Pharmacodynamics Flashcards
What is pharmacodynamics?
Relationship between drug concentration and intensity of action at the receptor level
What do drugs act on?
Most drugs act via an interaction with certain proteins either of the host or of the pathogen
What are the four types of protein are targeted by drugs:?
- Enzymes
- Carriers (transporters)
- Ion channels
- Receptors
When should the term receptor be used?
The term receptor is only used when the interaction triggers a cascade of events for signal transmission
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
What is a drug?
Drug is a molecule that interacts with specific molecular components of an organism to produce biochemical and physiological changes/effects
What are characteristics of drugs/ other terms used to describe them?
- Any chemical that can affect living processes
- Drugs can prevent, mitigate, diagnose or treat disease (pharmacotherapeutics)
- It could be a prescription or over the counter (OTC) drug
- Drugs may be viewed as exogenous ligands
What are the types of drug targets?
- receptors, enzymes, transporters, ion channels.
What is the target for NSAIDs? What does their inhibition cause?
yclooxygenases are the target site for NSAIDs and their inhibition leads to the suppression of
proinflammatory prostaglandins
What is the target site for cholinersterase inhibitors?
• Acetylcholinesterase (metabolizes acetylcholine), is a target site for cholinesterase inhibitors e. g., neostigmine and physostigmine
How may antibiotics work with enzymes?
Antibiotics may act by inhibiting enzymes involved in cell wall biosynthesis, nucleic acid metabolism and repair, or protein synthesis
Enzyme as a Target: Cyclooxygenase-1 and 2
Non-steroidal antiinflammatory drugs (NSAIDs) block the ________-_ and __ and stop thereby the synthesis of _________.
cyclooxygenase-1, 2, prostaglandins
Enzyme as a Target: Acetylcholinesterase (AChE)
What is AChE? How does it work?
cAChE is a cholinergic enzyme primarily found at postsynaptic neuromuscular junctions, especially in muscles and nerves. AChE breaks down acetylcholine (ACh) into acetic acid and choline. The primary role of AChE is to terminate neuronal transmission and signaling between synapses to prevent ACh dispersal and activation of nearby receptors
What are carriers? How so they work? What are examples?
- Carriers, also termed membrane transport proteins are target sites for many drugs
- The Na+/K+/2Cl- symport in the nephron is the site of action of furosemide and other diuretics such as torasemide. The biophase (effect site) for all diuretics is the urine, not plasma to develop their diuretic action
- Sodium pump Na+/K+ AT Pa s e , AT P- p o w e re d ion pumps, are the target sites for cardioactive digitalis
- The K+/H+ pump in the gastric parietal cells is the target site for proton pump inhibitors such as omeprazole
What carriers in the nephron are the site of action for furosemide? What other drugs can also utilize this path?
The Na+/K+/2Cl- symport in the nephron is the site of action of furosemide and other diuretics such as torasemide. The biophase (effect site) for all diuretics is the urine, not plasma to develop
their diuretic action
What are the target sites for cardioactive digitalis? What about omeprazole
• Sodium pump Na+/K+ AT Pa s e , AT P- p o w e re d ion pumps, are the target sites for cardioactive
digitalis • The K+/H+ pump in the gastric parietal cells is the target site for proton pump inhibitors such as
omeprazole
What is the molecular target of cardic glycosides? What is the purpose of these gradients?
The molecular target of cardiac glycosides is the Na+/K+ ATPase, which maintains sodium and potassium gradients across the plasma membrane. Those gradients are required for the regulation of cell volume, active transport of molecules or the creation and propagation of the action or resting potential of electrically excitable cells such as cardiac cells
What carriers do furosemide and bumetanide block? What does this cause?
The diuretics furosemide and bumetanide block the NKCC carrier (sodium, potassium, 2 chloride carrier aka BSC = bumetanide-sensitive carrier) causing a decrease in NaCl reabsorption and a concomitant increase in water elimination by the kidneys
What does omeprazole block? What does this cause?
Omeprazole blocks the activity of the H+/K+ ATPase in the parietal cells of the stomach reducing the secretion of protons and the formation of hydrochloric acid (HCl)
What is the main target of most calcium channel blockers like antiarrhythmic drug verapamil?
