Lecture 4/5 - Pharmacodynamics Flashcards
What is different about how corticosteroids interact with the cell?
Act on nuclear receptors, altering genes expressed. this causes its effects to be expressed for several weeks even with the drugs gone
What is an electrostatic interaction?
Attraction between functional groups w/ opposite charges
Can be either strong or weak depending on the charge strength
Describe hydrogen bonds.
Hydrogen covalently bonded to an electronegative atom
Weak
What tends to act on intracellular receptors?
Hormone/drug crosses plasma membrane
What is commonly the effect of intracellular receptor activation?
As a complex, stimulates gene transcription OR removes an inhibtion
What is the typical characteristics of intracellular receptor reaction time?
Normally has a lag period but will persist over time
What five examples given in lecture activate intracellular receptors?
Corticosteriods Mineralcorticoids Sex steroids Vitamin D Thyroid hormone
What is the structure of a transmembrane protein?
Polypeptides w/ extracellular hormone binding domain + cytoplasmic enzyme domain
What are the three kinds of enzymes involved with the transmembrane proteins?
Tyrosine kinase + Serine kinase + Guanylyl cyclase
What happens to the transmembrane protein receptors once stimulated?
They are down regulated
What are three examples given in lecture of protein tyrosine kinase receptors?
Insulin + Epidermal GF + PDGF
Describe ligand-gated channels.
Receptor is linked to an ion channel, when ligand binds channel is opened and ions rush in or out of the cell
What ion is paired with acetylcholine/nicotinic receptors?
Na
What ion is paired with GABA receptors?
Cl-
What ion is paired with benzodiazepine receptors?
Cl
What ion is paired with the glutamate receptor?
Ca or Na
Describe a G-protein coupled receptor.
Coupled with G-protein to intracellular second messengers, spans the whole membrane
What do G proteins interact with?
GTP, stimulate binding + hydrolysis = GDP
What do Gs receptors do?
Stimulation the formation of cAMP
What do Gi receptors do?
Inhibit the formation of cAMP
What does cAMP do if it is activated?
PDE breaks down cAMP
cAMP also binds to intracellular protein kinases = phosphorylation of PKA + CREB
What is a major Gs receptor?
Beta1
What is a major Gi receptor?
Alpha 2
What compounds stimulate Gs?
EPI - NE - Isoproterenol - Dobutamine - Histamine - FSH - ACTH
What compounds stimulate Gi?
NE - EPI - Dexmedetomidine - Acetylcholine - Morphine - Serotonin
What does Gq activate?
Phospholipase C
What does PLC do?
Hyrolyze PIP2 into
IP3
DAG
What does IP3 do?
release calcium stores
What does DAG do?
Stimulate PKC
What compounds stimulate Gq?
Acetylcholine - NE/EPI - Phenylephrine - Serotonin
How does the amount of drugs bound to receptors compare to the amount of free drug?
Negligible
What is response directly related to?
Number of receptors occupied
When do you get a maximal response?
When all receptors are being used, at this point no matter how much drug you introduce into the system it will do nothing
What does a sigmoid dose response curve allow you to do?
Determine EC50 (effective concentration)
What direction are more potent drugs on dose-response curves?
Left
What does the slope tell you on a dose-response curve?
How fast response changes with dose
What does the quantal dose-response curve show you?
Frequency of desired effect with each dose (a yes or no response)
use frequency distribution plot
What are the two components to therapeutic ratio?
ED50 + LD50
What is Kd?
Concentration needed to produce half the maximal binding
What is affinity ?
Measures the binding of drug to receptor
What is Potency?
Dose require to produce a given effect
What tells you potency?
EC50
What is efficacy?
Degree of biological response via the binding of the drug to the receptor. NOT POTENCY
What is intrinsic activity?
= efficacy, ability of the drug to initiate response
Number btwn 1 and 0
What type of activity do agonist have?
Affinity + Intrinsic
What type of activity do antagonists have?
Affinity + no intrinsic
What type of activity do partial agonist have?
Affinity + lower intrinsic
What is an agonist?
Bind to receptor and cause a response
What is an antagonist?
Binds to receptor but does not cause a response, blocking the agonist from doing it’s job
What is a partial agonist?
Binds to receptor and causes response but not as good on one, will block the max effect of the agonist
What are the four types of antagonists?
Competitive
Non-competitive
Functional
Chemical
What is a competitive antagonist?
Compete for binding site w/ agonist but with zero activity
What effects does the competitive antagonist have?
Decrease affinity
NO EFFECT on maximal dose response
Shift curve to the right
Can the agonist overcome the competitive antagonist?
Yes, in high enough doses
What are non-competitive antagonist?
Bind irreversibly to receptor so agonist cannot bind, can also bind to a secondary site preventing the agonist from acting
What are the effects of a non-competitive antagonist?
Max response is decreased
EC50 may or may not change
What is a functional antagonist?
Acts through different receptor mechanisms to alter response, less specific and harder to control
What is a chemical antagonist?
Neutralizes drug or compound
What is a partial agonist?
Partial agonist produce response but w/ lower efficacy than full agonist
For most drugs, what is the duration of activity linked to?
Time that drug is bound to receptor, meaning once drug is cleared from the blood stream action is terminated
What happens when a partial agonist combines with a full agonist?
Competition for the receptor will occur causing a decrease in the response, causing them to look like antagonists
What is an inverse agonist?
Does the opposite, physiologically, of what the Agonist does
Example: if the agonist increases heart rate the inverse will decrease it
What causes tolerance?
Chronic administration of drugs
How is pharmacokinetic tolerance?
Drug induces its own metabolism
Drug increase metabolism of another drug
What is pharmacodynamic tolerance?
Up or Down regulation of receptor
