Pharmacodynamics Flashcards
What is pharmacodynamics?
relationship between drug concentration and intensity of action at the receptor level
- how the drugs work
What 4 types of proteins are targeted by drugs?
- enzymes
- carriers (transporters)
- ion channels
- receptors
When is the term receptors used?
only when the interaction of certain regulatory proteins triggers a cascade of events for signal transmission and cell communication
What is a binding site? How does the drug act at this site?
the site at which the drug selectively binds to its desired target (lock and key), resulting in some kind of response
as an exogenous ligand
What is a drug?
a molecule that interacts with specific molecular components of an organism to produce biochemical and physiological changes/effects
Types of drug targets:
What are the target enzymes for NSAIDs, neostigmine/physostigmine, and antibiotics?
NSAIDs: cyclooxygenases are inhibited to lead to the suppression of proinflammatory prostaglandins usually produced by the arachidonic pathway
NEOSTIGMINE/PHYSOSTIGMINE: acetylcholinesterases usually found at postsynaptic neuromuscular junctions are inhibited to stop the breakdown of ACh into acetic acid and choline, which allows neuronal transmission and signaling between synapses to continue
ANTIBIOTICS: enzymes involved in cell wall biosynthesis, nucleic acid metabolism and repair, or protein synthesis
NSAIDs and the arachidonic acid pathway:
Neostigmine/physostigmine and acetylcholinesterase:
What carriers are targeted by furosemide/torasemide, cardioactive digitalis, and omeprazole?
FUROSEMIDE/TORASEMIDE: NKCC symporter in the nephron (urine is the effect site) is blocked, causing a decrease in NaCl reabsorption and an increase in water elimination
CARDIOACTIVE DIGITALIS: Na/K ATPase, that maintains sodium and potassium gradients required for the regulation of cell volume, active transport, or the creation or propagation of electrically excitable cells
OMEPRAZOLE: K/H pump in gastric parietal cells is blocked which reduced the secretions on protons and formation of HCl
Cardioactive digitalis and Na/K ATPase:
Furosemide/bumetanide and NKCC:
Omeprazole and H/K ATPase:
What ion channel does verapamil (antiarrhythmic) target?
voltage-dependent gated calcium channels on the membranes of cardiac cells are blocked, stopping the alteration of cardiac action potential or its generations/propagation, which changes the spread of activation or the pattern of repolarization
- suppresses cardiac arrhythmias
Are enzymes, ion channels, and carriers classified as receptors? Why is β1-adrenoceptor a good examples of a receptor?
NO
serves as the recognition site for adrenaline and other catecholamines - when bound, a train of reactions is initiated, leading to an increase in force and rate of the heart beat
What are G-protein-coupled receptors? What are 4 examples?
largest family of receptors that are the target of at least 50% of commercial drugs and are involved in almost all physiological processes
- neurotransmitters (adrenaline, ACh, dopamine)
- hormones (angiotensin, calcitonin, gastrin)
- olfactory stimuli
- opioids
GPCR activation stimulates what 3 pathways/enzymes? What second messengers are produced in each?
- phospholipase C - DAG and IP3
- adenylate cyclase - cAMP
- ion channel - calcium
What is the target of albuterol (bronchodilator)?
β2-adrenergic receptors in the plasma membrane of airway smooth muscle cells - when bound by albuterol, β2-AR changes the conformation of the linked GPCR, which activates adenylate cyclase and induces the conversion of ATP into cAMP and activated protein kinase A
- results in smooth muscle relaxation in the airways
Where can receptors be found?
surface or inside of cells
What are examples of endogenous ligands? Exogenous ligands?
ENDOGENOUS: neurotransmitters, hormones
EXOGENOUS: drugs
The distinction between agonists and antagonists only exists for what drug targets?
pharmacological receptors
What are drug receptor theories? What are the 2 models?
collection of evolving models that permit qualitative and quantitative descriptions of the relationships between drug concentration and their effect
- occupancy model
- two-state model
What is the occupancy theory? What does it assume in regards to drug response? When is maximal effect gained according to this theory? When is the response terminated?
the receptor-ligand interaction is described as a biomolecular interaction and the receptor-ligand complex is responsible for the generation of an effect
drug response is a linear function of drug occupancy at the receptor level (more occupied/activated receptors by agonists = more/stronger effects)
when the drug occupies all receptors; when the drug dissociates from the receptor
What are the 4 main assumptions gained from the occupancy theory (graded activation model)?