• Voltage-dependent gated calcium channels are the main target of the most calcium-channel
blockers, such as the antiarrhythmic drugs verapamil
What drugs typically block ion channels located on the membrane of the cardiac cells? How does this work?
Several antiarrhythmic drugs block ion channels located on the membrane of cardiac cells, thereby altering the cardiac action potential or its generation or propagation. This results in changes of the spread of activation or the pattern of repolarization. Thereby, these drugs suppress cardiac arrhythmia
What are receptors? Do enzymes, ion channels, and carriers classified in this way?
Is a term reserved only for regulatory proteins that play a role in cell communication
• Note, enzymes, ion channels, and carriers are not clasified as receptors
What are the recognition site for adrenaline and other catecholamines? What occurs when adrenaline binds to this site?
The β1 adrenoceptor serves as a recognition site for adrenaline and other catecholamines. When adrenaline binds to this receptor, a train of reactions is initiated, leading to an increase in force and rate of the heart beat
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
What is an adrenoreceptor?
Adrenergic receptor
What is the largest family of receptors?
G-protein-coupled receptors (GPCR; metabotropic receptors)
Commercial drugs typically act in what way? How will this be the effect of new drugs? What are examples of this?
G-protein-coupled receptors (GPCRs; metabotropic receptors)
• The largest family of receptors (~900 in humans)
• 50% of all commercial drugs act in a GPCR directly or indirectly. Many new drugs will probably be
target GPCRs
• GPCRs are involved in almost all physiological processes!!!
Examples:
o Neurotransmitters (adrenalin, acetylcholine, dopamine, etc)
o Hormones (angiotensin, calcitonin, gastrin, etc)
o Olfactory stimuli
o Opioids
Cell Signaling via G-Protein coupled Receptors (GPCRs)
GPCRs as Targets: Beta 2 adrenergic receptor
How does albuterol produce its effect?
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)
What is a receptor? What is their effector system? What does it recognize?
- Receptor is a molecule or a polymeric structure on the surface of or inside a cell
- Receptors possess an effector system called signal-transduction pathways
- A receptor recognizes and binds an endogenous compound, also termed ligands
Endogenous neurotransmitters, such as hormones, are __________ _____.
endogenous ligands
Drugs may be viewed as ?
exogenous ligands
What occurs after a drug attaches to a receptor site?
After attachment to a receptor site, a drug may produce a cascade of biochemicalnevents that result in drug action.
Drugs ______ or ______ the actions of endogenous ligands
mimic, prevent
Where does the distinction between agonists and antagonists exist? Can it be used in for other drug targets?
The distinction between agonists and antagonists only exists for pharmacological receptors. We cannot usefully speak of agonists for the other classes of drug target
Types of protein targeted by drugs?
- Enzymes
- Carriers (transporters)
- Ion channels
- Receptors
What is an antagonist? What is an agonist?
Agonist: induces cell signalling event
Antagonist: inhibits agonist- induced cell signaling events
What are drug receptor theories? What are the 2 main theories?
Drug receptor theories consist of a collection of evolving models that permit qualitative and quantitative description of the relationship between drug concentration and their effect
- Occupancy Model (theory)
- The two-state model
______ _____ was the first model proposed by Clark in 1923
Occupancy theory
In occupancy theory how was the receptor- ligand interaction described? What did this model assume?
The receptor-ligand interaction was described as a biomolecular interaction and the receptor-ligand
complex was considered responsible for the generation of an effect
• This model assumes that drug response is a linear function of drug occupancy at the receptor level
In the occupancy model, what must the drug do to acheive maximal effect? How does that affect response?
• The drug has to occupy all receptor to achieve a maximal effect (Emax) and the response is
terminated when the drug dissociates from the receptor
▪ Response is proportional to the number of activated receptors. The more receptors occupied
by a drug the greater the response
What does each part of this equation mean?
Effect = Emax X ([Drug]/kd + [Drug] )
In which Effect is the observed effect; Emax is the maximal possible effect; kd is the equilibrium constant of dissociation (a parameter measuring affinity) and Drug is the drug concentration
In the occupancy model what is important about the unliganted receptor? What explains the level of response? What is an antagonist?
