Week 3 - Pharmacodynamics Flashcards
Pharmacodynamics describes the relationship between drug _________ and _____ of action at the ______ level.
concentration, intensity, receptor
Most drugs act via an ________ with certain proteins either of the ____ or of the ______
interaction, host, pathogen
**Four types of protein are targeted by drugs:
- Enzymes
- Carriers (transporters)
- Ion channels
- Receptors
The term receptor is only used when the interaction triggers a _____ of events for _____ ______.
cascade, signal transmission
Binding site
First, the drug molecule and its _____ must interact.
The selective interaction must result in a response = ?
target, Lock and Key
Drug responses more commonly reflect the interaction of the drug, acting as a _____, with receptor
ligand
Drug is a molecule that interacts with _____ molecular components of an organism to produce ______ and _____ changes/effects.
specific, biochemical, physiological
Drugs may be viewed as ________ ____.
exogenous ligands
Inhibitors →
Normal reaction inhibited.
False substrate →
Abnormal metabolite produced
Prodrug
Make cards for remaining
Cyclooxygenases are the target site for ______ and their inhibition leads to the ______ of ________ _______.
NSAIDs, suppression, proinflammatory prostaglandins
Acetylcholinesterase (metabolizes _______), is a target site for ________ inhibitors e.g., ?
acetylcholine, cholinesterase, neostigmine and physostigmine
Antibiotics may act by _____ enzymes involved in cell ____ biosynthesis, _____ ____ metabolism and ____, or ______ synthesis.
inhibiting, wall, nucleic acid, repair, protein
Enzyme as a Target: Cyclooxygenase-1 and 2
Do not need to memorize these mechanisms
Non-steroidal antiinflammatory drugs (NSAIDs) block the ________-_ and __ and stop thereby the synthesis of _________.
cyclooxygenase-1, 2, prostaglandins
Enzyme as a Target: Acetylcholinesterase (AChE)
AChE is a ________ enzyme primarily found at
________ neuromuscular junctions, especially in ______ and _____.
cholinergic, postsynaptic , muscles, nerves
_______ breaks down acetylcholine (ACh) into _____ ____ and choline. The primary role is to ________ neuronal transmission and signaling between _____ to prevent ACh dispersal and ______ of nearby receptors
AChE, acetic acid, terminate, synapses, activation
Carriers, also termed ______ _____ proteins, are _____ sites for many drugs.
membrane transport, target
The Na+/K+/2Cl- symport in the nephron is the site of action of _______ and other _____ such as torasemide. The biophase (effect site) for all diuretics is the _____, not _____ to develop their diuretic action.
furosemide, diuretics, urine, plasma
Sodium pump Na+/K+ ATPase, ATP-powered ion pumps, are the target sites for __________ _______.
cardioactive digitalis
The ______ pump in the gastric parietal cells is the target site for proton pump ______ such as ______.
K+/H+, inhibitors, omeprazole
Carrier as a Target: The Na+/K+ ATPase
The molecular target of cardiac glycosides is the ___________, which maintains sodium and potassium gradients across the plasma membrane.
Na+/K+ ATPase,
Those gradients are required for the regulation of ___ _____, ____ transport of molecules or the creation and propagation of the ____ or ___ potential of electrically excitable cells such as _____ cells.
cell volume, active, action, resting, cardiac
Carrier as a Target: NKCC Carrier
The diuretics furosemide and bumetanide block the ____ carrier (?) causing a decrease in ____ reabsorption and a concomitant increase in water _______ by the kidneys.
NKCC, sodium, potassium, 2 chloride
carrier aka BSC = bumetanide-sensitive carrier, NaCl, elimination
this carrier was discovered with this drug
Carrier as a Target: H+/K+ ATPase (Proton pump)
Omeprazole interacts with this transporter
Omeprazole blocks the activity of the _____ ______ in the ____ cells of the _____
reducing the secretion of ____ and the formation of _______ ____ (___)
H+/K+ ATPase, parietal, stomach, protons, hydrochloric acid, HCl
Some drugs can produce their effects by interacting with ___ _____.
ion channels
Voltage-dependent gated ____ channels are the main target of the most calcium-channel ______, such as the _________ drugs _____.
calcium, blockers, antiarrhythmic, verapamil
Ion Channels as a Target: Na+ and K+ Channels
Receptor 0, 1, 3
Several antiarrhythmic drugs ____ ion channels located on the membrane of ____ cells, thereby altering the cardiac _____ _____ or its generation or propagation. This results in changes of the spread of _____ or the pattern of ______. Thereby, these drugs suppress ________ ______.
block, cardiac, action potential, activation, repolarization, cardiac arrhythmia
Receptors is a term reserved only for _______ proteins that play a role in _____ _______.
regulatory, cell communication
**Note, ______, ____ _______, and ______ are not classified as receptors
enzymes, ion channels, carriers
Some important properties of receptors are illustrated by the action of _______ (?) on the heart.
adrenaline, epinephrine
The β1 adrenoceptor serves as a recognition site for _______ and other ______. When ______ binds to this receptor, a train of reactions is initiated, leading to an ______ in force and ____ of the _____ ____.
adrenaline, catecholamines, adrenaline, increase, rate, heart beat
Adrenoceptor = ?
Adrenergic receptor
What is the largest family of receptors?
G-protein-coupled receptors (GPCR; metabotropic receptors)
50% of all commercial drugs act in a _____ ______ or ______. Many new drugs will probably be target ____.
