WEEK 1 - Drug Molecules, Drug Targets, Pharmacodynamics, & Introduction to Pharmacokinetics

Question 1

What is a drug?

Answer 1

A molecule that interacts with a specific molecular component (aka drug target) of an organism to cause physiologic changes within that organism.

Question 2

What is a drug target?

Answer 2

A macromolecule in the body or other organism (by infection), which is usually a protein, that a drug binds to and then mediates biochemical and physiologic changes.

Normally these proteins have have endogenous molecules (ligands) that bind to and interact with them.

Question 3

What are some important drug characteristics? (6)

Answer 3

• Physical nature.
• Degree of ionisation.
• Relative lipid solubility.
• Molecular size.
• Drug reactivity.
• Selectivity.

Question 4

What does the degree of ionisation (polarity) depend on?

Answer 4

Depends on pKa of the drug and pH of body component.

Question 5

What is pKa?

Answer 5

pH at which 50% of drug is ionised and %50 is unionised.

Question 6

True or False:
Does the degree of ionisation (polarity) affect solubility in different components? If so how?

Answer 6

True.
The degree of ionisation of a molecule influences the drugs ability to pass through membranes in the compartments of interest.

Question 7

What are Ionised and Un-ionised molecules more soluble in?

Answer 7

Ionised molecules are more water soluble (hydrophilic).
Un-ionised molecules are more lipid soluble (lipophilic).

Question 8

True or False:
Does molecular size affect diffusion in desired compartments? If so why?

Answer 8

True.
As molecular size is very diverse, it affects a molecules ability to diffuse between body compartments. Therefore affecting its interaction with the target.

Question 9

Why does the shape of a drug affect their binding with its target?

Answer 9

The shape of the drug/molecule is complementary to the shape of he target site (e.g. lock and key).

Question 10

Explain drug reactivity in terms of Ionic, Hydrophobic, Hydrogen, and Covalent bonds….

Answer 10

Drugs interact with their targets by means of chemical forces/bonds.
Covalent bonds have the highest strength of interaction.
Ionic bonds have the second highest strength of interaction.
Hydrogen bonds have the second lowest strength of interaction.
Hydrophobic bonds have the lowest strength of interaction.

Question 11

How does chemical and 3D structure determine biological activity?

Answer 11

• Changing the key chemical groups can change the biological effects of the agent.
• In pharmacological properties minor changes can lead to major changes

Question 12

What is selectivity?

Answer 12

Ideally a drug should be sufficiently unique that it only binds to one receptor in one tissue type, having a single specific effect.
Realistically no drug achieves this.
Instead drugs are selective for targets - therefore they bind preferentially to the target and are less likely to bind to other molecules in the body.

Question 13

What are small molecules? Give example/s:

Answer 13

• Classical drug molecules (e.g. Aspirin)
• These are produced by chemical synthesis.

Question 14

What are biopharmaceuticals? Give example/s:

Answer 14

• Large biological agents;
  + proteins (hormones, cytokines, monoclonal antibodies, vaccines).
  + Stem cells
  + Gene therapy
• These are produced in living cells.

Question 15

What are antibodies and monoclonal antibodies?

Answer 15

Antibodies are proteins made by the immune system to target a specific protein.

Monoclonal antibodes are made in a lab to taget one binding site on a single antigen.

Question 16

How are Monoclonal Antibodies (mAbs) produced? And what are their effects?

Answer 16

They are produced by injecting an antigen into an organism. Lymphocytes inside the organism then produce an antibody, while the tumour cells divide rapidly. Then Hybridoma are formed which divide rapidly and produce antibodies.

They effect both the altering signalling and cell lysis.

Question 17

What is the nomenclature of mAbs?

Answer 17

Prefix +

Target Substem +
- Bone -o(s)-
- Cardiovascular -c(i)-
- Tumour -t(u)-
- Immune Directed -l(i)-
- Virus Directed -v(i)-

Source Substem +
- Mouse -o-
- Chimeric -xi-
- Humanised -zu-
- Human -u-

-mab

Question 18

Comment on the size, production, structure, stability, and immunogenicity on small molecules:

Answer 18

Small Molecules:
Size - low molecular weight.
Production - by chemical synthesis.
Structure - simple, independent of manufacturing process.
Stability - mostly stable.
Immunogenicity - mostly non-immunogenic.

