Mechansims Of Drug Action Flashcards
Drug effects vs drug action
Drug effects on human body
Drug action at cellular or molecular level
Which molecule is needed for drugs to work
Protein molecules = receptors, regulatory proteins, enzymes, transport proteins, structural proteins, tumor antigens
But drugs do not necessarily affect the proteins always
What is responsible for the selectivity of drug action
Receptors
Types of bonds between drugs and the sites
Weak hydrogen bonds
Ionic bonds
Covalent bonds
Van der Walz bonds
Important receptors for drugs
Tumor necrosis factor receptors
Toll-like receptors
Notch receptors
Hedgehog receptors
Which receptor activated by IL-1
Sphingomyelinase-linked receptor
How do the receptors function
Receptors should be activated by signals
Signal should be transduced
Transduced signal should be amplified
Ionotropic receptors
Effects are observed very fast
Receptor itself a channel for the ion
Nicotonic receptors : Na channel
GABAa receptors: Cl channel
Metabotropic receptors ( G-protein coupled receptors)
Linked to G-protein
Slow
Muscarinic
5-HT
Opioid
Dopaminergic
Peptide transmitters
Adrenoceptors
Olfactory sensory receptors
GPCRs
Features of G-protein coupled receptors
G proteins are associated with GTP,GDP
G proteins have 3 subunits: alpha,beta,gamma
Receptors has two states
Resting state
Activated state —> Ga leaves and activates Adenylyl cyclase which produces cAMP
Targets of G-proteins
Adenylate cyclase system
Phospholipase C/ Inositol phosphate system
Regulation of ion channels
Functions of G-proteins
3 types of Galpha: Gs, Gi, Gq
Gs and Gi show affinity to Adenylate cyclase
Gi inhibts Adenylate cyclase
Gs activates Adenylate cyclase
Gq controls Phospholipase C
Phospholipase C/ İnostiol phosphate system
Activation of this system is the second important messenger system
PLC— PIP2— IP3+DAG
IP3—> release of Ca
DAG—> activates Protein Kinase C
Muscarnic receptors
In myocardium
Conductance of K channels and produce hyperpolarication, inhibition of the cell
Opioids receptors
Open K channels and produce hyperpolarization
Gs
Effector ?
Effects?
Effector= Adenylate cyclase —> Stimulation
= Ca channels—> Stimulation
= Na channels—> Inhibition
Gi
Effector?
Effects?
Effector= Adenylate cyclase—> Inhibiton
= Ca,Na,K channels—> Inhibiton
Gq
Effector?
Effects?
Effector= PLC,PLA2—> Stimulation
* specific for eye
Features of Tyrosine kinases linked receptors
Growth factors, cytokines and insulin receptors
Extracellular ligand binding site
Intracellular polypeptide chain
Stimulation of these causes dimerization of receptors and activation of thyrosine kinase
Growth factors that activate Thyrosine Kinases
Epidermal Growth Factor= stimulates proliferation and differentiation of epi cells
Platelet-derived growth factor= stimulates growth of smooth muscle cells,glial cells and fibroblasts
Thyrosine kinase receptor diseases
Mutatation in these receptors causes cancer
Congenital malformations
Cytokine receptors
Activated by bringing together two JAK kinases
JAKs activate STATs
STATs are the transcriptional factors that regulate gene expression
Serine/Threonine Kinases Receptor
Growth factor receptors
Activated by the formation of dimeric structure
Activate Smads—> controls cellular proliferation and differentiation
Guanylate-cyclase linked receptors
Act on 2 types of guanylate cyclase
Tumor necrosis factor receptor family
Lymphocytes produce 3 forms of TNF
Shock and inflammation
Killing tumor cells
Protection from bacterial infections
Development of the immune system
Regulate Cell proliferation
Regulate Death
Alter gene expression by activating NF-kB
Toll like receptors
Sense and responses to infection
Required for resistance to fungal infections
Dimeric TLRs on the plasma membrane of DCs —> sense foreign molecules and respond by secreting TNF,IL-1,IL-6
TLR3 located in endosomes which binds to dsRNA
Notch receptors
Ligands= Delta
Regulate cellular fates during embryonic development
Force the neighboring cells to chose a different fate than their own
Hedgehog receptors
Two membrane proteins= Patched, Smoothened
Required for signal transduction during development
Regulate cellular differentiation
Formation of neural tube
Mutation of this causes developmental defects
Patched mutation causes basal cell carcinoma
Smoothened is a proto-oncogene
Which molecules produce gene transcription through intracellular receptors
Thyroid hormones
Vitamin D
Steroids
Receptors that produce gene transcription have 3 domains
DNA-binding domain
Ligand binding domain
Domain that binds transcription factors
When receptors that produce gene transcription are inactive they bind to which molecules
HSP
Endogenous or Synthetic agonists
Bind to receptors and activate them
Antagonists
Bind to receptors but do not activate them
Inhibit the binding of the agonists
Do not produce any effect
Partial agonists **
In the presence of antagonist—> act as agonists
In the presence of agonists—> act as antagonists
LOWER EFFECT
Inverse agonists
Opposite effects of agonists
Reduce the activity below the basal levels
Occupies the receptor so that agonists can not bind
Biased agonists
Agonist that activates only one portion of a receptors signaling pathway while inhibiting the other portion
Types of Antagonism
Competitive
Irreversible
Chemical
Physiological
Competitive antagonism
Compete for the receptor against the agonists
Higher concentrations are required for full inhibition
E max does not change
Reversible if agonist concentration is increased
Irreversible antagonism
Bind to receptors at very high affinity
Bind irreversibly
Produce ab uncompetitive antagonism
Spare receptors can stop them to produce irreversible effects
E max can not be reached
Pharmacological antagonism
Competitive antagonism
Irreversible antagonism
Chemical antagonists
Do not require a receptor
One drug inhibits or inactivates other drug
Physiological antagonism
Drug that counters the effects of another by binding to a different receptor and causing opposing effects
Potency
Refers to the EC50 or ED50 of the drug
Affinity and coupling efficiency for the drug determines it
Efficacy
Meausre of the ability of the drug to treat condition it is indicated for
Ability can depend on the ROA, absorption, distribution
Therapeutic index
TD50/ED50
Median toxic dose/ median effective dose
DNEL,NOAEL,LOAEL
DNEL: Derived no effect level
NOAEL: No observed adverse effect level
LOAEL: Lowest observed adverse effect level
Idıosynchrasy
Drug reaction that is not normal, not seen in other patients
Depends on genetics or biological differences
Hypersensitivity
Tachyphlaxis
Type of tolerance
Tolerance develops so fast
Continuous administration of an agonist may produce
Tolerance
Overshoot —> the number of receptors decrease the effector systems become more hypersensitive
Up-regulation
Down-regulation
Up-regulation: increase in the number of receptors
Down-regulation: decrease in the number of receptors
Desensitization
Effect of drug is decreased due to function of receptors affected
2 types: Homologus,Heterologous