- the unliganded receptor is silent (no basal activity)
- level of response is explained by the concept of efficacy
- more receptors occupied by the drug = greater response
- an antagonist is a drug with a null efficacy but blocks access to the receptor from other ligands
Why was the occupancy theory debunked?
the physiological response produced by a ligand was shown to not be directed proportional to occupancy of receptors and it was evident that some drugs acting at the same receptor could elicit differential maximal effects at maximal receptor occupancy, leading to the notion of partial agonists vs. full agonists
What model is most consistent with observations of agonists and antagonists? What does this model state? What initiates the pharmacological response?
two-state model assumes that the receptor molecule exists in two extreme conformations with the active and inactive forms in dynamic equilibrium, which can be shifted by the binding of ligands to the receptor
conformational change of the receptors from an inactive state to an active state
What is the drug effect proportional to, according to the two-state model?
active receptor - inactive receptor ratio
What are agonists? What are the 3 types according to the two-state model?
a drug with a higher affinity for the active receptors (Ra) than the inactive ones (Ri), which drives the equilibrium to Ra and activates the receptors
- FULL AGONIST: drug selective to Ra, driving all the receptors in its active state to get a maximal response
- PARTIAL AGONIST: drug that only has a moderately greater affinity for Ra than it does Ri, causing its effect to be lower than a full agonist (submaximal)
- INVERSE AGONIST: drug with a high affinity for Ri than for Ra, which shifts the equilibrium toward Ri, and produces an effect opposite to that of an agonist
What are neutral agonists? How does it act?
a drug that binds to Ra and Ri with equal affinity, which does not alter the equilibrium between Ra and Ri, causing no effect of its own
as a competitive antagonist
(no action, just blocks receptors)
What is the difference between agonists and antagonists? How is efficacy explained in the two-state model?
AGONIST: elicits a response
ANTAGONIST: neutral agonist that produces no response
the relative affinity of the drug for one of the states of the receptor
Why is the GABA-benzodiazepine receptor a good example of the two-state model? How does diazepam factor into this?
exists in two states:
1. active, open channel conformation with high affinity for GABA
2. inactive, closed channel conformation with low affinity for GABA
- both exist in equilibrium
it’s an agonist that shows high affinity for the active conformation, which stabilizes the binding of GABA
(inverse agonists favor the inactive conformation)
When is a drug said to be an agonist? What is the difference between primary and allosteric agonists?
when it binds and activates receptors to mimic stimulatory effects of endogenous ligands
PRIMARY: drug binds to the same site as endogenous ligands
ALLOSTERIC: drug binds to a different region of the receptor
How do most anesthetic drugs modulate GABA receptors?
allosterically binds to it and disrupts corresponding physiological circuits
Antagonists are viewed as silent ligands. So why are they used?
most drugs are used this way and they prevent the action of natural agonists, such as neurotransmitters and hormones
(bind, but unable to trigger any action of their own)
Give an example of a drugs used as both an agonist and antagonist.
BUTORPHANOL is an antagonist to mu receptors and agonist at the kappa receptors
What is drug affinity? What is it affected by? What does it determine?
ability of a drug to bind to a receptor
chemical structure of the drug
concentration of drug required to for the drug-receptor complexes that are responsible for drug action
What is drug efficacy? What does it characterize? Why do pure antagonists have no intrinsic efficacy?
drug’s ability, once bound, to initiate changes that lead to the production of responses
level of maximal response (Emax) induced by an agonist
it does not initiate a change in cell functions
(efficacy =/= clinical efficacy)
What is drug potency? What is EC50? What is the most potent drug?
concentration of drug required to achieve a given effect
concentration of an agonist which produces 50% of the maximum possible response for that agonist
one with the lowest EC50
Drug potency comparison:
how much drug is needed for an effect
low EC50 = high potency
When is low potency a disadvantage?
when the effective dose is too large to be convenient
- spot-on, eye drops, intraarticular administration —> volume to be administered must be small and only relative potent drugs can be administered this way
What does the potency of an antagonist measure? What is used to classify it?
