PHAR232 - Weeks 1 & 2 Flashcards
define pharmacokinetics
the study of how a drug is absorbed, distributed, metabolized, and excreted by the body.
Define pharmacodynamics
the study of how a drug interacts with the body and produces its effects.
What are the key targets of pharmacodynamics?
-Receptors
- Enzymes
- Voltage-gated ion channels
- Uptake/transport proteins
- Other cellular constituents
What is the key issue with pharmacodynamics?
Specificity e.g. one target or many
What is a drug specificity?
Drug has single action at a tissue or organism level
What is drug selectivity?
Ability for a drug to affect one type of cell, leaving another virtually untouched (usually distinguishes between receptors and subtype receptors)
What are 3 the types of agonists e.g. activators?
» agonists (= true agonists)
» partial agonists
» inverse agonists
what are the 4 types of antagonists (blockers/inhibitors)
Competitive antagonist: Competes with the agonist for binding to the same receptor site, reducing the agonist’s ability to activate the receptor.
Non-competitive antagonist: Binds to a different site on the receptor than the agonist, resulting in a conformational change that reduces the receptor’s response to the agonist.
Allosteric antagonist: Binds to an allosteric site on the receptor, leading to a conformational change that affects the receptor’s ability to respond to the agonist.
Partial agonist: Binds to the receptor and activates it to a lesser extent than a full agonist, producing a submaximal response even when all receptors are occupied.
can antagonists change
physical conformation of a receptor?
No
Define drug affinity meaning
ability of drug to bind receptor
» is it easy? is it hard? is it influenced by cofactors or mediators?
What does a drug efficacy relate to?
» ability to activate receptor (fully? partially?)
to elicit effect (response)
» degree to which agonist exerts an
effect
What is a drug potency mean?
» range of concentrations required to have impact
» if low concentration of drug needed for maximal effect, then drug has high potency
What are 3 key features that an agonist has to have to change receptor conformation and activate it?
» affinity
» efficacy
» potency
What is allosteric modulation?
- molecule binds to a specific site on receptor or enzyme,(known as an allosteric site)
- Causes confirmational change
- either enhances (positive allosteric modulation) or inhibits (negative allosteric modulation) function
Define partial agonists
agonists unable to fully change receptor (target) conformation = partial agonists
maximum effect never achieved with partial agonist
what is an inverse agonist?
drugs that interact with receptor to create non-active conformational change e.g. can create altered conformation that ensure
receptor stays inactive
what is constitutive activity>
receptor “works” in
absence of ligand (i.e.
receptor always “on”)
What are 3 key features of an antagonist drug?
= occupies receptor to prevent
agonist-triggered activation
* has affinity not efficacy
* do not change receptor conformation
What are 3 different types of antagonists
- competitive antagonists
- non-competitive antagonists
- irreversible antagonists
How does a competitive antagonist work?
binds to same place on target as
agonist & therefore, competes for binding
What are 2 examples of competitive antagonists?
- Beta blockers
- Anti-histamines
What are 2 mechanisms to which non-competitive antagonists work?
- Binding to a different part of a receptor
- Binding to different coponent in signalling chain that allows agonist to exert its effect
NOTE: agonist will not be able to exert maximal
effect no matter how much agonist is added
What is an example of a non-competitive antagonist?
Ketamine
How does ketamine exert a non-competitive antagonist affect?
ketamine = polyamine
antagonist of NMDA glutamate
receptor
- does not compete with
glutamate for binding
– has its own site
Define Irreversible Antagonists
+ binds to target molecule & either cannot be removed or
+ can only be removed with difficulty
- removal of drug requires destruction of receptor
By what 3 mechanisms do irreversible antagonists cause an affect?
– decreases total number of available targets for agonist to bind over prolonged period
» decreases maximum possible response of agonist
– time delay to restoration of full tissue potential due to requirement for synthesis of
replacement proteins
What is chemical antagonism?
