Pharmacodynamics II Flashcards
Give examples of intracellular receptors
Corticosteroids Mineralocorticoids Sex steroids Vitamin D Thyroid Hormone
How do intracellular receptors work?
Binding specific DNA sequences near the gene whose expression is to be regulated. This causes changes in protein transcription.
Course of action for steroid drugs?
Characteristic Lag Period
Effects persist after the concentration has been reduced to zero due to slow turnover of most enzymes and proteins
Examples of protein tyrosine kinases.
Insulin
EGF
PDGF
Protein tyrosine kinases span the lipid bilayer ____ times
one
What is the mechanism for protein tyrosine kinase activity
Hormone binds EC domain and change conformation
Receptor molecules bind, brining together kinase domains
Kinase phosphorylates itself
Tyrosine residues in both cytoplasmic domains become phosphorylated
Enzymatic Activity is activated
How are protein tyrosine kinases turned off?
Receptor Down Regulation and endocytosis of receptors
Examples of ligand-gated channel drugs
Acetylcholine
GABA
Glycine, Aspartate, Glutamate
Acetylcholine causes the opening of the _____ channel
nicotinic acetylcholine receptor
Time delay between agonist binding an ligand gated channel opening?
milliseconds
Going very fast is important for things like nerve signalling
Three common second messengers of GPCRs
cAMP
Calcium Ion
Phosphoinositides
Describe the process of GPCR activity
G-GDP inactivity, G-GTP can activate
Phosphorylation inactivates
What is EPAC?
Exchange Protein Activated by cAMP
A cAMP stimulated kinase recently discovered that may influence many effects of GPCRs
Phospholipase C results in the release of _____ and _______
Phosphoinositides and Diacylglycerol
Downstream effect of photphoinositides
Release of Calcium
Downstream effect of diacylglycerol
Protein Kinase C activation
Quantal log-dose response relationships are…
Quantal log-dose response relationship
ex. sleep and death
What is a drug threshold?
The minimum effective dose of the drug which evokes an all-or-none pharmacological response
How are the doses required to produce a quantal effect typically distributed?
log-normally
The resulting cumulative frequency constitutes a quantal dose-response curve
What is Median Effective Dose (ED50)
Dose required to produce the stated effect in 50% of the population
What is the median lethal dose?
The dose required to produce death in 50% of the population
What is the Therapeutic Index/Ratio?
LD50/ED50 OR TD50/ED50
What does one look for in a therapeutic index in a potential drug
A larger ratio indicate a larger gap between effective and toxic doses that will imply a decreased likelihood of accidental patient harm when pursuing a maximal efficacy
What is seen in graded log-dose response relationships
The responding system is capable of showing progressively increasing effects with increasing concentrations of the drug
What is drug tolerance?
A condition of decreased responsiveness to a drug acquired after prior or repeated exposure to a given or related drug
Two ways for development of drug tolerance
- Decrease in effective concentration of the agonist at the site of action
- Decrease in the normal reactivity of the receptor
What drugs most commonly cause downregulation of receptors or changes in receptor affinity?
CNS drugs such as narcotics, depressants, and stimulants
What is cross tolerance?
Tolerance developed to one drug that is also seen with drugs belonging to the same class
Ex. Morphine use leads to tolerance of all narcotics
Important molecular steps in receptor downregulation
GPCR kinase is triggered. It phosphorylates beta arrestin, which binds to the receptor and internalizes it for degradation or recycling.
What is tachyphylaxis?
Acute development of tolerance following a rapid, repeated administration of a drug. Ex. ephedrine
What is a drug allergy?
An adverse response to a foreign chemical resulting from previous exposure to the substance.
What happens at inital exposure when developing a drug allergy.
Drug or metabolite acts as a hapten and combines with a protein to generate an antigen. The antigen induces latent synthesis of antibodies.
Subsequent exposure to drug results in an antigen-antibody response.
Describe the drug allergy dose response.
There isn’t an apparent one. A minute amount of drug results in response.
How could you test for a drug allergy?
Skin Test
Unique characteristic of Type I allergic response?
First exposure IgE to be produced
Becomes fixed to mast cells and basophils
Subsequent exposure causes drug to bind to Fab of IgE
Histamine, PGs released
Unique characteristic of Type II allergic response?
Ab dependent cytolytic response
IgG and IgM mediated
Abs activate the complement system, resulting in cell lysis
Blood Cells are primary targets
Unique characteristic of Type III allergic response?
Immune complex fomation
Drug reacts with soluble Ab (IgG)
Deposits in vasculat endothelium, Cell mediated inflamm.
Serum sickness, hemolysis, and allergic nephritis
Unique characteristic of Type IV allergic response?
Hours or Day after exposure before reaction
Mediated with antigen contact with sensitized T lymphocytes and macrophages
Release of cytokines –> Neutrophils and macrophages
Example of a Type IV drug reaction
Contact dermatitis with a topical cream
Idiosyncratic reactions to drugs are often caused by…
differences in drug metabolizing enzymes