Question 19

Comment on the size, production, structure, stability, and immunogenicity on biopharmaceutical drugs (e.g. proteins):

Answer 19

Biopharmaceutical Drugs (Proteins):
Size - high molecular weight.
Production - in living cell structures.
Structure - complex, defined by exact manufacturing process.
Stability - unstable and sensitive to external conditions.
Immunogenicity - more likely to be immunogenic.

Question 20

How do drugs cause biological changes? Examples? (2)

Answer 20

By changing the environment (e.g. changing the pH or solute concentration).
An example is Antacids (work by counteracting or neutralising any excess stomach acid) and Alginates (form a ‘raft’ that floats. on top of the stomach contents).
OR
By binding to a target to cause physiological changes.
An example is statins binding to and inhibiting the enzyme invovled in cholesterol production.

Question 21

Types of Drug Targets?

Answer 21

There are Proteins and Nucleic Acid & Ribosomes…

Nucleic Acid & Ribosomes are common targets for treating infections and cancer.

Proteins consist of Receptors (Ion Channels, GPCRs, Receptors linked with enzyme domains, Intracellular Receptors), Enzymes and Adhesion Molecules.

Question 22

Explain Ion Channels, and what they are important in…. Example?

Answer 22

Ion Channels regulated the movement of ions across membranes.
This happens very fast (milliseconds).
It is particularly important in:
- Neurotransmission
- Cardiac Conduction
- Muscle Contraction
- Secretory Processes

An example is Nicotinic Receptors (2 x acetylcholine (Ach) molecules bind, then the channel opens, allowing Na2+ to move into the cell).

Question 23

Explain G Protein Coupled Receptors (GPCRs), and the different types…

Answer 23

G Protein Coupled Receptors (GPCRs) are transmembrane receptors, which activate intracellular signalling molecules known as G proteins.
They are most the abundant receptors in the body.
This process happens fast (seconds).
The types include:
- Gs
- Gi
- Gq

Question 24

Explain Transmembrane Receptors with Linked Enzymatic Domains…

Answer 24

Transmembrane Receptors with Linked Enzymatic Domains is when ligand binding leads to the activation of the enzymatic domain.
This has a slower effect (hours).
Has several different groups:
- Tyrosine Kinase Receptor (Largest)
- Insulin receptor

Question 25

Explain Intracellular receptors, and give and example…

Answer 25

Intracellular Receptors are small lipophilic molecules that can diffuse through the plasma membrane.
They bind to intracellular receptors which are transcription factors.
Complex binds to DNA, alters gene transcription.
Slower effect (hours).
An example is the receptors for steroid hormones:
- Steroid hormones are small lipophilic molecules which can easily diffuse through the plasma membrane.
- They bind to transcription factors in cytoplasm or nucleus.
- Ligand - receptor complex usually dimerizes in the nucleus.
- Alters gene expression.

Question 26

What are Enzymes? What are the different types? Examples?

Answer 26

Enzymes are catalysts in the body (speed up reactions). Drugs usually inhibit the activity of the enzymes.
Types include:
- Reversible Inhibitors
- Irreversible Inhibitors (typically form a covalent bond with the active site permanently inactivating the enzyme).
Extracellular (e.g. Acetylcholinesterase).
Intracellular (e.g. HMG Co A reductase).

Question 27

What are Adhesion Molecules? How do they work as drug targets?

Answer 27

Adhesion Molecules are proteins on the cell surface that enable cells to bind to make contact with each other.
As drug targets:
They are used in Multiple Sclerosis;
- Autoimmune disease
- T cells enter into the CNS and damage the myelin sheath.
- Interaction between a4B1 and VCAM1 important to enable entry to CNS.
- Natalizumab binds to intergrin on the autoimmune T cells and stops them from binding to VCAM1

Question 28

Explain Competitive Antagonists…

Answer 28

They bind reversibly to the ligand/active/agonist binding site of a receptor.
They block agonists from binding.
The receptor is maintained in the inactive conformation.
Adding more agonist with overcome the antagonist effects [ AR <—> A + D + R <—> DR* ].
In the presence of the antagonist, higher concentration of agonist required for same effect.
Potency of the agonist is decreased, and efficacy is not effected.

