Drug metabolism

Question 1

Phase 1 metabolism

Answer 1

The chemical alteration of a drug i.e. oxidation which can change the drugs biological affect. The drug will have a different function

Question 2

Phase 2 metabolism

Answer 2

Often involves adding groups to the drug i.e. in conjugation reactions. Chemically modifies the drug ready for excretion, making them inactive. Tends to make them more water soluble so they can be excreted from the kidneys

Question 3

Pharmacodynamic

Answer 3

This is what the drug does to the body, the events caused by the interaction of the drug with its receptors or other primary sites of action.

Question 4

Graph of drug dose against response

Answer 4

X axis is agonist concentration, Y axis is response. At first there is a steep rise in drug effect with only a small change in concentration, it then plateaus out to reach 100% effect. Because the line is so steep it makes it hard to work out the particular effect of a drug dose on the body.

Question 5

Logarithmic graph of drug dose against response

Answer 5

The X axis is a logarithmic scale, , meaning you go up in factors of ten from 10 to 100 to 1000. As it uses a logarithmic scale the gradient of the curve is a lot less steep meaning the graph is more useful in seeing the particular effect of ligand concentration on the effect of the drug.

Question 6

Affinity

Answer 6

The likelihood of a drug binding to its receptor, how likely the drug is to form an agonist-receptor complex. Shows whether the drug will produce the desired affect at low concentration.

Question 7

Efficacy

Answer 7

The actual effect of the drug after its bound to the receptor

Question 8

Potency

Answer 8

The strength of the drug, or the amount needed to produce a certain response

Question 9

Agonist

Answer 9

A ligand (drug, hormone or neurotransmitter) that binds to a receptor and causes a biological cellular response. The agonist-receptor complex triggers an intracellular action which brings about a biological effect

Question 10

Antagonist

Answer 10

A substance which inhibits the action of an agonist by stopping it from binding to the receptor. It binds to the receptor but does not activate it, it may have a higher affinity for the receptor then the full agonist. The efficacy of the antagonist is zero as it produces no biological effect.

Question 11

Partial agonist

Answer 11

Full agonists have an efficacy of one, the efficacy of a partial agonist is less then 1 but above 0. A partial agonist can never achieve a 100% biological response even when occupying all available receptors. A full agonist on the other hand can produce a maximum response whilst occupying only a small percentage of receptors available.

Question 12

Types of antagonists

Answer 12

Receptor antagonists and non-receptor antagonists. Receptor antagonists are split into active site binding and allosteric binding. Non-receptor antagonists are split into chemical and physiological antagonists

Question 13

Physiological antagonists

Answer 13

When two substances compete for the same receptor, like glucagon and insulin.

Question 14

Allosteric antagonist

Answer 14

The antagonist does not bind to the same active site as the agonist but still blocks it from binding. There is not competition to bind to the same site on the receptor, so they are non-competitive allosteric antagonists

Question 15

Competitive active site antagonists

Answer 15

. The competitive antagonists bind to the agonist recognition site meaning they compete with the agonist for occupation of binding site. Antagonism can be overcome by increasing agonist concentration. The higher the concentration of the agonist or antagonist the more likely they are to bind to the receptor. Presence of antagonist reduce potency/efficacy of agonist. Antagonists bind reversible. The dose response curve will be shifted to the right.

Question 16

Non-competitive (irreversible) antagonists

Answer 16

The antagonism cannot be overcome by increased concentration of agonist, meaning maximal response can never be achieved, even with a high dose. Some will stick to the binding site on the receptor where the agonist binds, or it can bind to a different part of the receptor deactivating the receptor.
In the graph the maximum efficacy will be reduced. The greater the antagonist concentration the more flattened the curve will be. The graph will be the same just down.

Question 17

Drugs first pass metabolism

Answer 17

When drugs are administered via the oral route they are absorbed via the gut wall and pass via the portal system to the liver. The drugs are exposed to liver metabolising enzymes which may reduced the amount of the drug reaching the plasma, meaning a larger dose is required. Lot of variation between individuals.

Question 18

Characteristics of drugs- small hydrophobic molecules

Answer 18

Small hydrophobic molecules are fast moving and lipophilic so can quickly move across the cell membrane i.e O2, CO2

Question 19

Characteristics of drugs- small uncharged polar molecules

Answer 19

Fast moving and although they carry no overall charge, the polar nature of the molecule offers some resistance to diffusing through the lipid cell membrane, includes water, glycerol and ethanol

Question 20

Characteristics of drugs- large uncharged polar molecules

Answer 20

Slower moving and the polar nature of the molecule offers some resistance to diffusing through the lipid cell membrane. Includes amino acids, glucose and nucleotides.