The unliganded receptor is silent (no basal activity)
- The level of response is explained by the concept of efficacy
- The more receptors occupied by a drug the greater the response
• An antagonist is a drug with a null (molecular) efficacy but that
blocks access to the receptor of other ligands
What was seen that alerted scientists to refine this theory? what model is the most consistent with the most observations of agonists and antagonists?
This model was confirmed in a limit number of cases…..
The physiological response produced by a ligand is not directly proportional to occupancy and it was evident that some drugs acting at the same receptor could elicit different maximal effects at maximal receptor occupancy leading to the notion of partial agonist versus full agonist
With the help of molecular biology and the use of physiologically based models was possible to better understand how a agonist actually works.
Today, The two-state model of drug action is consistent with the most observations of agonists and antagonists
What is the two state model?
This model assumes that the receptor molecule exists in two extreme conformations with the active and inactive forms in dynamic equilibrium
• This equilibrium may be shifted by the binding of ligands to the receptor
• It is the conformational change of the receptors from an inactive to active state that initiates
the pharmacological response
What is important to remember about drug binding to R in the two state model?
Drug binding to R may shift the equilibrium in either direction
What is an agonist? What is a full agonist? What is a partial agonist? What is an inverse agonist?
A drug with a higher affinity for Ra than for Ri will drive the equilibrium to Ra and thereby activate the receptor
Full agonist
A drug is selective enough regarding Ra to drive all the receptor in its active state and get a maximal response
Partial agonist
A drug has only a moderately greater affinity for Ra than for Ri, its effect will be lower than for a full agonist
Inverse agonist
A drug with a higher affinity for Ri than for Ra will shift the equilibrium towards Ri and will produce an effect opposite to that of an agonist
What is a neutral agonist?
A drug that binds Ra and Ri with equal affinity will not alter the equilibrium between Ra and Ri, will have no net effect of its own, and will act as competitve antagonist
Neutral Agonist is the same as an Antagonist
neutral, one
What is an example of the two state model? How can we see this when it comes to GABA- benzodiazapine receptors?
GABA-benzodiazepine receptor exists in two conformations:
• An active open channel conformation with high affinity for GABA and an inactive closed
conformation with low affinity for GABA (the two forms are in equilibrium)
• Diazepam (an agonist) shows high affinity for the active conformation stabilizing the binding
of GABA to the activated conformation
• The inactive conformation would be favored in the presence of an inverse agonists
What is the difference between a inverse agonist and an neutral agonist?
Neutral: Just blocks agonists. No action
Inverse: They have affinity for for the other receptor and it causes the opposite effect.
When is a drug said to be an agonist? What will it produce?
- A drug is said to be an agonist when it binds and activates receptors to mimic stimulatory effects of endogenous ligands
• It produces a measurable physiological or pharmacological response (characteristic of the receptor (e.g., contraction, relaxation, secretion, enzyme activation)
What is a primary agonist? An allosteric agonist?
Primary agonist: A drug binds to the same site as the endogenous ligands
Allosteric agonist: A drug binds to a different region of the receptor
How do most anesthetic drugs modulate GABA receptors?
Most anesthetic drugs allosterically modulate GABAR and disrupt corresponding physiological circuits
What does a full (pure) agonist produce? What is an example ?
Full (pure) agonist: produces a maximal effect
• Morphine and fentanyl are full agonist of opioid (mu)receptors and able to initiate strong analgesia
What is a partial agonist? What is an example?
Partial agonist: produces only a submaximal effect regardless of the amount of drug applied
• Buprenorphine is a partial agonist. Even if it is unable to achieve a same level of analgesia provided by a full agonist, it may be preferred for postsurgical analgesia because it causes fewer adverse effects
What is an inverse agonist? What is an example?
Inverse agonist: produces an effect opposite to that of an agonist
• Cimetidine and ranitidine are inverse agonists of H2 receptors
What is an antagonist? What are they viewed as? What are most drugs in therapeutics? What is their job?