Question 29

Explain Non-Competitive Antagonists…

Answer 29

They bind to:
- binding / active site covalently
- an allosteric site, stopping receptor activation even if an agonist is attached to the active site.

They reduce the efficacy of an agonist, and have little effect on potency.

Question 30

Explain Non-Receptor Antagonists…

Answer 30

They are chemicals which inactivate the ligand/agonist directly.
They oppose physiological effects mediated through different receptors / pathways (e.g. excess thyroid hormones cause and increase in heart rate, and blocking adrenergic receptors can decrease heart rate).

Question 31

Explain Partial Agonists…

Answer 31

They are molecules that bind to a receptor and only produce a partial response.

Question 32

Explain what Supersensitivity is, and how it works….

Answer 32

If an antagonist is given to a patient repeatedly, the cell with adapt and become more sensitive to the stimulation by agonists.

If nerve is cute —> structure will become responsive to smaller amounts of transmitter than normal.

How:
1) Increase the number of receptors.
2) Increase postsynaptic responsiveness with no increase in receptors (unknown mechanism).
3) decrease the removal / increase production of transmitter from the synapse.

If someone was given a drug that blocks signal transmission (antagonist) for a long time, then steps1-3 will occur.
If drug was stopped suddenly, they will have a rebound effect.

Question 33

What is Pharmacodynamics?

Answer 33

The effect the drug has on the body, but more specifically the study of quantifying the relationship between the concentration of the drug and the patient’s response.

Question 34

What is the Ligand Receptor Binding equation and principles?

Answer 34

L = R <—> LR (where R is Ligand/Drug and R is Receptor)

If [L] increases, the concentration of [R] also increases.
If [R] increases, the concentration of [LR] also increases.

Therefore an increase in the effect of a drug can result from an increase in the concentration of either the drug or the receptor

Question 35

What is the Equilibrium dissociation Constant - Kd ?

Answer 35

When L + R <—> LR

Kd = [L][R]/[LR] = k2/k1

Where K1 = association rate constant
Where K2 = the dissociation rate constant

At equilibrium, R is 50% bound and 50% unbound.
Thus Kd is the concentration of Ligand (drug) when half the receptors are occupied.

Question 36

Explain Affinity…

Answer 36

Affinity is how tightly bound a drug binds to its receptor (Kd is a measure of affinity).

Kd’s reciprocal is the affinity constant Ka.

Question 37

Explain Graded-Dose Response Curves, and what properties are they used to determine…

Answer 37

Graded Dose-Response Curves show that as the concentration of drug increases, the magnitude of its pharmacological effect also increases.

The response is a graded effect, meaning it is continuous and gradual.

They can be used to determine 2 important properties of drugs:
1) Potency
2) Efficacy

Question 38

How to interpret Potency based on Graded Dose-Response Curve…

Answer 38

E = measurable effects of drug.

Emax = maximal effect of drug.

EC50 = concentration at which the drug elicits 50% of its maximal response (potency).

Question 39

How to interpret Efficacy based on a Graded Dose-Response Curve….

Answer 39

The efficacy is the maximal response (Emax)

And it refers to a drug’s ability to effectively activate the receptor once it has bound to it.

Question 40

What states can receptors be thought of exisiting in?

Answer 40

1) Inactive state

2) Activated state

Question 41

Explain what an agonist is, and what the different types of Agonists are…

Answer 41

An Agonist that binds to a receptor and activates the receptor usually mimicking the effect of the endogenous ligand.

D + R (inactive) <—> DR* (active)

There are 2 types of Agonists:
- Partial
- Inverse

Question 42

Explain what a Partial Agonist it, and its function…

Answer 42

A partial Agonist is a molecule that binds to a receptor at its active site and produces only a partial response - Emax is lower than a full agonist.

Some receptors stabilised in the inactive state and some in the active state [D + R <—> DR <—> DR*]

Can act as a competitive antagonist - inhibiting the binding of more efficacious full agonists.

Question 43

Explain was Inverse Agonists are, and their functions…

Answer 43

• Inverse Agonists stabilise the R (inactive form) [ R* + D <—> DR ]

Question 44

Explain the Therapeutic Window…

Answer 44

The Therapoeutic Window is the range of doses that effects a therapeutic response, without unacceptable adverse effects.

