Topics 8, 9, 10, 11 - Pharmacology

Question 1

Define pharmacology

Answer 1

The study of drugs on living systems.

Question 2

Define pharmacodynamics

Answer 2

The mechanism of drug action

Question 3

Define pharmacokinetics

Answer 3

The absorption, distribution, metabolism (biotransformation) and excretion of a drug
Study on a quantitative basis

Question 4

Define agonist

Answer 4

A drug that binds to a receptor to produce an effect that mimics the action of neurotransmitters or hormones. Agonists have high affinity and intrinsic activity/efficacy.

Question 5

Define antagonist

Answer 5

A drug that decreases the activity of other drugs or endogenous ligands. Classic competitive antagonist have affinity but no efficacy.

Question 6

Define partial agonist.

Answer 6

Basically an agonist but it does not have maximal effect even if all receptors are occupied. Has affinity but less intrinsic activity/efficacy than agonists.
Can even act as antagonists in presence of full agonists.

Question 7

How do antagonists and agonists affect equilibrium?

Answer 7

Agonists shift equilibrium to the active state.

Antagonists don’t have an effect on equilibrium but prevent agonists from exerting their effect on tissues.

Question 8

What can cause a drug to have adverse effects?

Answer 8

Drugs bind to proteins in the living tissues to have an effect. These proteins will be present in other tissues in the body which is the reason why drugs can cause side effects (unintended actions of the drug).
Additionally, some drugs can have low specificity to the protein which causes more side effects.

Question 9

Name and explain the mechanism on 5 types of drug targets

Answer 9

1. Enzymes - drugs can target ACE and cyclo-oxygenase (important for NSAID metabolism)
2. Transporters - drugs can target receptors which control the entry and exit of substances into the cell e.g. anti-depressants
3. Ion channels - receptor operated ion channels require binding to open its channels to allow the movement of ions in and out of a cell. E.g. in LA, lidocaine binds to voltage gated sodium channels and blocks it so sodium ions can not go into the cell and depolarise it, so no action potential is produced and there’s no sensation of pain. Other examples include nicotine’s Acetylcholine which allows sodium ions to influx in response to non-depolarising neuromuscular blocker agents. And benzodiazapenes lead to chloride influx when GABA binds to its receptor.
4. Receptors. G-protein coupled receptors are complex receptors with 7 domains which span the cell membrane. When GTP binds, three subunits interact due to the activity of enzymes and ion channels inside the cell, and produce a response very rapidly and lasts a few mins. This is the mechanism for clinically useful drugs such as adrenoreceptors (alpha and beta methyldopa and salmeterol), antihistamines and mu opioid receptor (naloxone).
5. Nucleic acids. Ligand enters cell and binds to a receptor. The ligand-receptor complex then binds to a specific DNA sequence in the nucleus and alters gene expression. This is used in drugs like androgens, oestrogen, corticosteroids and maybe metronidazole. This is slow and takes hrs but may last for many days.

Question 10

What are some causes of drug response variability in people?

Answer 10

Some people will be resistant to drugs and some will be sensitive.
Depends on genetics, age, diet, comorbid disease, drug-drug interactions

Question 11

What are two measures you should look at before prescribing drugs?

Answer 11

1. Therapeutic index
   The window of activity where benefits outweigh risks. For narrow drugs, this means pt could very quickly experience toxicity. For wider windows, this means there’s a higher safety margin.
2. NNT
   The amount of people a drug needs to be prescribed to before one doesn’t suffer adverse effects. Want this to be as low as possible.

Question 12

Describe how drug responses can change over time.

Answer 12

Can become either sensitive or desensitised.
If prescribed an agonist, would become desensitised as receptors are down regulated. You’d experience tolerance or tachyphylaxis - diminished response.
If prescribed an antagonist, would become sensitive as receptors are up regulated. You’d experience super sensitivity because of changes in no. of receptors and/or changes in intracellular signalling.

Question 13

What are biologics and biosimilars?

Answer 13

A biopharmaceutical drug that has immunomodulatory properties and can repair, enhance and stimulate the immune response.
It is very specific and has wide ranging uses.
The activity depends on the biologically active agent it has e.g. insulin, erythropoietin and infliximab.
Infliximab is an anti-TNF monoclonal antibody. TNF is an inflammatory mediator and cytokine implicated in rheumatoid arthritis, ankylosing spondylitis and ulcerative colitis.
They are expensive and usually taken via injection or iv. Biosimilars have similar drug mechanism but at lower cost to NHS.

Question 14

How does infliximab work?

Answer 14

Infliximab is an anti-TNF monoclonal antibody. TNF is an inflammatory mediator and cytokine implicated in rheumatoid arthritis, ankylosing spondylitis and ulcerative colitis.

Question 15

Give a very basic overview of pharmacokinetics.