GPCR, directly, indirectly, GPCRs
______ are involved in almost all physiological processes
GPCRs
Examples of GPCRs
o Neurotransmitters (adrenalin, acetylcholine, dopamine, etc)
o Hormones (angiotensin, calcitonin, gastrin, etc)
o Olfactory stimuli
o Opioids
“Oh No Harry, Opioids!”
Cell Signaling via G-Protein coupled Receptors (GPCRs)
GPCR receptor
Once a ligand binds to receptor, works in function with GTP protein. Once this reaction occurs, this protein can stimulate three different pathways (red, green, blue).
GPCRs as Targets: Beta 2 adrenergic receptor
Receptor once activated works with protein G.
Describe the function of the bronchodilatory albulterol.
The bronchodilator albuterol produces its effect through interaction with β2- adrenergic receptors (β2AR) located in the plasma membrane of airway smooth muscle cells.
The β2AR is linked to a stimulatory guanine-nucleotide–binding protein (Gs).
Albuterol binding to the β2AR changes the conformation of Gs, leading to the activation of adenylate cyclase (AC), which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP).
cAMP activates the protein kinase A (PKA) which leads to smooth muscle cell relaxation in the airways (bronchodilation)
Receptor is a ______ or a ______ structure on the ______ of/or _____ a cell.
molecule, polymeric, surface, inside
Receptors possess an _____ system called signal-transduction pathways.
effector,
A receptor recognizes and binds an _______ compound, also termed _____.
endogenous, ligands
Endogenous neurotransmitters, such as hormones, are __________ _____.
endogenous ligands
Drugs may be viewed as ?
exogenous ligands
After attachment to a receptor site, a drug may produce ?
a cascade of biochemical events that result in drug action.
Drugs ______ or ______ the actions of endogenous ligands
mimic, prevent
The distinction between agonists and antagonists only exists for ________ receptors. We cannot usefully speak of agonists for the other classes of drug target.
pharmacological
Types of protein targeted by drugs
- Enzymes
- Carriers (transporters)
- Ion channels
- Receptors
Agonist and Antagonist Ligands
Agonist interacts with receptor -→ induces?
Antagonist?
Drug receptor theories consist of a collection of _______ models that permit ______ and _____ description of the relationship between drug ______ and their ____.
evolving, qualitative, quantitative, concentration, effect
______ _____ was the first model proposed by Clark in 1923
Occupancy theory
The receptor-ligand interaction was described as a ________ interaction and the _____-_______ complex was considered responsible for the generation of an effect.
biomolecular, receptor, ligand
The occupancy theory model assumes that drug response is a ______ function of drug occupancy at the _____ level.
linear, receptor
This model postulated that when there is more receptor occupied by agonist → greater reaction.
The drug has to occupy ____ ______ to achieve a _____ effect (Emax) and the response is terminated when the drug ______ from the receptor.
all receptor, maximal, dissociates
Reaction is only possible with agonist or anatagnoist is bound to receptor. Once dissocaited, no reaction anymore.
Response is proportional to the number of ______ _____. The more receptors occupied by a drug the ______ the response.
activated, receptors, greater
In which Effect is the ______ effect; Emax is the _______ possible effect; kd is the _________ constant of _______ (a parameter measuring _____) and Drug is the drug _______
observed, maximal, equilibrium, dissociation, affinity, concentration
Agonist activates these receptors → very high Emax response.
Antagonist does not activate receptor.
Two-state model of receptors
Drug binding to R may shift the equilibrium in either direction
Two-state model of receptors
R1 reacts with LRa, etc.
Difference between classical receptor versus two-state model.
Which drug is more potent?
A b/c EC50 is not high here.
The higher the potency, the lower the EC50
The volume to be administered must be small and only
relative potent drugs can be administered this way
Drug C is a more potent antagonist than drug B
In the presence of a competitive antagonist the dose-response curve for an agonist is shifted to the _____ without a change in ____ or ______ ____.
What happens to potency?
What happens to Efficacy?
right, slope, maximum effect
Decreases
No change
The ED50 of an agonist will _______ in the presence of increasing dose of competitive antagonist (its potency ________). Thus, it will take more _______ to achieve the same effect that occurred in the _______ of antagonist.
increase, decreases, agonist, absence
In the presence of a noncompetitive antagonist, the maximal response (efficacy, Emax ) of the
agonist is ________
reduced
Partial agonist versus full agonist
Affinity = capacity of the drug to bind to receptor.
Bupe has a higher affinity but the efficacy is not as high as morphine
Drugs A and B have similar intrinsic efficacies and can produce the same amount of cAMP accumulation.
Do these drugs necessarily have the same clinical efficacy to reduce blood pressure? No
Drug B produces receptor coupling to machinery that increases cAMP throuhout the cell. Greater
effect on VSMC relaxation.
Drug A produces receptor coupling to machinery that increases cAMP only in certain regions of
the cell. Less effect on VSMC relaxation
Despite drugs A and B each having the capacity to induce similar levels of cAMP production (similar intrinsic efficacies), therapeutically, drugs A and B have different abilities to reduce blood pressure (different clinical efficacies).
ED50 = median therapeutic (or effective) dose TD50 = median toxic dose Therapeutic Index (TI) = TD50/ED50
In the example, TI = 300/100 = 3
A CSF > 1 indicates that a dose effective in 99% of the population is _____ than that which would be _____ (?) in 1% of the population
less, lethal, toxic
The therapeutic window is the range of drug doses that provides ______ efficacy with minimal _______ AKA the range between _______ and the _______ of the _____ curve.
therapeutic, toxicity, ED50, start, curve.
Penicillin has a ______ therapeutic index.
Large
Label the chart accordingly