Question 21

Characteristics of drugs- ions

Answer 21

Although small and fast moving, they carry a full ionic charge which makes it difficult to move across the lipid cell membrane, although there will be a steady but very slow movement over time to balance electrochemical gradients. Includes H+ and Cl-

Question 22

Characteristics of drugs- PH

Answer 22

Can affect drug ionisation and its ability to move through the membrane. The pKa of a drug is the value of the pH of the drug at which it exists in a 50% ionised state.

Question 23

Bioavailability

Answer 23

The proportion of the drug dose in the systemic circulation following administration. Expressed as ‘F’ which can be a number between 0 and 1 or a percentage

Question 24

Factors which will affect bioavailability

Answer 24

Route of administration
IV- 100% because you bypass the GI and liver
Orally- low as metabolised in liver, different between people as it depends on the amount of drug metabolising enzymes you have
Rectally- higher then oral, lower then IV, as it goes through the GI but some is absorbed in the blood vessels of the rectum which will bypass the liver and go straight into the systemic circulatory system.

Question 25

Drug definition

Answer 25

A chemical other then nutrition that when administered to a living organism produces a biological effect. Beneficial in healthcare but illness can be caused by adverse drug reactions. Errors in prescribing can also cause death

Question 26

Medicine

Answer 26

A substance or combination of substances that when administered correctly are viewed as having properties which can prevent or treat a disease in a person

Question 27

Clinical pharmacology

Answer 27

Incorporates all aspects of the scientific study of drugs in humans to optimise effective drug treatment

Question 28

Therapeutics

Answer 28

The area of medicine concerned with the treatment of disease

Question 29

Pharmacology

Answer 29

The branch of medicine concerned with the uses, effects and modes of actions of drugs.

Question 30

Pharmacokinetics

Answer 30

Concerned with the movement of drugs within the body, the rate of distribution will be affected by membrane permeability and blood perfusion

Question 31

Blood perfusion with drugs

Answer 31

Determines how quickly a drug on reaching the systemic circulation will be transported round the body, also dependent on the drugs ability to cross membranes e.g. to diffuse out of the blood stream and into surrounding tissues

Question 32

Distribution of highly lipid soluble drugs

Answer 32

Can easily move across membranes but accumulate in adipose tissue which will act as a store for the drug, meaning the plasma concentration of the drug will fall. So more of the drug is required to have the desired plasma concentration and effect. As the drug is metabolised and concentration falls the equilibrium sifts and the drug will start to move out of the adipose tissue and into the plasma. The drug will be in the plasma for longer as it receives a steady floe of the drug from the tissues.

Question 33

Drug distribution- plasma protein binding

Answer 33

This reduces the drug action but also clearance as less of the drug is present in its free form in the plasma. So plasma bound drugs are often slower acting but with prolonged therapeutic effects as the plasma protein bound form of the drug acts as a store which exists in equilibrium with its free form.

Question 34

Routes of drug administration

Answer 34

Either classified as enteral (via the gastrointestinal tract) or parenteral routes (other then via the GI tract)

Question 35

The enteral route of drug administration

Answer 35

Via the GI tract, includes oral (swallowing), sublingual or buccal (medication dissolves under the tongue) or rectal

Question 36

Parenteral route of drug administration

Answer 36

Not via the GI tract. Includes subcutaneous (under the skin)topical (through skin or other surface i.e. the eye), intradermal (into the skin), intramuscular (into skeletal muscle), intraperitoneal (into peritoneal cavity), intravenous (into blood via vein). Also intra-arterial (into blood via an artery), intrathecal (into spinal cord), nasal or inhalation, and pulmonary (into the lungs)

Question 37

What to consider when choosing a drug administration route

Answer 37

It it cheap?
Can it be self-administered?
Is it non-invasive?
How will the drug get to its target?
Can the drug pass through membrane barriers?
Is it okay if the drug undergoes first pass metabolism ?

Question 38

Volume of distribution

Answer 38

The volume in litres that the drug distributes into.

Question 39

Single compartment model

Answer 39

Consider the body as a single whole water compartment with no physiological barriers. The drug rapidly equilibrates through the entire body. Volume of distribution in the entire body water volume. The removal of the drug could be determined by constant value or Kel which is the elimination rate constant. The Concentration (C) of the drug would therefore decline in a time dependent fashion until removed from the body. Theoretical model as the body is composed of multiple compartments

Question 40

Multiple compartment model- drugs

Answer 40

The body is composed of multiple compartments with multiple physiological barriers separating them. Drugs may move between compartments with the blood plasma acting like a superhighway moving drugs that reach the bloodstream around the body

Question 41

The 4 phases of pharmacokinetics

Answer 41

• Absorption= modes of drug entry into the body or routes of administration
• Distribution= the movement of the drug around the body and how the drug reaches its target.
• Metabolism= chemical changes to the drug molecules once its inside the body
• Excretion= how the drug and its metabolites are removed from the body

Question 42

Cytochrome P450 enzymes (CYPs)

Answer 42

A family of isoenzymes which metabolise different chemicals. Mostly in liver cells but are widespread. CYP-mediated metabolism can switch drugs on or off and package them ready for excretion

Question 43

Drug excretion

Answer 43

There is a large difference in renal excretion rates between drugs, most drugs are excreted as urine. The phase 1/ phase 2 metabolites are excreted readily, as they tend to be water soluble or can be converted into a water-soluble molecules in phase 2 metabolism.