Answer 15

• Drug crosses a barrier like skin, gut walls or alveolar membrane to get into body.
• Then is carried around in blood to tissues where it crosses capillaries and cell walls.
• Depending how widely distributed the drug was, this affects the conc. which has knock-on effects onto metabolism and excretion.
• Then it’s metabolised. The enzymes act on the drug and it can undergo multiple biotransformations to become compounds. This can affect activity of the drug and it can become more or less active.
• Drug and metabolites excreted by kidneys or liver.

Question 16

What can alter effectiveness of drug and pt comfort with it?

Answer 16

ADME

Question 17

What two routes of absorption of a drug are there?

Answer 17

ENTERAL ROUTE - in or through the GIT system. Oral, rectal, buccal, sublingual.
PARAENTERAL ROUTE = any way other than GIT. IV, intramuscular, subcutaneous

Question 18

How can the absorption of tablets be slowed down?

Answer 18

Enteric coating can slow down drug absorption in the GIT and allow safe passage through the stomach

Question 19

What methods are there of a drug entering a cell?

Answer 19

• If molecular size is reasonable size, can diffuse into the cell e.g. in the glomerulus of the kidney
• If small, it can pass into the cell via pores like aquaporins e.g. alcohol and carbon dioxide
• Some drugs require a carrier to facilitate their transport e.g. iron in the GIT and L-DOPA at the blood-brain barrier
• Pinocytosis or cell drinking is the method by which insulin is absorbed in the CNS and botulinum toxin in the GIT.
• Conc gradient and lipid solubility determines whether a drug can diffuse.

Question 20

What determines whether a drug can diffuse into a cell?

Answer 20

Conc gradient and lipid solubility determines whether a drug can diffuse.

Question 21

What is mycophenolate mofetil?

Answer 21

An immunomodulatory drug used in the suppression of inflammatory mucosal diseases and other things.

Question 22

Define bioavailability

Answer 22

The proportion of a drug in dosage form that is available to the body.
It is not the same as effectiveness.

Question 23

What can affect bioavailability?

Answer 23

Mode of administration.

• IV administration will have 100% bioavailability.
• Topical administration can have variable bioavailability depending on things like whether it was occluded or covered. Or whether it was applied on a wet surface like mucosa (which may absorb the drug more readily) or the skin.

First-pass metabolism/presystemic elimination.

Question 24

Why are drugs sometimes prescribed by brand name?

Answer 24

The plasma concentration between drugs can vary. So if a diff brand drug is used, it may be sub-therapeutic doses or toxic.
This is important for drugs like mycophenolate mofetil.

Question 25

What is another name for first-pass metabolism?

Answer 25

Presystemic elimination.

Question 26

Define first pass metabolism and the effect and problems it has.

Answer 26

First-pass metabolism is where the liver or gut wall metabolises the drug so well that there’s little left in the circulation to act on target tissues and so it has less bioavailability.
This means that more of the drug will be required to ensure there’s a clinically beneficial effect so a higher dose will need to be given.
The issue with this is that it’s difficult to predict how much first-pass metabolism will occur in each person as it can vary so you have to give large doses and can’t predict the plasma concentration or effect of the drug.
This occurs in drugs like lidocaine, verapamil, GTN and proponalol.

Question 27

After absorption, where are the drugs distributed to?

Answer 27

Drugs are distributed to tissue compartments (plasma, interstitial, intracellular, transcellular, body fat)
Most go to interstitial.

Question 28

What is Volume distribution? What other things can affect it?

Answer 28

Vd is a theoretical measure of how much volume is required to keep the plasma concentration of the drug the same as when it was first administered. They can be large so not possible sometimes.
Vd = amount of drug in body/conc of drug in plasma.
- Those with kidney or liver problems have a higher interstitial fluid and higher Vd as people have problems with fluid retention and so more amounts of the drug are required for therapeutic dose.
- When dehydrated, tissue volume is depleted and lower Vd so lower amounts of drug are required as it can become toxic.

Question 29

Describe the action of drugs in the blood.

Answer 29

The plasma proteins most drugs bind to are albumin and alpha-1 acid glycoproteins. They bind and go to the target tissue and then when they unbind, that’s when the drug is pharmacologically active. Only free unbound drug is pharmacologically active. Here it exerts its action.
Plasma protein drugs are not filtered out by the kidney.

Question 30

How does blood supply affect distribution?

Answer 30

Blood supply affects equilibrium of conc of a lipid-soluble drug. In other words, it affects the distribution of a drug.
In the brain and heart they have a good blood supply so distribution occurs well here.
In fat, which is poorly perfused, distribution is a bit more tricky.

Question 31

What drug interaction can occur in distribution?

Answer 31

Drug X can displace drug Y from its plasma proteins so there’s increased conc. of free drug Y. However, the kidney can increase elimination to offset this.

Question 32

What is metabolism/biotransformation?

What are the usual metabolites? Is this all the time?