- After attachment to the receptor site, some drugs may be unable to trigger any action on their own
- Drugs are able to block the action of other agonist
• Antagonist are viewed as silent ligands (drugs)
- Most drugs used in therapeutics are receptor antagonists and prevent the action of natural agonists such as neurotrasmitters and hormones
Can a drug be both an agonist or antagonist? What is an example?
- Some drugs may be both agonist or antagonist
- Butorphanol, a central-acting opioid analgesic, is mainly an antagonist at the mu receptor but is an agonist at the kappa receptor
Affinity is determined by the ?
chemical structure of the drug
Affinity determines the ?
concentration of drug required to form the drug-receptor
complexes that are responsible for drug action (biological response)
Whar is the the constant of affinity (Ka)?
The numerical representation of affinity for both agonist and an antagonist is the
What is drug efficacy? What is it used to characterize?
Efficacy is the drug‘s ability, once bound, to initiate changes that lead to the production of responses
• Efficacy is used to characterize the level of maximal response (Emax) induced by an agonist
Does a pure antagonist have intrinsic efficacy? Why? What should we not confuse the term efficacy with?
In contrast, a pure antagonist has no intrinsic efficacy because it does not initiate a change in cell functions
The efficacy term is not to be confused with the drug‘s clinical efficacy whereby an antagonist may be fully efficacious
What is drug potency? What is expressed by? What can it be used for? How do the potencies of drugs vary with the numerical value of EC50?
Potency: Concentration of drug required to achieve a given effect
• It is expressed by EC50
- EC50 (ED50): Concentration of an agonist which produces 50% of the maximum posible response for that agonist
- Potency can be used to compare drugs with similar effects
• Potencies of drugs vary inversely with the numerical value of their EC50
The most potent drug is the one with the lowest EC50
In terms of potency, what value of EC50 would indicate the most potent drug?
The most potent drug is the one with the lowest EC50
The higher the potency, the lower the EC50
Which drug is more potent?
The higher the potency, the lower the EC50
Drug A is more potent
When a drug is low in potency is that always a bad thing? When would it be a disadvantage? What are examples of drugs that need to be more potent when administered?
A low potency is only a disadvantage when the effective dose is too large to be convenient.
The volume to be administered must be small and only relative potent drugs can be given in these ways:
- Spot on
- Eye drop
- Intraauricular administration.
What is the potency of an antagonist determed by? When would a drug be a more potent antagonist?
The potency of an antagonist (the effect is an inhibition) is determined by its IC50
IC50 = the concentration of an antagonist that reduces the response of an agonist by 50%
Same as EC50, smaller the value more potent the antagonist.
What antagonist is more potent?
Drug C is a more potent antagonist than drug B
What is competitive antagonism? When is it reversible competative antagonism? What is an example? What is an irreversible competitive antagonism?
Competitive antagonism: Antagonists act on the same receptor as the agonist
➢ It is reversible competitive antagonism when it can be surmounted by increasing the concentration of agonist
Agents acting by competitive antagonism:
• Atropine (an antimuscarinic agent)
• Propranolol (a beta blocker)
➢ In irreversible competitive antagonism, a displacement of the
antagonist from its binding site cannot be achieved by increasing the
agonist concentration. There are few drugs of this type.
When is irreversible competitive antagonism used?
Irreversible competitive antagonism are used as experimental probes for investigating receptor functio
In the presence of a competitive antagonist the dose-response curve for an agonist is?
What happens to potency? Efficacy?
shifted to the right without a change in slope or maximum effect.
Potency: Decreases
No change in efficacy
When will the ED50 of an agonist increase? What does this mean?
The ED50 of an agonist will increase in the presence of increasing dose of competitive antagonist (its potency decreases). Thus, it will take more agonist to achieve the same effect that occurred in the absence of antagonist.
What is noncompetitive antagonism? When does this occur?
A drug blocks the cascade of events, normally leading to an agonist response, at some downstream point
This occurs with Ca2+ channel blockers, such as nifedipine, which prevent the influx of calcium
ions through the cell membrane and nonspecifically block any agonist action requiring calcium
mobilization
In the presence of a noncompetitive antagonist, the maximal response (efficacy, Emax ) of the agonist is reduced
The drug receptor interaction is responsible for ?
the specificity of drug action
When may a drug be specific at a low concentration? If the concentration is increased what occurs? Can a drug display activity towards more than one receptor?