- agonist becomes physically bound to chemical
antagonist & removed from availability - therefore, agonist is incapable of interacting
with target & therefore effect is reduced
What is an example of chemical antagonism?
ion resin cholesterol-lowering
drugs & chelating agents
- ion exchange resin (e.g. cholestyramine) binds
cholesterol in gut preventing absorption
What is the goal of Pharmacokinetic Antagonism?
remove agonist from system more quickly reducing its ability to reach target & exert effect:
- promoting agonist elimination, or
- altering agonist distribution
» therefore, changes pharmacokinetics of drug
» e.g. changes drug half-life
What is Physiological Antagonism?
competition between 2 opposing systems in
the body
What are 4 key elements that defines a drug pharmacokinetics?
- Absorption
- Distribution
- Metabolism
- Elimination
Learning Objectives – How Drugs Act 1 & 2
By the end of this week, you should be able to:
* identify the routes of administration of drugs;
* discuss the implications for the organism of the different routes of administration;
* discuss the impact of common medical conditions on the route of administration of drugs;
* differentiate between the two main branches of pharmacology, namely pharmacodynamics and pharmacokinetics;
* define the key characteristics of drug action, namely affinity, efficacy and potency;
* apply the key characteristics of drug action to novel situations involving data and clinical scenarios;
* define true agonist, inverse agonist, partial agonist;
* apply definitions of agonists to novel situations involving data and clinical scenarios;
* define competitive antagonist, non-competitive antagonist and irreversible antagonist;
* apply the definitions of antagonist to novel situations involving data and clinical scenarios;
* define physiological antagonism, pharmacokinetics antagonism and chemical antagonism; and
* apply the definitions of antagonism to novel situations involving data and clinical scenarios.
identify the routes of administration of drugs;
- Oral
- Sublingual
- Inhalation (gases, vapors, aerosols)
- IV
- Intramuscular (IM)
- Subcutaneous (fatty tissue injections)
- Transdermal
- Rectal
- Intranasal (Sprays, drops)
Define drug affinity
the ability of a drug to bind to its specific target, such as a receptor, with a high degree of selectivity and strength.
Define drug efficacy
represents the drug’s capacity to produce a desired effect or response upon binding to its target, typically measured by the maximum effect it can produce.
Define drug potency
Potency relates to the concentration or dose of a drug required to produce a specific effect, reflecting its relative strength or activity in achieving the desired response.
UNDERSTAND HOW BETA BLOCKERS WORK
LOOK AT PHYSIOLOGY
What foes “shift to the right” mean ?
Means more AGONIST required for response if ANTAGONIST is present.
It takes more DRUG to get my original response if an antagonist is present.
What are examples of competitive antagonists?
Beta blockers
anti-histamines
What is a key element of a non-competitive antagonist?
An AGONIST will NOT be able to exert MAXIMAL EFFECT no matter HOW MUCH agonist is added
What is a key similarity between irreversible antagonists and non-competitive antagonists?
Shapes of the curves on dose-dependent are identical to non-competitive and irriversible antagonists.
You will not be able to differentiate what antagonist it is based on the curvature. Both will have curves that look the same.
How would you be able to differentiate between an irreversible antagonist and a non-competitive antagonist?
- Drug disassociation times from binding essays (irreversibles will NOT unbind)
- Structural analysis of drug-recepter interactions (how many receptors are occupied)
How would you describe antagonism?
It’s the PROCESS
Chemical antagonism
- Doesn’t care about the enzyme/receptor
- Cares about the DRUG it wants to antagonise
- AGONIST becomes physically bound to ANTAGONIST and removed from availability
What is pharmacokinetic antagonism?
GOAL: remove agonist from the SYSTEM more quickly
- promotes agonist ELIMINATION
- alters agonist DISTRIBUTION
- changes drug HALF LIFE
- e.g. alcohol and warfarin - alcohol increases P450 enzyme for drug elimination (reduces total warfarin effect)
Pharmacokinetic antagonism example: ST JOHNS WORT
How many estimated cytochrome P450 mono-oxygenases have been established?
74 genes identified
What is physiological antagonism ?
- Competition between 2 opposing systems in the body
e.g. beta blockers (lower BP) and muscarinic antagonist (increases BP)
