Pharmacodynamics I and II Flashcards
What are effectors?
Molecules that translate the drug-receptor interaction into a change in cellular activity
What are receptors?
specific molecules in a biological system with which drugs interact to produce changes in the function of the system. (Most are proteins)
*High affinity - low capacity
What are some examples of receptors that are not proteins?
receptors that are not proteins: nucleic acids (DNA, RNA), sugars, lipids
What are four factors of affinity?
- shape
- size
- charge
- atomic composition
Are drugs irreversibly or reversibly bound to receptors?
some drugs bind irreversibly (via covalent bonds - whole things gets endocytosed), some bind reversibly
Which drug has a higher affinity? a - Drug A with Kd of 1mM b - Drug B with a Kd of 1 nM c - Drug C with a Kd of 1uM d - Drug D with a Kd of 0.1uM
want drug with the smallest Kd
smallest Kd has highest affinity
answer: b - drug B with a Kd of 1nM
* Kd = dissociation constant
How well a drug binds to a receptor is dictated by the ____ of the drug for the receptor
affinity
D+ R DR
Kd = k^-1 / k^+1
Lower Kd has high or low affinity?
high affinity (doesn't mean it will have highest effect)
Why do companies want to make drugs with higher affinities?
less side effects
What is the evidence for receptors?
FIX QUESTION
- extreme potency/efficacy of drugs
- chemical selectivity (i.e., similar molecules produce similar effects)
- molecular cloning and reconsititution
What are the three interrelated components of drug receptors?
- recognition
- transduction
- amplification
agonist
fill in
antagonist
fill in
What are two mechanisms of …??
- ligand-gated channels
- 2nd messenger linked
Influx of what ion will cause depolarization?
Na+
What are three types of metabotropic receptors involved in 2nd messenger-linked SOMETHING?
- G-protein-coupled receptors
- kinase-linked receptors
- nuclear receptors (steroids will bind these)
g-protein
fill in
What is efficacy?
- ability of a drug to induce a response by itself (i.e., antagonist has no efficacy)
Drugs may produce their biological effects by means of different actions on what locations?
- enzyme active sites
- on nucleic acids
- on membrane protein structures
- on transport mechanisms
- on gene transcription
- on ion channels
What is potency?
- potency is dosage (concentration) of a drug that is needed to induce, or block a response
- -> e.g., EC50 is concentration or dose of drug that causes 50% of maximum effect
A drug’s binding to a receptor is usually weak and easily reversible. What type of bonding/forces do these weak binding forces include?
- ionic bonds (complementary charges)
- hydrogen bonds
- van der Waals forces
*stronger, irreversible binding is done via covalent bonds
The binding of which, an agonist or antagonist, to a receptor causes a change in the shape of the receptor?
agonist
- after binding of an agonist, changes in membrane function or receptor conformational folding may occur - (change in shape)
- an antagonist will bind a receptor without change in receptor shape, but block the binding pocket for agonists
After a drug molecule interacts with a receptor, what changes occur?
- changes in distribution of chemical charges
- changes in folding of the receptor protein
and/or - changes in drug receptor conformation
*these occur to activate the transducer mechanism to which the receptor is coupled
What are the three interrelated components of drug receptors?
- RECOGNITION SITE that binds the drug molecule
- TRANSDUCER mechanism that translates binding into a biochemical change
- an AMPLIFICATION mechanism
*result in alteration of cellular function
What does an antagonist do?
interacts with receptor recognition site to induce change in cell function (increase or decrease)
What does an antagonist do?
interacts with receptor recognition site but does not itself induce change in cell function, only blocks access of agonist (exogenous or endogenous) to receptor site
What does a partial agonist do?
interacts with receptor recognition site but a partial agonist cannot induce a maximum response
What is affinity?
ability and attraction of drug-receptor interaction
What is intrinsic activity?
ability of a drug to induce intracellular activity
What do ligand-gated channels (inotropic receptors) result in?
hyperpolarization or depolarization
What are the four drug targets (receptors) that drugs act on?
1 - ligand gated ion channels (inotropic)
2-4 - Second Messenger receptors (metabotropic)
–2- G-Protein coupled receptors (GPCRs)
–3- Kinase receptors
–4- Nuclear receptors
(enzymes (NSAIDS cox1 and cox2) and transporters are two other categories of receptors)
How does a G-protein-coupled receptor work?
agonist binds to receptor which activates G (+/-) by associated with receptor and exchanging of GDP on G with GTP. G protein is now active, dissociates from receptor and other subunits (gamma, beta) and interacts with other proteins/enzymes (effectors) that amplify the effect. (open up an ion channel or activate effector and second messengers)
How does Kinase-linked receptor work?
