PHAR232 - Weeks 1 & 2 Flashcards by Renee Grandi

define pharmacokinetics

the study of how a drug is absorbed, distributed, metabolized, and excreted by the body.

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Define pharmacodynamics

the study of how a drug interacts with the body and produces its effects.

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What are the key targets of pharmacodynamics?

-Receptors
- Enzymes
- Voltage-gated ion channels
- Uptake/transport proteins
- Other cellular constituents

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What is the key issue with pharmacodynamics?

Specificity e.g. one target or many

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What is a drug specificity?

Drug has single action at a tissue or organism level

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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)

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What are 3 the types of agonists e.g. activators?

» agonists (= true agonists)
» partial agonists
» inverse agonists

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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.

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can antagonists change
physical conformation of a receptor?

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Define drug affinity meaning

ability of drug to bind receptor

» is it easy? is it hard? is it influenced by cofactors or mediators?

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What does a drug efficacy relate to?

» ability to activate receptor (fully? partially?)
to elicit effect (response)
» degree to which agonist exerts an
effect

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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

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What are 3 key features that an agonist has to have to change receptor conformation and activate it?

» affinity
» efficacy
» potency

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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

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Define partial agonists

agonists unable to fully change receptor (target) conformation = partial agonists

maximum effect never achieved with partial agonist

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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

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what is constitutive activity>

receptor “works” in
absence of ligand (i.e.
receptor always “on”)

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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

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What are 3 different types of antagonists

competitive antagonists
non-competitive antagonists
irreversible antagonists

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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)