Pharmacology

Question 1

signalling molecules

Answer 1

• Also known as chemical messengers
  
  • Proteins, e.g., insulin
  • Peptides, e.g., glucagon, growth hormone
  • Sugars
  • Lipid-derived molecules
  • Hormones
  • Cytokines
  • Neurotransmitters
  • Pheromones
  • Gaseous molecules (NO, H2S)

Question 2

Chemical signals:

Answer 2

1. Synthesis and release of the signalling molecule
   
   2. Transport of the signalling molecular to the target cell
   3. Detection of the signal by a specific receptor.
   4. A change in cellular behaviour triggered by activation of the receptor (activated by intracellular signalling)
   5. Removal of the signal, which often terminate the cellular response. In some cases this may be removal of the receptor.

Question 3

Agonists vs antagonists

Answer 3

agonist-> bind to and activate receptors.

antagonist -> bind to and inactivate receptors.

Question 4

different types of transmembrane/cell surface receptors

Answer 4

• GPCRs
• Ion channel linked
• Enzyme linked

Question 5

GPCRs

Answer 5

mindmap

Question 6

different kinds of intercellular signalling

Answer 6

• endocrine: long distance slow communication through the blood and only certain cells respond as its receptor dependent
• juxtacrine: cells with direct contact can form gap junctions and signal
• paracrine: signal to neighbouring molecules
• autocrine: molecules that can respond to its own signals
• neuronal: nerve endings respond to signals

Question 7

What happens after receptor activation?

Answer 7

1. Receptor activation leads to intracellular signalling cascades and second messenger systems
   
   2. These lead to changes in cell function
   3. Signals are turned off, e.g.,
      -Chemical signals are enzymatically degraded.
      -G proteins become inactivated by GTPases.
      Cells return to previous state (unless more signal is around).

Question 8

The three stages of Intra cell communication:

Answer 8

1. Reception
   
   • A chemical message binds to a protein on the cell surface.
     2. Transduction:
   • The binding of the signal molecule alters the receptor
   • This starts a cascade of reactions.
     3. Response:
   • The transduction pathway triggers a response
   • The responses can vary from turning on a gene, activating an enzyme, rearranging the cytoskeleton.

Question 9

how is signalling controlled

Answer 9

• By post translational modification, e.g., phosphorylation
• By regulating whether a G protein has bound GDP or GTP
By provision of activators such as Ca2+ and cAMP.

Question 10

protein phosphorylation

Answer 10

• Kinase is an enzyme that phosphorylates proteins.
• Kinase add a phosphate group
• Most common amino acids:
-Serine -Threonine -Tyrosine

* Phosphatase is an enzyme that dephosphorylates proteins. 
* Phosphatases remove the phosphate group.

Serine/Threonine kinases:
• Ca2+/calmodulin-dependent protein kinases or CaM kinases.
• Protein Kinase A (PKA)
• Protein Kinase C (PKC)
• Mitogen-activated protein kinases (MAPK)

Tyrosine kinases:
• Non receptor tyrosine kinases e.g., Src family kinases- knowledge of these kinases has been fundamental to our understanding of cancer.
Receptor tyrosine kinases (RTKs) e.g., Epidermal growth factor receptor (EGFR)

Question 11

ion channels

Answer 11

-five transmemembrane subunits come together to form a channel
-transports Na+, K+, Ca2+, Cl- ions along an electrochemical gradient.
-opens in response to changes in transmembrane potential: voltage gated ion channels
-opens in respond to changes in chemicals: ligand gates ion channels/ionotropic receptors
-once activates, allows ions to move through.
E.g., Nicotinic (acetylcholine receptor), GABA receptor, glycine receptor, 5-HT3 receptor, etc.

Question 12

Second messenger systems

Answer 12

concentration changes in response to receptor activation by agonist:
AC -> cAMP
PLC -> InsP3/DAG
GC -> cGMP

Question 13

Enzyme linked receptors:

Answer 13

• single membrane spanning domain
• cytoplasmic enzymes that induce signalling are normally protein tyrosine kinases.
• extracellular ligand binding domain, a single transmembrane helix, a cytoplasmic region containing the protein tyrosine kinase activity

Receptor Tyrosine kinases: ligand binding activates enzyme activity within the cytoplasmic domain.

• the respond usually required receptor dimerisation.
• tyrosine residues in the intracellular domains are auto-phosphorylated in respond to the signal
• typically, responses are slow

Question 14

Cytoplasmic/Nuclear

Answer 14

• For signals that can cross the cell membrane
  
  • Huge family of receptors
  • Examples include oestrogen, thyroid, retinoic acid, and steroid hormone receptors.
  • Alter gene transcription (and hence protein levels) directly.

Question 15

Administration of drugs

Answer 15

• Oral
• Injection: IV, IM, SC
• I halation
• Sunlingual or buccal
• Rectal
• Other epithelial surfaces (skin, cornea, vaginal, nasal mucosa)

Question 16

First pass metabolism

Answer 16

metabolism that is undergone by a swallowed drug by the time it reaches the rest of the body.

Question 17

Cytochrome P450

Answer 17

superfamily of enzymes that metabolise more than 75% of drugs used in medicine

Question 18

effect on metabolism of enzymatic inhibition and induction of drugs.

Answer 18

inhibitor= slower metabolism (increased therapeutic effect)
induction= faster metabolism (decreased therapeutic effect)

Question 19

Molecular Mechanisms of Drug Action

Answer 19

1. Direct physicochemical effect
   
   2. Transport systems
   3. Enzymes
      Interaction with the 4 major types of receptors

Question 20

Drug affinity

Answer 20

how tightly a ligand binds to a receptor, expressed numerically as the dissociation constant Kd

Question 21

Drug Efficacy

Answer 21

the ability of an agonist to produce a biological effect. expressed numerically as Rmax.

Question 22

Drug potency

Answer 22

amount requred to produced an affect of given intensity. depends on affinity and efficacy

Question 23

EC50

Answer 23

half maximal effective concentration
-a measure of potency
-conc of a drug, antibody or toxicant which induced a response halfway between the baseline and max after a specific exposure time.
in vivo, this is called an ED50 (half maximal effective dose)

Question 24

receptor selectivity

Answer 24

the extent to which the receptor can recognise and respond to the correct signals, represented by one ligand or group of related ligand

Question 25

drug selectivity

Answer 25

drug’s ability to bind to particular receptor types or subtypes, such as beta1 or beta2 adrenoreceptors. no drug is fully selective, ideally want it to have a high degree of selectivity.

Question 26

densensitisation and tolerance of drugs mechanism

Answer 26

desensitise: effect of a drug gradually diminishes when it is given continuously or repeatedly
tolerance: more gradual decrease in responsiveness to a drug
Mechs:
-change in receptors
-translocation of receptors
-exhaustion of mediators
-increased metabolic degradation
-physiological adaptation
-active extrusion of drug from cells

Question 27

t1/2 of a drug

Answer 27

half life of a drug: time for plasma conc to reduce by half.

Question 28

therapeutic window

Answer 28

the range of drug concentrations within which the drug exhibits maximum efficacy (desired effect) and minimum toxicity in the majority of the patients. quantified by the therapeutic index:
TI=TD50/ED50