Question 44

How interactions between drugs affect drug metabolism

Answer 44

If multiple drugs are prescribed which are metabolised by the same isoenzyme then the patient is likely to suffer from adverse effects. If both drugs are metabolised by the same enzyme then the enzyme will become saturated meaning a reduced proportion of the drug will be metabolised, there will be more of the active form of the drug then you’d predict.

Question 45

Molecular targets for drug action

Answer 45

Ligand gated ion channels (ionotropic receptors)
G-protein coupled receptors (metabotropic)
Kinase linked receptors
Nuclear receptors- drug goes through the nuclear membrane, binds to a receptor and changes transcription and translation

Question 46

Factors influencing variability in response to drugs- change in receptors

Answer 46

The physical characteristics of the receptor can undergo a confirmation change, or the receptor could be phosphorylated. This could reduce the effectiveness of the drug to bind to the receptor

Question 47

Factors influencing variability in response to drugs- loss of receptors

Answer 47

When the receptors are internalised and removed from the cell membrane, due to increased exposure to medication. There are less receptors for the drug to bind to

Question 48

Factors influencing variability in response to drugs- exhaustion of mediators

Answer 48

Repeated drug exposure can cause the neuron to be depleted of the neurotransmitter or mediator

Question 49

Factors influencing variability in response to drugs- increased metabolic degradation

Answer 49

Can be caused by barbiturates and ethanol, changes metabolism of drug. Drinking water increases absorption of the drug

Question 50

Factors influencing variability in response to drugs- physiological adaption

Answer 50

For example thiazide diuretic- mechanism not completely understood.

Question 51

Factors affecting gastrointestinal absorption

Answer 51

• Gut motility= how long the drug is in the GI effects how much can be absorbed, the more time its there the more of it will be absorbed
• Gut PH- can be deactivated by acid
• Interaction with other chemicals in the gut- i.e. food and other drugs
• Particle size and formulation- pharmaceutical preparation can effect how much of the drug is absorbed. Can be formulated to be fast or slow releasing

Question 52

Factors affecting drug response summary

Answer 52

Change in receptor, loss of receptors, exhaustion of mediators, increased metabolic degradation, Physiological adaption

Question 53

Therapeutic index (TI)

Answer 53

The toxic dose of the drug found in 50% of the population (TD50) divided by the minimum effective dose for 50% of the population (ED50). A high therapeutic index (TI) suggests that the drug is safe, as there is a big difference in the amount of the drug which will cause a toxic effect and the amount which is safe to use.

Question 54

How one drug can influence the absorption of another

Answer 54

For example, a drug can increase intestinal movement, speeding the passage of a second drug through the intestine, meaning the second drug has less contact with the intestinal wall, thereby decreasing absorption. Opposite can also happen

Question 55

How a drug can affect the metabolism of another

Answer 55

For example, a drug can block the inactivation of a second drug in the liver, increasing the blood level and pharmacological effect of the second drug.

Question 56

How a drug can affect the excretion of another

Answer 56

For example, a drug can facilitate the excretion of a second drug by the kidney, decreasing the blood level and pharmacological effect of the second drug.

Question 57

Drug selectivity

Answer 57

A measure of how selective the drug is when binding to its target receptor, compared to other receptors we do not want it to bind to as this could cause unwanted side effects

Question 58

Drug specificity

Answer 58

Refers to the actual effect of the drug. If the drug is highly effective it will produce only the desired effects of the drug and few adverse side effects

Question 59

How pharmaceutical factors effect drug response

Answer 59

How we synthesise and package the drug can effect its bioavailability at set time points after administration. Effects the amount of the drug which reaches the plasma and therefore drug effectiveness.

Question 60

Tolerance

Answer 60

The reduction in response to a drug after repeated administration. Clinically, a higher dose is required to obtain the original response. Tolerance may take days/weeks/months to develop.

Question 61

Desensitization

Answer 61

A rapid signal reduction in response to stimulation, the drug therefore has less of an effect. Desensitization is cause by altered coupling of receptors to signal transduction pathways and receptor internalization