Carrier mediated transport - drugs binds to transmembrane protein, which then transfers them across to the other side of the membrane

3 and 4 are most common, 1 is rarely used by drugs, and 2 is also rarely used by drugs as the gaps between the cells are so small

Question 24

Most drugs tend to be more water soluble than lipid soluble.

How can a drug exist in both forms - a water soluble and lipid soluble version?

Answer 24

The drug can exist as an ionised and unionised form. e.g. unionised = OH, NH3 | ionised = O-/H+, NH4+ depending on if they are a weak acid or base

Question 25

How does pKa and pH affect whether the drug is in its ionised or unionised form?

Answer 25

``` pKa = dissociation constant pH = [H+] ``` 1. pKa of drug = pH of tissue, then the drug will be equally dissociated between the two forms 2. Aspirin = weak acid = pKa of 3.5. For weak acids, as the pH decreases, the unionised form starts to dominate. As the pH increases, the ionised form starts to dominate. 3. Morphine = weak base = pKa of 8.0. For weak bases, as the pH decreases, the ionised form starts to dominate. As the pH increases, the unionised form starts to dominate.

Question 26

Why is it not an issue if weak basic drugs get trapped in the stomach, and weak acidic drugs get trapped in the blood?

Answer 26

Weak basic drug in stomach will pass through the stomach and get absorbed in the small intestine via transport proteins Weak acidic drug in the blood will circulate the body until it meets transport proteins on tissues that allows it to get across the membrane

Question 27

What are the 4 most important carrier systems relating to drug action? What is the purpose of these carrier systems?

Answer 27

1. Renal tubule 2. Biliary tract 3. Blood brain barrier 4. Gastrointestinal tract Carrier systems = drug access to the bloodstream, drug access to certain tissues, and excretion of drugs from the body

Question 28

What factors influence different tissues to have different amounts of exposure to the drug?

Answer 28

1. Regional blood flow: different tissues receive different percentages of the cardiac output - Liver = 27%, Heart = 4%, Brain = 14%, Kidneys = 22%, Muscles = 20% 2. Plasma protein binding - drugs binding to proteins such as albumin 3. Capillary permeability - different capillaries have different spaces between the endothelial cells 4. Tissue localisation - whether they are more lipid based or water based as that affects equilibrium achieved when drugs diffuse in

Question 29

What can regional blood flow be affected by?

Answer 29

Exercise - more blood flow to muscles | Ingestion / digestion - more blood flow to digestive system

Question 30

What 3 factors is the amount of drug bound to plasma proteins dependent on? How do the 3 factors link together?

Answer 30

The free drug concentration The affinity for the protein binding sites The plasma protein concentration D (Free Drug) + P (Protein binding site) ↔ DP (Drug-protein binding site)

Question 31

Can drugs bound to plasma proteins diffuse into tissues? Are acidic or basic drugs more likely to bind to albumin?

Answer 31

No - drug must dissociate from protein first Acidic

Question 32

What are the 4 different types of capillary structures? Where are they found?

Answer 32

1. Continuous - H2O filled junctions, most common 2. Blood brain barrier - tight junctions, brain, highly controlled what can access brain tissue 3. Fenestrated - allow passage of small molecular weight substances, found in the glomerulus (kidney) 4. Discontinuous - found in the liver, random big gaps between capillary endothelial cells for metabolism

Question 33

How can drugs be localised to certain tissues / areas?

Answer 33

If a drug is lipid based, it is more likely to be retained in lipid based tissue than water based tissue and vice versa Lipid soluble drugs diffuse according to lipid gradient - and that affects equilibrium Water soluble drugs diffuse according to water gradient - and that affects equilibrium

Question 34

How are drugs metabolised in the liver to aid elimination and excretion of the drug? What are the 2 steps?

Answer 34

Phase 1: introduce a reactive group to the drug Phase 2: add a conjugate to the reactive group Both stages together act to decrease lipid solubility which then aids excretion and elimination

Question 35

What does phase 1 metabolism in the liver do? What is the most common method in phase 1 metabolism?

Answer 35

Introduce reactive polar groups into their substrates via oxidation, reduction and hydrolysis Oxidation reactions = starts with a hydroxylation step utilising enzymes from cytochrome P450 family. The aim is to incorporate oxygen into non-activated hydrocarbons

Question 36

What are pro-drugs?

Answer 36

Drugs that are given in an inactive form, then produce an effect once it has been metabolized to the respective metabolite Usually occurs in Phase 1 e.g. liver damage from paracetamol overdose is from a metabolite, not paracetamol itself

Question 37

What does phase 2 metabolism in the liver do?

Answer 37

The attachment of a substituent group so metabolite is nearly inactive and less lipid soluble than the phase 1 metabolite = facilitates excretion in the urine or bile Enzymes = predominantly transferases

Question 38

What is meant by first pass metabolism? What is the problem with first pass metabolism? What is the solution? What is the problem with the solution?

Answer 38

Usually for orally administered drugs - absorbed from the small intestine and enter hepatic portal blood supply where they first pass through the liver before they reach the systemic circulation. Problem - the drug by then is heavily metabolized so little active drug reaches systemic circulation Solution - administer a larger dose Problem with solution - the extent of first pass metabolism varies amongst individuals, side effects hard to predict

Question 39

What are the different routes via which drugs can be excreted?

Answer 39

The 2 most common are via the kidneys (in the urine) or via the liver (in bile) Or else, via the lungs (e.g. alcohol breath test) or breast milk

Question 40

What are the 3 major routes of drug excretion via the kidneys?

Answer 40

1. Glomerular filtration - molecular weight less than 20,000 2. Active tubular secretion (or reabsorption) - proximal tubule capillary endothelial cells have two active transport carrier systems (one for basic, one for acidic) 3. Passive diffusion across tubular epithelium - generally leads to reabsorption (esp. if they are lipid soluble) from the kidney tubule but that can depend on pH of urine (acidic reabsorbed more at lower pH, basic reabsorbed better at higher pH)

Question 41

How are drugs excreted via the biliary system?

Answer 41

Liver cells transport some drugs from plasma to bile – via transporters Effective at removing phase 2 glucuronide metabolites. Drugs in the bile are then excreted into the intestines and eliminated in the faeces

Question 42

What is enterohepatic recycling and why does it significantly prolong drug effect?

Answer 42

1. A glucuronide metabolite is transported into the bile 2. The metabolite = excreted into small intestine, 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