Pharmacodynamics (EXAM 2) Flashcards
what is pharmacology?
science of interactions of chemical compounds with biological systems
what is pharmacodynamics?
the study of biochemical and physiological effects of drugs and the mechanisms of their actions
what is pharmacokinetics?
the study of absorption, distribution, biotransformation, and elimination of xenobiotics
what are the many characteristics of drugs?
- Defined by actions
- Most act on receptors
- Endogenous drugs or xenobiotics
- Includes poison/toxin
solids/liquids/gasses - Covalent, electrostatic, and hydrophobic interactions
- Ions to larger proteins/antibodies/vaccines, majority are small molecules
- Drug shape and rational drug design for receptor specificity
what are the sites of drug action?
extracellular, intracellular, on the cell target
describe the extracellular site?
- Neutralization of excessive gastric acid by antacids
- Ex: cholestyramine resin in reducing cholesterol absorption
describe the intracellular site?
- Drugs used to treat infections
- Drugs used for cancer therapy
- Ex: hormones such as estrogen
describe the on cell target site?
- Comprises cell-membrane receptors
- Many drugs act by combining with receptors on the surface of the cell
- Examples
— Acetylcholine and muscarinic or nicotinic receptors
— Growth factors (EGF/FGF) and GF receptors
— Monoclonal antibodies (mABs)
how can we relay affinity to the law of mass action and receptor occupancy?
- Effect of a drug is directly proportional to the amount of drug-receptor complex formed
- Lower Kd (d*r/dr) → higher affinity
- Higher affinity → more drug receptor complex and receptor occupancy → more intense drug effect
- Based on koff and kon rates of drugs
what are the components in a receptor binding assay?
- orthosteric: agonist/antagonist, partial agonist, inverse agonist
- allosteric: PAMS, NAMS
- each receptor has one orthosteric site and can have many other allosteric sites
what are the principles of receptor bindng assays that measure affinity?
- affinity is the ability to interact with the receptor
- kD is a measure of affinity
– low= tight
– high= loose - affinites can differ from drug to drug
- affinity = potency
what is pharmacologic profiling?
heterologous competition testing several unlabeled compounds simultaneously
how can we use the graphical data for pharmacologic profiling?
- cheng-prusoff equation
– has IC50 value and from that we can determine the Ki - Ki is a measure of kD
- Ki for each can be computed and compared and affinity rank can be calculated
how can we apply affinity to receptor selectivity?
- the log 3 rule
– 10%, 50%, 90%
—> one log above and one log below
what is Bmax?
total number of receptors on a given cell or tissue
how can we use bmax with drug action?
it is the max affect of a drug
– it is the concentration of all receptors where they are all occupied and reach max conc.
how can we identify and compare dose response curves for each type of ligand in the spectrum?
- Super agonist is > 100% response
- Agonist is 100% response
- Partial agonist is 50% response
- Silent antagonist is 0% response or opposite
- Partial inverse agonist is -50% response or negative effect
- Full inverse agonist is -100% response
what is the difference between agonist and antagonist receptor binding?
- Agonist binding: binding of an agonist results in an induced fit that activates the receptor
- Antagonist binding: binding of an antagonist results in a different induced fit that does not activate the receptor
how can we use graphical data to compare potency and efficacy for active ligands?
efficacy: goes toward max response or up
potency: goes to the left for increasing potency
what is a partial agonist?
- Produces a reduced response even at full receptor occupancy
- Cannot produce the same max effect as a full
- Partial agonist may inhibit competitively the response to a full agonist
- Mechanisms complex but probably related to drug binding to inactive form of receptor
EXAMPLES: abilify, buspar, buprenorphine
how can we apply the concept of partial agonist theory to managing drug therapy?
We know an agonist can open an ion channel immediately, so when we have a partial agonist we can see that there is a complex in between the open and closed state. It can also take longer with both a complex and a flip state before closing or opening the channel
Also we can use this theory to determine the total response between full agonists and partial agonist and produce a dose response curve to compare the two
what are the features of inverse agonists?
- Requires constitutive activity
- Produces the opposite response of an agonist
- Can have full and partial inverse agonists
- Response can be altered by agonist, partial agonist, and antagonist
- Stabilize inactive form of receptor
—- Ex: rimonobant
what is reversible competitive inhibition?
