Lecture 1 - How Do Drugs Work?

Question 2

How do drugs travel through body?

Answer 2

Via blood and other bodily fluids

Question 3

What type of proteins do drugs usually target?

Answer 3

Proteins on the cell surface

Question 3

What happens when drug reaches site of action?

Answer 3

they bind to receptors, located on cell outer membrane. This can trigger the activation of enzymes inside the cell.

Question 4

Properties of Drugs

Answer 4

Absorption (depends on factors like solubility)
Distribution (some drugs may binds to plasma proteins, only free drug can bind to receptors to create effect)
Metabolism
Excretion (usually via urine)

Question 5

What are receptors?

Answer 5

Usually integral proteins, bind to ligands (agonists/antagonists)

Question 6

What are Ligands?

Answer 6

specific chemicals (natural or synthetic) that bind to specific receptor to invoke biological response, changing the function of the cell

Question 7

Up-regulation of receptors

Answer 7

Increased no. of receptors to increase sensitivity, often in response to low conc. of agonist

Question 8

Down-regulation of receptors

Answer 8

decreases sensitivity, mechanism to avoid overstimulation (by being bombarded frequently/intensely by agonist)

Question 9

Agonist

Answer 9

activate receptors causing a cellular response

Question 10

Important properties of Agonists

Answer 10

Efficacy (ability to induce a conformational change and how effective it is in inducing a response) and Affinity (how strongly it binds to the receptor)

Question 11

Antagonists

Answer 11

Block receptors, should be designed to have higher affinity than the agonist. They have AFFINITY for receptor but not EFFICACY (don’t induce conformational change to initiate a response)

Question 12

How drugs influence cellular signalling

Answer 12

they can change the signalling process and drugs are often targeted to it. Targeting allows for better designed drugs and better therapy.

Question 13

Signal Transduction

Answer 13

• INTERcellular signal chemical (first messenger (ligand)) could be a drug, hormone, neurotransmitter and doesn’t enter cell.
• binds to receptor provoking an immediate response of a series of chemical changes (activating INTRAcellular second messengers) in the cell.
• Chemical changes alter physiology of the cell.
• Signal transduction enables amplification of signal.
• Drugs can change these effects to cause an alteration in the cellular response.

Question 14

What could happen after beginning of signal transduction?

Answer 14

1. Direct opening of ion channels
   
   2. Direct activation of an enzyme
   3. Indirect/inactivation of enzyme, indirect opening/closing of ion channels, or involve a g-protein (molecular switch)

Question 14

(1) Direct Opening of Ion Channels

Answer 14

receptor protein is an ION CHANNEL that forms a pore in the plasma membrane through which specific ion type can pass. They are opened/closed depending on whether the agonist is bound, which causes a conformational change which opens it. Ions flow through channel down concentration gradeint.

Question 15

What cell types have more receptor operated ion channels?

Answer 15

excitable cells (muscle and nerve cells) which respond to changes in electrical activity

Question 16

(2) Enzyme Linked receptors

Answer 16

Receptors are transmembrane proteins which posses enzyme activity. They have a LIGAND-BINDING DOMAIN on outer face of p. membrane and a CATALYTIC/ENZYMATIC DOMAIN on inner face. When this receptor is stimulated by agonist, receptors catalytic activity is increased

Question 17

A class of Enzyme-linked receptors

Answer 17

TYROSINE KINASE RECEPTORS. Activation via agonist causes the transfer of a phosphate group onto specific amino acids in the receptor. This causes proteins to be recruited from cytosol, which become the ‘scaffold’ to the receptor. This transmits the signalling info. to the cell.

Question 18

Indirect second messengers:

Answer 18

• Cyclic nucleotides (cAMP)
• Inositol triphosphate (IP3)
• Diacylglycerol (DAG)
• Calcium ions (Ca2+)

Question 19

G-protein-coupled Receptor Signalling

Answer 19

has 3 protein parts: 7 transmembrane receptors, G-protein, effector enzyme

Question 20

how does GPCR signalling work?

Answer 20

ligand binds to transmembrane receptor which causes a 3-dimensional or conformational change of the receptor, allowing it to interact with the G-protein. G-protein then loses GDP and gains GTP. G-protein can then interact with effector enzyme and increases its catalytic activity. The effector enzyme produces specific ‘second messenger’ molecules. These alter the biochemical machinery inside the cell by interacting with their specific target molecules), which either phosphorylate other specific proteins (phosphorylation cascade) or release intracellular stores of Ca2+.

Question 21

What is a G-protein?

Answer 21

guanine nucleotide-binding proteins.

Question 22

De-activation of GPCR

Answer 22

agonist dissociates from receptor. G-protein is an enzyme (GTPase) which will convert GTP to GDP, switching itself off no longer interacting with effector enzyme which will return back to normal state and second messengers will eventually be broken down and no longer pass on the signal.

Question 23

What are Kinase Tyrosine receptors?

Answer 23

Activation of the receptor by its agonist causes the transfer of a phosphate group onto specific amino acids (i.e. specific tyrosines) in the receptor itself. This results in the recruitment of proteins from the cytosol, which become ‘scaffolded’ to the receptor. This scaffold transmits the signalling information to the cell.