- A drug may be specific at a low concentration if it activates only one type of target(enzyme, receptor, etc)
- If the drug concentration is increased several targets may be involved simultaneously
- Most drugs can display activity towards a variety of receptors. Specificity is unusual.
Most drugs can display activity towards ?
a variety of receptors. Specificity is unusual
What are the clinical implications of the dose-response curve?
• Increasing the dose of a drug when the response is submaximal will enhance the therapeutic
effect
• Increasing the dose of a drug when the response is maximal will not improve the therapeutic
effect but may elicit toxic effects
What are 2 terms that are often confused? What is the definitions of both?
- These two terms are often confused
- Efficacy is the parameter of interest for a clinician but potency may be a limiting factor if the drug has to be administered in a small volume
- Efficacy (Emax) gives information on the maximum reachable effect of a drug
- Potency is an expression of the activity of a drug in terms of the concentration of the drug required to produce a defined effect. It does not reflect how effective a drug is
- Each drug has its own Emax and EC50
Efficacy (Emax) gives information on the ?
maximum reachable effect of a drug
Potency is ?
an expression of the activity of a drug
in terms of the concentration of the drug required
to produce a defined effect. It does not reflect
how effective a drug is
Each drug has its own ?
Emax and EC50
Partial agonist versus full agonist
Partial agonist may be more or less potent than ___ agonists
full
When is buprenorphine most often used? Is it effective as an analgesic? What does its partial agonist activity occur? Where does it show a high affinity for its receptors?
• Is most often used as an analgesic for mild to
moderate pain
- Is not as effective as an analgesic as full agonist (morphine)
- Has a partial agonist activity at the mu-receptor and is considered 30 time more potent than morphine
- Shows a high affinity for mu-receptors in the CNS
Efficacy of morphine vs buprenorphine vs naloxone?
Morphine > buprenorphine > naloxone
Affinity of morphine vs buprenorphine vs naloxone?
Buprenorphine = naloxone > > morphine
Clinical efficacy refers to the ?
therapeutic effectiveness of the drug in patients. It is the maximal therapeutic effect that can be produced by a drug
Intrinsic efficacy describes ?
the capacity of agonists to activate a receptor
Many useful therapeutics agents are ?
antagonists. Whereas these molecules exhibit NO intrinsic
efficacy but they exhibit remarkable clinical efficacy
***
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?
cAMP generation leads to ?
vascular
smooth muscle cell relaxation which
can lower blood pressure
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).
Quantal responses are known as ?
the relationship between the dose of the drug and the proportion of a population of patients that responds to it
Quantal dose-response curves are useful for ?
determining doses to which most of the
population responds
What are the parameters determined from quantal dose-response curves?
ED50
TD50
LD50
What is ED50?
ED50
• Median effective dose
• Dose at which 50% of subjects exhibit a therapeutic response to a drug
• in a graded dose-response curve ED50 = the dose of a drug that produces
50% of the maximal effect
What is TD50?
TD50
- Median toxic dose
- Dose at which 50% of subjects experience a toxic effect
What is LD50?
LD50
- Median lethal dose
- Dose at which 50% of subjects die
What is the formula for therapeutic index?
TI = TD50/ED50
What is the therapeutic index?
The therapeutic index (IT) of a drug is the ratio of the dose that produces toxicity in half the population (TD50) to the dose that produces a clinically desired or effective response (ED50) in half the population
What is TI used for?
The TI is a measure of a drug‘s safety, because a larger value indicates a wide margin
between doses that are effective and doses that are toxic
ED50 = median therapeutic (or effective) dose TD50 = median toxic dose Therapeutic Index (TI) = TD50/ED50
In the example, TI = 300/100 = 3
What is CSF?
CSF is a certain safety factor
A CSF > 1 indicates that a dose effective in 99% of the population is less than that which
would be lethal (toxic) in 1% of the population
The range of drug doses that provides therapeutic efficacy with minimal toxicity
