Pharmacology Flashcards
signalling molecules
- 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)
Chemical signals:
- Synthesis and release of the signalling molecule
- Transport of the signalling molecular to the target cell
- Detection of the signal by a specific receptor.
- A change in cellular behaviour triggered by activation of the receptor (activated by intracellular signalling)
- Removal of the signal, which often terminate the cellular response. In some cases this may be removal of the receptor.
Agonists vs antagonists
agonist-> bind to and activate receptors.
antagonist -> bind to and inactivate receptors.
different types of transmembrane/cell surface receptors
- GPCRs
- Ion channel linked
- Enzyme linked
GPCRs
mindmap
different kinds of intercellular signalling
- 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
What happens after receptor activation?
- Receptor activation leads to intracellular signalling cascades and second messenger systems
- These lead to changes in cell function
- 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).
The three stages of Intra cell communication:
- 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.
- A chemical message binds to a protein on the cell surface.
how is signalling controlled
• 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.
protein phosphorylation
• 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)
ion channels
-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.
Second messenger systems
concentration changes in response to receptor activation by agonist:
AC -> cAMP
PLC -> InsP3/DAG
GC -> cGMP
Enzyme linked receptors:
- 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
Cytoplasmic/Nuclear
- 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.
Administration of drugs
- Oral
- Injection: IV, IM, SC
- I halation
- Sunlingual or buccal
- Rectal
- Other epithelial surfaces (skin, cornea, vaginal, nasal mucosa)
First pass metabolism
metabolism that is undergone by a swallowed drug by the time it reaches the rest of the body.
Cytochrome P450
superfamily of enzymes that metabolise more than 75% of drugs used in medicine
effect on metabolism of enzymatic inhibition and induction of drugs.
inhibitor= slower metabolism (increased therapeutic effect) induction= faster metabolism (decreased therapeutic effect)
Molecular Mechanisms of Drug Action
- Direct physicochemical effect
- Transport systems
- Enzymes
Interaction with the 4 major types of receptors
Drug affinity
how tightly a ligand binds to a receptor, expressed numerically as the dissociation constant Kd
Drug Efficacy
the ability of an agonist to produce a biological effect. expressed numerically as Rmax.
Drug potency
amount requred to produced an affect of given intensity. depends on affinity and efficacy
EC50
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)
receptor selectivity
the extent to which the receptor can recognise and respond to the correct signals, represented by one ligand or group of related ligand
drug selectivity
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.
densensitisation and tolerance of drugs mechanism
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
t1/2 of a drug
half life of a drug: time for plasma conc to reduce by half.
therapeutic window
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