- Antagonist combines with the same site on the receptor as the agonist
- Antagonism can be reversed by increasing the dose of the agonist
- competitive goes to the right and is same as regular in size
what is irreversible non-competitve inhibition?
- Usually bind to the same site as an agonist, but will not be readily displaced
- Irreversible inhibition is generally caused by covalent reaction between antagonist and receptor
- Inhibition persists even after an irreversible antagonist is removed. Duration of action dependent of receptor turnover
how can we use spare receptor to explain drug action?
- When max response can be elicited by an agonist at a conc. That does not result in 100% occupancy of available receptors
—> Ex: response of heart muscle to catecholamines can still be obtained when 90% of beta receptors are occupied by an irreversible antagonist - Important in the action of irreversible antagonists
what is chemical antagonism?
- occurs between an agonist and an antagonist to form an inactive product
- Agonist is inactivated in direct proportion to the extent of the chemical reaction with the antagonist
–> Ex: calcium antacids and tetra. Antibiotics, cyanide and sodium nitrite
what are the mechanisms of allosteric modulators?
PAMS
NAMS
Signaling texture
what are allosteric modulators potential benefit in drug therapy?
- Bind at sites unique from agonist or antagonist
- Increased specificity for receptors that have similar orthosteric binding site
- Increased safety due to ceiling effect
- Provide more physiological/ temporal signaling
—> EX: PAMS of dopamine receptors for parkinsons
what is efficacy?
biological response resulting from receptor interaction
what is potency?
does of drug required to produce a particular effect of given intensity
what is a non-competitive antagonist
- produces its effect at a site of the receptor other than the site used by the agonist
- Agonist and noncompetitive do not compete with one another for a single binding site
- Cannot be completely reversed by increasing the conc. Of agonist
- Increasing antagonist conc. Increase the KD and dec. Emax of agonist
spare receptors are:
system/tissue dependent
- some cells have no reserve
- coupling efficiency is a determinant
- may differ for responses with same receptor
what is functional antagonism?
- 2 drugs influence a physiological system but in opposite directions
- Each drug is unhindered in the ability to elicit its own characteristic
–> Ex: effect of histamine on BP can be offset by epinephrine - Can lead to contraction or relaxation based on path
what are the 5 classes of receptors
intracellular receptors
cytokine receptors
protein kinase receptors
ion channels
GPCRs
what are intracellular receptors
- Intracellular receptors (regulate gene expression) (steroids)
— Stimulate the transcription of genes in the nucleus by binding to specific DNA sequences near the gene whose expression is regulated
– Additional non receptor receptors
——– Effector enzymes that regulate cellular function include membrane potential, protein phosphorylation, translation, transcription, etc.
———–> Kinase, cyclase, phosphatases, ubquitinases
what are cytokine receptors
simplest
- JAK-STAT pathway
- mechanism: binds, activation leads to JAK, phosphorylation to STAT, dimerizes and travels to regulate transcription
–> Examples: GHs, erythropoietin, interferons
what are protein kinase receptors
- Mechanism: ligands dimerize,conformational change, phosphorylation happens and recruits GRAB, leads to activation of RAS, RAS leads to transcription
—> Examples, EGF, PDGF, insulin - Kinases add a phosphate group
- This pathway can be turned off by blocking
- RTKs as drug targets
—> Lots of ways to target an receptor
what are the two types of ion channels
voltage gated and ligand gated
what do voltage gated ion channels do
- No ligand just membrane potential
- Bind at allosteric sites
- In order to block we have to activate
–> Ex: na, ca,k - Involved in pain, epilepsy, arrhythmias, vascular tone, neurotransmitter release
- Channels can be regulated by phosphorylation and G proteins
what do ligand gated ion channels do
- Many drugs act by mimicking or blocking endogenous ligands that regulate flow of ions through channels
–> Ex: acetylcholine, gamma-aminobutyric acid, glutamate, etc. - When bind the signal is transmitted across membrane and alters electrical potential
- Very fast (milliseconds)
–> Important in rapid transfer of signals across synapses
what are g couples protein receptors
- Very popular in human genome and largest family
- 40% of drugs target GPCRs
- 3 classes (A,B,C)