Is quantified by the Therapeutic Index;
= TD50 / ED50

( TD50 = the dose of drug that causes a toxic response in 50% of the population )
( ED50 = the dose of drug that is effective in 50% of the population )

** Drugs with a small therapeutic index may require plasma concentration monitoring **

Question 45

How does concentration determine the magnitude of effect?

Answer 45

The magnitude of drug action is usually related to the magnitude of the concentration at the target site.

Question 46

List the movement of drug in the body…

Answer 46

1) Dose of formulated drug
> administration
2) Disintegration of dosage form —> dissolution
> absorption
3) Drug in systemic circulation
> Elimination or Distribution
4) If Elimination drug is metabolised or excreted - end of line. If Distribution the drug is distributed to organs, tissues and site of action.
> Elimation (see above) or Pharmacological response
5) Clinical Response or Adverse effect (toxicity).

[ Steps 1-4 are Pharmacokinetics ]
[ Step 5 is Pharmacodynamics ]

Question 47

What does “ADME” stand for? Explain each step briefly…

Answer 47

Absorption: process of input into the systemic circulation from an extravascular administration site.

Distribution: reversible movement of drug between systemic circulation and other organs / tissues of the body.

Metabolism: chemical modification of the drug’s structure (“biotransformation”).

Excretion: movement of drug into excretory fluids (e.g. urine, faeces) or expired air.

** Elimination: irreversible loss of drug from body by Metabolism or Excretion **

Question 48

Briefly explain the basic pharmacokinetics parameters…

Answer 48

Primary Parameters:
Uniquely determined by physiological / biochemical factors.

Bioavailability (F):
The fraction of an extravascular dose which reaches the systemic circulation intact.

Volume of Distribution (Vd):
Measure of drug distribution throughout the body.

Clearance (CL):
Measure of the efficacy of drug elimination from the body. It’s a function of the ability of the eliminating organ to extract the drug from the blood flowing through it.

Question 49

Briefly explain Absorption, and its considerations…

Answer 49

Absorption can be thought of as the process of crossing barriers to get into the blood.

Considerations:
- Route
Which is best for the clinical situation? Which routes can the drug be delivered?
- Rate
Time avaliable may be limiting (e.g. GIT). Slow release may allow more convenient dosing.
- Extent (%of total amount) absorbed
Better known as ‘bioavailability’.

Question 50

Name and briefly explain the different routes of administration…

Answer 50

Intravenous Administration:
- Directly injected into a vein / artery.
- No absorption.
- Rapid.
- Can precisely control rate of delivery.

Enteral Administration:
- Includes Oral, Rectal, and Sublingual.
- Oral: most common, safe, convenient, and economical. Absorbed from GIT. Must pass through liver before getting to systemic circulation (first-pass metabolism).
- Sublingual: absorption from under the tongue. Drug must be highly lipophilic and potent. Directly into systemic circulation.
- Rectal; usually only if person is vomiting / unconscious, 50% of drug absorbed will bypass the liver during absorption. Absorption often irregular and incomplete.

Parenteral Administration:
- Through the skin.

Question 51

Explain the First-Pass Effect in terms of oral absorption…

Answer 51

Once the drug is in the bloodstream, it is removed from the body both:
- Physically via excretion
- Destructively via metabolism (biotransformation).

The liver contains many enzymes that metabolise many compounds:
- Endogenous compounds.
- Exogenous compounds (“xenobiotics”) - including drugs.

The portal circulation of the GIT flows into the liver before entering the systemic circulation:
- Some drugs are metabolised before reaching the “body”.

Question 52

What is the Half-Life equation?

Answer 52

Half-Life is the time taken for 50% of the drug to be eliminated form the body.

t(1/2) = ln(2)’Vd / CL

Where:
Bigger Vd = longer t1/2
Bigger CL = shorter t1/2

Question 53

What are the 4 biological fluid concentrations:

Answer 53

1) Input:
E.g. 100mg every 6 hours
Most drugs administered for an extended period.

2) Output dependent on:
Efficacy of removal (CL).

3) Dose rate selected based on:
Concentration required and clearance.

4) Dose interval selected based on:
Therapeutic window and half-life.