Module 1: Principle Of Pharmacology

Question 1

What is. Pharmacology?

Answer 1

The study of drugs and poisons

Question 2

What is a drug?

Answer 2

Any substance used to exert a biological effect

Question 3

What impacts the ease & rate of uptake of drug into the body?

Answer 3

The route of administration (ie oral, IV, etc)

The absorption

Question 4

What are the 2 main tissue reservoirs?

Answer 4

Body fat

Blood proteins

Question 5

What are the 2 main divisions of pharmacology?

Answer 5

Pharmacokinetics (movement around the body)

Pharmacodynamics (examination of drug interactions)

Question 6

What is specificity and selectivity?

Answer 6

Specificity - drug having a single action at a tissue or organism level

Selectivity - ability of drug to affect one type of cell above others

Question 7

What is an agonist?

Answer 7

Activator, Causes a shape change in the receptor.

Can be true agonist, partial agonist OR inverse agonist (causes a shape change AWAY from the active conformation)

In they key/lock metaphor - the agonist is the key that opens the lock

Question 8

What is affinity?

Answer 8

Ability of drug to bind receptor.

Occupation is governed by affinity

Question 9

What is efficacy?

Answer 9

Ability to activate receptor to elicit effect. (Only agonists have efficacy)

Activation is governed by efficacy

Question 10

What is potency?

Answer 10

Range of concentrations required to have an impact

Question 11

What is biased agonism?

Answer 11

Where different agonists can bind to the same receptor but cause different responses.

In other words, the shape change induced by the agonist can favour one signalling cascade over another

Question 12

What are the 2 possible mechanisms for action of partial agonists?

Answer 12

1. That the partial agonist only elicits a partial conformational change
2. That the partial agonist elicits a full conformational change, but not all of the time

Question 13

What is an inverse agonist?

Answer 13

Drug that interacts with a receptor to create a non-active conformational change. So it IS still a shape change, but in the opposite direction to the active form.

Question 14

What is an antagonist?

Answer 14

An anti-agonist - it prevents the action of an agonist. It can bind to a receptor but not change it’s conformation.

It has affinity, potency but does not have efficacy

Question 15

What are the 3 main categories of antagonist?

Answer 15

• Competitive antagonist (competes against agonist for same site on receptor)
• non-competitive antagonist (ie straight jacket when trying to raise your arm - binds to a different site on the receptor that stops the agonist)
• irreversible antagonist (binds to same site on receptor, but can’t be removed)

Question 16

What is the difference between Antagonist and antagonism?

Answer 16

Antagonist is the compound

Antagonism is the process

Question 17

What is chemical antagonism?

Answer 17

An agonist itself becomes chemically bound to a chemical antagonist (ie bind to the agonist rather than receptor)

Question 18

What is pharmacokinetic antagonism?

Answer 18

Changing the agonist half-life in the body by promoting elimination or altering its distribution/uptake

Question 19

What is physiological antagonism?

Answer 19

Competition between 2 opposing systems in the body, ie when 2 drugs administered that affect opposing systems and effects cancel out.

Question 20

What is the purpose of a receptor?

Answer 20

To translate an incoming signal into a cellular response

Question 21

What are the primary groupings of receptors?

Answer 21

Ionotropic (ion channels)

Metabotropic (rely on metabolic event)

Kinase linked receptors

Nuclear receptors

Question 22

What response scales can you expect with ionotropic and metabotropic receptors?

Answer 22

ionotropic - milliseconds

Metabotropic - seconds

Question 23

How do ligand-gated Ion Channels avoid accidental activation?

Answer 23

It will often require 2 simultaneous events to activate the channel (ie binding of 2 ligand molecules)

Question 24

Where are ligand-gated ion channels located?

Answer 24

In electrically excitable cells (ie heart, brain, nerves, skeletal muscles)

Question 25

What effects can ligand-gated ion channels cause in a cell?

Answer 25

A change in membrane potential of the cell - can have a flow on effect on voltage-gated ion channels. Either stimulators (influx of + ions) = depolarisation Or Inhibitory (influx of - ions) = hyperpolarisation

Question 26

What are GPCRs?

Answer 26

G Protein coupled receptors

Question 27

what category of receptor does GPCR fall into?

Answer 27

Metabotropic

Question 28

What is the basic structure of GPCRs?

Answer 28

- 7 transmembrane domains (can form a circle for binding pocket to nestle into) - Extracellular N terminus - Intracellular C terminus The 3rd intracellular loop and the C terminal tail shift their position and act like “chopsticks” to “pick up” the G protein

Question 29

What is a PAR and what type of receptor is it? And what is it’s role?