- Ligands act by modulating effectors and concentrations of second messengers
who invented cyclic AMP in 1971
earl sutherland
what are the affects of allosteric modulators on ion channels
Allosteric modulators that activate or inhibit ion channels by binding to domains other than the pore are more favorable than channel blockers because they have the capability to target channels more specifically and regulate their activities more precisel
what are the affects of allosteric modulators on GPCRS
Allosteric modulators may stabilize, disrupt, or induce structural conformations that preferentially (biased) signal via one or multiple pathways, at magnitudes unlike the endogenous ligand. C. Many GPCRs are targeted by large endogenous ligands, such as peptides and proteins
what are the features of G protein activation
- effectors: channels, enzymes, regulatory proteins
- second messengers: cAMP, CA2+, phosphoinositides
what are the components of the signaling process for gpcrs
R
- extracellular ligand is detected by cell surface receptor
G
- this receptor in turn trigger activation of G protein located on cytoplasmic face of the plasma membrane
E
- activation of Galpha and Gamma/beta then changes the activity of the effector
– enzyme or ion channel
- this effector often changes the concentration of the intracellular second messengers which produce an effect
– greatly amplified response
what are the subtypes of G proteins
Gas, Gai, Gas/11, Ga12/13, Gby
what is Gas effector
inc. adenylyl cyclase
what is Gas isoforms
gas, golf
what is Gai effectors
dec. adenylyl cyclase
what is Gai isoforms
Gai1, Gai2, Gai3
what is Gaq/11 effectors
inc. phospholipase C
what is Gaq/11 isoforms
Gaq
what is Ga12/13 effectors
recruit Rho guanine exchange factors
what is Ga12/13 isoforms
Ga12, Ga13
what is Gby effectors
dec. adenylyl cyclase
inc. ion channels (Ca and K)
what is Gby isoforms
B (1-5)
y (1-13)
what are the second messengers
cAMP
cGMP
calcium and phosphoinositides
what does the second messenger cAMP do
- Effector enzyme is adenylyl cyclase and enzyme that converts ATP to cAMP
- cAMP stimulates PKA
- Specificity of cMAP is defined by compartmentalization of signaling complexes
— Ex: B1 adrenergic receptors for asthma
what does the second messenger cGMP do
- Effector enzyme is guanylyl cyclase
- cGMP activates cGMP-dependent protein kinase
— PKG - Regulated by nitric oxide
- Much more specific than other messenger systems
what do the second messengers calcium and phosphoinositides do
- PLC results in release of phosphoinositides and diacylglycerol
- Phosphoinositides result in release of calcium
- Diacylglycerol active protein kinase C
–> Ex: muscarinic receptors in alzheimers
what are kinases
phosphorylation
- 800 genes in genome
- unique specificity
- inhibitors as drugs:
–> imantinib, trastuzumab
what are phosphatases
dephosphorylation
- 250 genes in genome
- very few drugs targets
—> ex: diabetes, PD, AD, allergy and asthma
what is the mechanism and consequence for homologous desensitization
- Does it to itself
- Rapid desensitization
– GRKs aka B-ARK
– Less responsive - Receptor uncoupling-arrestin binding
- Sequestration and fate (arrestin involvement)
— Recycling (dephosphorylation)
— Degradation (lysosomal degradation)
what’s the mechanism and consequence for heterologous desensitization
- Can do this to another receptor with kinases
- non-agonist/receptor-specific
- Involve signaling cascades from other receptors
— PKA or PKC phosphorylate receptor of interest - Blunt receptor response or alter G protein coupling
how can we use functional selectivity to design better drugs
we can use them to enhance therapeutic pathway
- TRV027-AT1 biased agonist that promotes B arrestin
– Blocks vasoconstriction in HF
– Beneficial in COVID
- Opioid therapy for analgesia
– B arrestin linked to tolerance and maybe respiratory depression
– Avoid this pathway
– we want the G protein pathway here
what is functional selectivity and its purpose in concentration response curves
- AKA agonist trafficking, biased agonism, ligand bias, differential engagement, and protein agonism
- Requires the receptor couple to multiple signal transduction pathways
– G protein and B arrestin - Display selectivity for one or more pathways when compared to another pathway
- Receptor binding to other pathways
what is the GPCR effector pathway for norepinephrine (receptor, effector, second messenger, later effectors, response)
Gas, adenylyl cyclase, cAMP, protein Kinase A, inc. protein phosphorylation
what is the GPCR effector pathway for dopamine (receptor, effector, second messenger, later effectors, response)