Answer 32

When enzymes process the drug molecules to increase, decrease or change the action of a drug.
It usually processes them to become a water-soluble, inactive/less active compounds.
Some drugs can survive the initial metabolism and can remain somewhat pharmacologically active.

Question 33

What are prodrugs?

Answer 33

These are drugs that are ingested in their inactive form and are metabolised to become the active form. e.g. Valaciclovir is a prodrug of aciclovir, and mycophenolate mofetil is a prodrug of mycophenolic acid.

Question 34

When does drug activity terminate then?

Answer 34

Termination of drug activity is not necessarily complete by metabolism stage.

Question 35

What can cause individual variations in drug metabolism?

Answer 35

Genetics

Polymorphism

Question 36

Is metabolism a constant?

Answer 36

No. It can be affected by other drugs - drug-drug interactions.
(Competitive and non-competitive inhibition of P450 enzymes)

Question 37

Where does metabolism occur?

Answer 37

Primarily liver. But kidney, gut, skin and lungs can also play a role.

Question 38

How does metabolism occur in the liver?

Answer 38

The liver has a rich blood supply and brings absorbed compounds from the gut (drugs and food) here for processing. The liver cells, namely the hepatocytes, contain the P450 enzymes on the SER (smooth endoplasmic reticulum). These enzymes control the conc of absorbed drugs. Following this first pass of metabolism, the drugs will re-enter systemic circulation for distribution to target tissues.

Question 39

What does CYP stand for and how many gene families produce it? Which is the most abundantly expressed?

Answer 39

CYP - cytochrome P450 dependent mixed function oxidases
Over a 100 gene families produce it but not all are involved in metabolism.
Most abundantly expressed is CYP3A4 which is used in over half of clinical drugs.

Question 40

What accounts for individual variation in drug metabolism?

Answer 40

Polymorphisms of genes that control the production of CYPs.

Question 41

How can P450 enzymes be inhibited and drug interactions occur?

Answer 41

Competitive inhibition - competing for the same enzyme e.g. warfarin and tamoxifen (breast cancer tx)
Non-competitive inhibition - one agent binds to the enzyme and prolongs the activity of the drug e.g. ketoconazole increases the effect of midozalam

Question 42

What is midozalam?

Answer 42

Common benzodiazepine used in iv sedation

Question 43

Where does excretion of drugs occur?

Answer 43

They are mostly excreted via the kidneys in urine.
Some can pass in breast milk to baby (so some drugs are contra-indicated in breastfeeding mums).
Some can be excreted in faeces - wouldn’t occur unless poor formulation of drug or pt has diorrhea
Some can be excreted by the lungs - volatile agents like GA gases
Some large molecules can be conjugated and excreted by bile

Question 44

What happens in the kidneys during excretion?

Answer 44

• Small molecular weight drugs removed by glomerular filtration
• Acids and bases actively transported into proximal tubule. Degree of protein binding does not affect this.
• Lipid-soluble molecules reabsorbed passively along lipid gradient across tubule cells

Question 45

What is the entero-hepatic shunt effect?

Answer 45

A drug is conjugated in bile, hydrolysed by gut bacteria to become active once again, then reabsorbed into the systemic circulation for an additional therapeutic/toxic effect.

Question 46

Distribution affects the concentration at which sites?

Answer 46

Sites of action, metabolism and excretion.

Question 47

What is half life?

Answer 47

The half life (T/2) is the amount of time it takes for half a drug to be excreted by the body. It can be very short or long (90 days for some corticosteroids).

Question 48

What are first order reactions/first order kinetics?

Answer 48

The amount of drug excreted compared to the amount of drug in circulation. This is directly proportional for most drugs so as more time goes on, more drug is excreted.

Question 49

What is plasma/systemic clearance?

Answer 49

The sum of all clearance processes i.e. by the kidney, liver, bile, lungs etc.

Question 50

For first order reactions, is clearance constant?

Answer 50

It’s constant. This means that if the plasma conc of a drug is doubled, the elimination will also be doubled.

Question 51

What are the causes of a long half life?

Answer 51

Low clearance rate, high volume distribution factors, or combination of both.

Question 52

When does dentistry use single dose administrations?

Answer 52

Midozalam for iv sedation

Penicillin for antibiotic prophylaxis

Question 53

Why are repeated doses sometimes required in medicine?

Can repeated doses lead to increased plasma concentrations?

Answer 53

For therapeutic window to be reached without dramatic rises and falls in plasma conc of the drug which can lead to rebound symptoms e.g. carbamazepine has a short half life so breakthrough pains can occur.
But the repeated doses shouldn’t lead to increasing plasma conc. as a steady state of administration vs. elimination is achieved over the course of the drug - usually occurs over 3-5 half life lives of the drug.

Question 54

What are loading doses?

Answer 54

A one off larger dose of the drug which may help it achieves its therapeutic window faster hastening clinical effects of the drug.