Answer 29

Protease-activated receptor. It is a type of GPCR. This is the “smoke alarm” warning system of the cell.

Question 30

How are PARs different from other types of GPCRs?

Answer 30

Same basic structure, but it has a tethered ligand that is cleaved to activate the receptor. This means they are “1 use only”

Question 31

What are 3 new GPCR types?

Answer 31

Proton-sensing and lysolipid-sensitive G protein coupled receptors - activated by protons or lipids - associated with cancer Calcium-sensing receptors - important role in suppressing parathyroid hormone secretion

Question 32

What are G proteins?

Answer 32

Heterotrimeric compounds composed of α, β and γ proteins in combination. They interact with GPCRs.

Question 33

How does the G protein α subunit activity differ from the β and γ subunits?

Answer 33

the α subunit is a GTPase. At rest it is bound with GDP, then when activated (binds with GTP instead), the GPCR receptor is activated and can interact with G protein. The enzyme part of α subunit can then cleave a phosphate to become GDP again (inactive form). Different types of α subunits have different effects on adenylate cyclise activity (activate or inhibit)

Question 34

What is the action of β-γ subunits of G proteins?

Answer 34

- acts as signalling molecules once liberated from α subunit | - appears to always function together

Question 35

What are the steps of G protein signalling?

Answer 35

1. GPCR inactive. G protein subunits together, α subunit bound to GDP. 2. GPCT receptor activated by ligand, conformational change in positioning of 3rd intracellular loop & C terminus tail allowing interaction with G protein. α subunit exchanges GDP for GTP and dissociates from βγ. 3. Both α and βγ active at specific target effectors. 4. α subunit cleaves phosphate to reform GDP, collapses in and rejoin βγ to form G protein again.

Question 36

What are RGSs and what is their job?

Answer 36

Regulators of G-protein signalling. Their job is to regulate α subunit activity

Question 37

What are the 3 types of RGS?

Answer 37

1. GAPs (GTPase-Activating Proteins) - promotes enzyme of activity to turn GTP to GDP which reduces action time of α. 2. GEFs (Guanine Nucleotide Exchange Factors) - encourages α subunit to drop GDP and uptake GTP, increases signalling of α. 3. GDIs (Guanine Nucleotide Dissociation Inhibitors) - prevents activation of G proteins

Question 38

What is the impact of RGSs?

Answer 38

- some neurodegenerative disorders associated with alterations to these - represent targets for drugs - activity of some poisons require inactivation of these - cancers proposed to include mutations of these

Question 39

Why is cAMP important?

Answer 39

It regulates many proteins either directly or through activation of PKA

Question 40

What is cAMP

Answer 40

Cyclic AMP - made by adenylate cyclase from ATP

Question 41

What is the activity of a protein kinase?

Answer 41

Moving phosphate molecules. As a result, critical to kinase cascades

Question 42

What are RTKs

Answer 42

Receptor tyrosine kinase

Question 43

What is the key summary of RTK activity?

Answer 43

``` Monomers form dimer Dimer self phosphorylation That attracts other proteins They get phosphorylated They trigger cascades Really important for gene transcription ```

Question 44

What is special about nuclear and cytoplasmic receptor transcription factors?

Answer 44

They are a receptor and also a transcription factor (rather than being a receptor that then activates a separate transcription factor)

Question 45

What are the classes of nuclear receptors?

Answer 45

Class I - move from cytoplasm into the nucleus, homodimer hybrid class - nucleus only, heterodimer with retinoid receptor Class II - nucleus only, heterodimer for all except retinoid receptor

Question 46

What are the 2 phases of gene transcription from nuclear receptors?

Answer 46

Primary response - direct regulation of small number of genes, within 30min Secondary response - gene transcribed in primary response are transcription factors that transcribe additional genes

Question 47

What are 2 primary types of signalling?

Answer 47

Neuronal - punctual & rapid Hormonal - can have a short-lived signal with long-lived response

Question 48

What is desensitisation?

Answer 48

Loss of sensitivity of a receptor to continuing stimulation by agonist. Loss of response due to ongoing treatment with a drug.

Question 49

What is arrestin and what does it do?

Answer 49

A compound that can recognise receptors that have gone through repeated cycles of phosphorylation/dephosphorylation. It binds and removes the receptor from the membrane. This is in the process of homologous desensitisation.

Question 50

What is homologous and heterozygous desensitisation?

Answer 50

Homologous: only the receptor that is in a constantly-activated state is regulated Heterologous: All receptors of a certain type are regulated (whether activated or not)

Question 51

What is remodelling?

Answer 51

Process by which cells adapt to continued presence of a drug to change the response of the entire network or organ