Gai, adenylyl cyclase, cAMP, protein kinase A, inc. protein phosphorylation
what is the GPCR effector pathway for glutamate (receptor, effector, second messenger, later effectors, response)
Gas, phospholipase C, Dag and IP3, protein kinase A, and Ca release, inc. protein phosphorylation, and activate Ca binding proteins
what is the GPCR effector pathway for LPA (receptor, effector, second messenger, later effectors, response)
Ga12, RhoGEF, Rho GTPase, effector, inc. endocytosis, motility, transcription
tell me about the Diversity of Gs-AC-cAMP system for cAMP
Gs-linked receptors
– 100s
Gs variants
– 3+
AC isoforms
– 10
PDE isoforms
– 11
PKA, EPAC, CNGC
tell me about the Diversity of Gq-PLCAC-IP3/DAG system for calcium and phosphoinostides
Gq-linked receptors
- Multiple types
PLC isoforms
- Cleaves PIP2, DAG, IP3
- 13
PKC isoforms
- 15
CaM targets
- 300
what are the significances of intracellular receptors
— Significances:
———– Has lag period and slow
———– Cannot be altered in minutes, takes hours
———– Effects can persist after conc. Is reduced to zero
———– Slow turnover
—————-> May be due to high affinity
what is the mechanism for intracellular receptors
— Mechanism: steroid, ligand binding domain, dna binding domain, altered transcription of gene
how can we measure the second messenger cAMP
Measure by:
- Protein-based biosensors
- Fluorescent approaches
- Radioactive assays are not popular anymore
Identify and define the key means by which drug effect is quantified and compared.
- Onset: when it hits the desired response for the first time
- Intensity: rate of energy expenditure
- Duration: the time it takes for the action to take plac
know the differences between quantal and graded drug responses
- Graded: maximal efficacy (progressive increase)
- Quantal: potential variability of response (all or none)
how to compare and calculate therapeutic index between drugs
- Relative safety of a drug expressed as LD50/ED50 or TD50/ED50
- The larger the ratio presumably the greater the relative safety
– Unfavorable (toxic and close together)
– Favorable (spread out and safer drug)
what are the factors that can modify the effects of drugs
- Drug tolerance
- Physiological
– Age
– Gender
– Pregnancy
– Food
– Circadian clock - Pathological
– Liver disease
– Renal disease
– Malnutrition - Genetic
– Pseudocholinesterase deficiency
– Malignant hyperthermia
– Oxidation polymorphism - Interaction with other drugs
– Pharmacokinetic
– Pharmacodynamic
– placebo
what is drug disposition tolerance
- Decrease in effective concentration of the agonist at the site of action
- Drug disposition/ metabolic tolerance
— I.e. phenytoin increases rate of biotransformation of a number of drugs which are metabolized by liver enzymes
— End result is decreased effect on drug
what is pharmacologic tolerance
- Decrease in normal reactivity of receptor
- Cellular or pharmacologic tolerance
— Downregulation of receptors
— Change in receptor affinity
— Most often seen with CNS drugs such as narcotics, depressants, and stimulants
how can we apply cross tolerance to disease management
bases to opioid receptors and tachyphylaxis
what are the opioid receptors doing
- Tolerance develops to one drug that is also seen with drugs belonging to the same class
—– For example, an individual tolerant to morphine develops some level of tolerance to morphine develops some level of tolerance to opioids that act on same receptor (e.g. heroin, methadone, codeine)
–> not always complete
what is the tachyphylaxis doing
- Acute development of tolerance following rapid and/or repeated administration of a drug
– The first administration of drug produces a much larger response than subsequent doses, when given after a brief interval
– Can NOT overcome this type of tolerance with increasing dose
—> Ex: amphetamine, ephedrine (norepinephrine release) and LSD
what are the on and off target adverse effects for intended tissue
on-dose too high and chronic activation or inhibition effects
off- incorrect receptor is activated or inhibited
what are the on and off target adverse effects for unintended tissue
on- correct receptor but incorrect tissue, dose too high, chronic activation or inhibition effects
off- incorrect receptor is activated or inhibited
what are the physiological response in multicellular/multi receptor context.
altered gene expression, relaxation, contraction
what causes gene expression changes
all pathways
what causes relaxation changes
epinephrine and acetylcholine and BNP from cAMP and cGMP
what causes contraction changes
angiotensin 2 from calcium, IP3, and adrenergic nerves