the effect it has on inhibition
IC50 = concentration of an antagonist that reduces the response of an agonist by 50%
(drug c is a more potent antagonist)
What is competitive antagonism? When is it reversible? Irreversible?
when the antagonists act on the same receptor as the agonist
when it can be surmounted by increasing the concentration of agonist
when displacement of the antagonist from its binding site cannot be achieved by increasing the agonist concentration (very few drugs are like this)
When are irreversible competitive antagonists typically used?
as experimental probes for investigating receptor function
How does competitive antagonism affect potency? Efficacy?
potency decreases because more drug (agonist) is needed to achieve the same response in the absence of the antagonist (ED50 increases)
no change - the desired response is still achieved
(dose-response curve for the agonist shifts to the right)
What is noncompetitive antagonism? What is a common example?
drug blocks the cascade of events, normally leading to an agonist response at some downstream point
calcium channel blockers, like nifedipine, prevent the influx of calcium ions through the cell membrane and nonspecifically block any agonist action requiring calcium mobilization
How does noncompetitive antagonism affect potency? Efficacy?
no effect on potency, the agonist is still able to bind
maximal response (Emax) is reduced since the magnitude of the response will not be the same as just the agonist
Comparison of competitive and noncompetitive antagonism:
What is drug specificity? When can drugs be specific at lower concentrations? Is specificity normal?
the measure of a receptor’s ability to respond to a single ligand; the capacity of a drug to cause a particular action in a population
if it activates only one type of target (as it increases, more targets can be involved)
NO - most drugs display activity towards a variety of receptors
What happens when the dose of a drug is increased when the response is submaximal? Maximal?
SUBMAXIMAL —> increases therapeutic effect
MAXIMAL —> doesn’t improve therapeutic effect, but may elicit toxic effects
How do potency and efficacy give information to a clinician? Which one tends to be a limiting factor?
POTENCY is an expression of the activity of the drug in terms of the concentration of the drug required to produce a defined effect (NOT effectiveness)
EFFICACY is a parameter of interest and gives information on the maximal reachable effect of a drug
potency
What is the difference between clinical and intrinsic efficacy? How do antagonists factor into this?
CLINICAL EFFICACY refers to the therapeutic effectiveness of the drug in patients - maximal therapeutic effect that can be produced by a drug
INTRINSIC EFFICACY describes the capacity of agonists to activate a receptos
antagonists are unable to activate receptors, so they have no intrinsic efficacy
however, they still have the ability to affect the patient so they have clinical efficacy
How can drugs that have similar intrinsic efficacy have very different clinical efficacies?
(Example: Drug A and B cause similar cAMP accumulation)
- Drug B produces receptor coupling to machinery that increases cAMP throughout the cell, causing a greater effect on vascular smooth muscle cell relaxation
- Drug A produces receptor coupling to machinery that increases cAMP only in certain regions of the cell, causing less effect on vascular smooth muscle relaxation
same amount of cAMP is accumulating, but its effect is not the same
What are quantal responses? What are quantal dose-response curves used for?
relationship between dose of the drug an the proportion of a population of patients that respond to it
determining doses to which most of the population will respond
What 3 parameters are determined from quantal dose-response curves?
- median effective dose (ED50) - dose at which 50% of subjects exhibit a therapeutic response to a drug (dose of drug that produces 50% of maximal effect)
- median toxic dose (TD50) - dose at which 50% of subjects experience a toxic effect
- median lethal dose (LD50) - dose at which 50% of subjects die
What is the therapeutic index (TI)? What is it a measure of?
the ratio of the dose that produces toxicity in have of the population to the dose that produces a clinically desired or effective response in half the population (TI = TD50/ED50)
drug safety - larger value indicated a wide margin between doses that are effective and those that are toxic
Therapeutic Index (ratio):
TI = 300/100 = 3
What is the certain safety factor? What does it meand when CSF>1?
aspect of the dose-response relationship and is the ratio of the lethal dose to 1% of the population to the effective dose to 99% of the population (LD1/ED99)
a dose effective in 99% of the population is less than that which would be lethal in 1% of the population
What is the therapeutic window? How is it measured?
range of drug doses that provides therapeutic efficacy with minimal toxicity
between ED50 and the start of the toxicity curve (NOT TD50!!)