Receptor and Effector are same substance. R/E gets bound by substance (drug, etc.) which leads to intracellular response: protein phosphorylation –> gene transcription –> protein synthesis –> cellular effects
How do nuclear receptors work?
drug, etc. enter cell, enter nucleus and bind receptor in nucleus which results in gene transcription –> protein synthesis –> cellular effects
What are six ‘pieces’ of evidence for the existence of drug receptors?
- extreme potency of some drugs
- similar molecules often produce similar effects
- stereoisomers usually differ in pharmacological activity or potency
- competitive antagonists
- radioligand binding
- cloning
What is the overall function of Gq proteins?
to increase phospholipase C activity leading to release of PIP2 into two components:
- IP3: results in release of intracellular calcium which activates CA2+ dependent kinases
- DAG: activates protein kinase C
Some G proteins can activate phospholipase A2 (PLA_2) which results in the release of what from the cellular membrane?
Arachidonic acid, which is acted upon by enzymes to produce many factors including prostaglandins, thromboxanes, and leukotrienes
What is the overall function of Gq proteins?
to increase phospholipase C activity leading to release of PIP2 into two components:
- IP3: results in release of intracellular calcium which activates CA2+ dependent kinases
- DAG: activates protein kinase C
*exchange of GDP for GTP; alpha portion will turn on PLC; PLC will convert a lipid into triglycerol, and increases intracellular Calcium, and activates protein kinase C
(PLC activates lipids to release Calcium)
What can block the arachidonic Acid pathway?
- NSAIDS
- aspirin
*these act on COX
What happens when a nuclear receptor (found in the cytoplasm) is bound by an agonist?
these receptors will enter the nucleus and alter gene transcription
The concentration of drug required to bind to a receptor is a measure of what?
affinity
Activation of G_alpha,s leads to…
increased cAMP and PKA activity
Activation of G_alpha,i leads to…
decreased cAMP and PKA activity
Activation of G_alpha,q leads to…
- increased IP3 and DAG
- increased PKC and CAM kinase activity
Activation of PLA2 leads to…
increased Arachidonic Acid Release
Activation of Tyrosine Kinase Receptors leads to…
phosphorylate proteins
Activation of Adenylate Cyclase leads to…
increased cAMP and PKA activity
Define mass-action relationships
the greater the number of agonist molecules, the greater the number of receptors occupied at any given moment
*therefore, responses to drug are graded or dose-dependent
What axis is expressed on a logarithmic scale?
dose
What is the threshold dose?
the lowest dose that just begins to cause a response
What is the shape of dose-response curves?
sigmoid
What is ED50?
the dose that produces a 1/2-maximal response
What can be indicative of the presence of ‘spare receptors’?
when the maximum response occurs when less than 100% of the receptors are occupied
What are partial agonists?
agonists whose maximum effect is less than that of full agonists and less than the maximum response of the tissue
*even if partial agonists occupy 100% of receptors, a maximum tissue response is not produced
What is efficacy?
the ability of an agonist to induce a biological response after interaction with a receptor
*also referred to as intrinsic activity
How does tissue amplification differ?
ex: biological responses can differ in children vs middle aged adults vs the elderly
What is potency?
the amount of drug required to bring about a response
Full agonist: affinity, efficacy?
- has affinity
- has full efficacy
Partial agonist: affinity, efficacy?
- has affinity
- deficient in efficacy
Pure antagonist: affinity, efficacy?
- has affinity
- no efficacy
What are antagonists?
they bind to the recognition site and occupy it, but are not able to activate the transducer component of the receptor system
What is the action of a pure antagonist?
to diminish access of agonist molecules to the receptor
How can an antagonist help?
it can block the excess in case of overdose of a drug or when the body itself makes too much of an endogenous molecule
What is characteristic of a competitive antagonist?
it can be overcome by increasing the concentration of agonist
What is a noncompetitive antagonist?
an antagonist that interacts irreversibly with the receptor recognition site (usually by formation of stable covalent chemical bonds)
*also referred to as irreversible antagonist
What is the equation for therapeutic window?
therapeutic window = TD50/ED50
What is the therapeutic index? How do you calculate it?
a relative measure of safety, calculated as the ratio of LD50 (lethal dose) to the ED50 for the desired effect (but can also referencce to unwanted side effects, not desired effects)
therapeutic index = LD50/ED50
The safer the drug, the _____ the therapeutic index.
larger
What happens when a partial and full agonist are used together?
a partial agonist can act like a partial antagonist in the presence of a full agonist
If ED50 is less than Kd, what does this say about the number of receptors?
there are excess receptors
Kd is 50% mark on drug binding curve
How do you tell which drug is more potent?
ED50
