Benedictine University Curve Of Agonist with 10GM ED50 Pharmacology Questions

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Draw a dose-response curve for a full agonist drug with an ED50 of 10 mg. Then, draw: 1. a curve where this drug is given along with a competitive antagonist 2. a curve where with drug is given along with a noncompetitive antagonistreference of the lecture is attached

PHARMACODYNAMICS
Week 1
Material on: Exam 1
What is pharmacology?

Study of substances (drugs) that interact with living systems through
chemical processes

Pharmacodynamics: actions of a drug on the body

Pharmacokinetics: actions of the body on a drug

A drug almost always has a receptor, usually a protein in the body
Physiological receptor: normal function is to be a receptor for something naturally
produced in the body. Examples:
• Generalized receptor: a protein that isn’t normally a receptor, but a drug binds to it
and alters its function. Examples:

What types of molecules can be drugs?

Any chemical that interacts with a system to produce a physiological
effect

Most drugs traditionally have been small molecules –
• FYI: most follow “Lipinski’s Rule of Five”
• Not more than 5 hydrogen bond donors (OH and NH groups)
• Not more than 10 hydrogen bond acceptors (notably N and O)
• A molecular weight under 500 g/mol
• A partition coefficient log P less than 5 (octanol/water)

Large amount of new drug development in the area of “biologicals”:
peptides/proteins/antibodies
RECEPTOR: the component of a cell or organism that interacts with a
drug and initiates the biochemical events leading to its effects.
DRUG
chemical
structure
RECEPTOR
The “Lock and Key” Analogy
binding site
Receptor Activation =
Biochemical Response
Estrogen
Receptor
Estrogen
Beta-2 video

Hydrogen bonds:
most common way
drugs bind receptor
What do drugs do when they bind to a physiological receptor?
Drugs can:
• Activate the receptor
Agonists

Block the endogenous ligand
Antagonists

Cause the endogenous ligand to be
weaker or stronger
Negative or positive allosteric
modulator
Major types of receptors: ligand-gated ion channels
Channel opens (allows ions to pass)
when a signaling molecule binds
Major types of receptors: G-protein coupled receptors
Activates G proteins which activate second messenger cascades
Major types of receptors: enzyme-linked receptors (most commonly receptor tyrosine
kinase)
Activates signaling cascades through phosphorylation of substrates
Major types of receptors: nuclear
Activates or inhibits gene expression
Comparison of receptors with endogenous ligands
Nuclear receptors
GPCR, RTK and LGIC

Located on cell membrane

Located in cytosol, translocate to
nucleus when ligand binds

Activate enzymes and second
messenger cascades

Main effect is regulation of gene
transcription

May cause changes in membrane
potential

Downstream, can lead to gene
transcription changes
Additional types of receptors

Do not have an endogenous molecule that acts on them, but are
affected by drugs

Examples: proton pump, voltage-gated ion channels, enzymes
Drug-Receptor Interactions

The physical properties of a drug (e.g., size, shape, and charge) and
structure of a receptor determines:
• Binding
• Selectivity
• Affinity
Drug-receptor binding
D + R
DR
DR*
Drug
DrugReceptor
Complex
DrugReceptor
Complex
ACTIVATED
Receptor
Signal
transduction
events
Reversible, bimolecular interaction
Follows law of mass action
Response
Drug-receptor interactions: selectivity

Ideal drug would function specifically on desired organ system and receptor

Most drugs are NOT ideal in this sense. They either:
Bind to the same receptors, but in multiple (undesired) organs; or
• Bind to different receptors, especially as drug concentration increases

Drug-receptor interactions: affinity

For any given drug, there is a quantitative relationship between drug
concentration and response

Higher drug concentration → More receptors occupied by drug →
Larger effect

The affinity of a drug for a receptor describes how readily and tightly
that drug binds to the receptor.
Affinity and KD
• The affinity of a drug for a receptor describes how readily and tightly that drug
binds to the receptor.



High affinity = good drug-receptor interaction; LESS drug needed to produce a response
Low affinity = poor drug receptor interaction; MORE drug needed to produce a response
Equilibrium dissociation constant = KD.




Drug concentration at which 50% of that receptor is bound by the drug.
Unit for KD = molar concentration (e.g., micromolar, nanomolar, etc…).
The lower the KD, the higher the affinity of a drug for a receptor.
The higher the KD, the lower the affinity of a drug for a receptor.
EXAMPLE:
Affinity for mu opioid receptor:
fentanyl > morphine > meperidine (Demerol)
Dose typically used for analgesia:
fentanyl: 0.1 mg; morphine: 10 mg; meperidine: 100 mg
Drug types based on how they interact with a receptor
Organize into a concept map:
Agonist
Full agonist
Partial agonist
Antagonist
Competitive antagonist
Noncompetitive antagonist
Inverse agonist
Positive allosteric modulator
Negative allosteric modulator
Biased agonist (don’t need to know this one)
Ligand-receptor binding curves

X axis: concentration of drug (ligand)

Y axis: fraction of receptors occupied by
drug
• LR: ligand-receptor complexes
• Ro: total receptors

X axis is usually logarithmic, making a
sigmoidal curve
Kd

Kd can be seen on binding curves as the
inflection point

It is the concentration where half of
receptors are occupied

In an “ideal” situation, 50% of receptors
bound leads to half-maximal effect
Drug-receptor interactions

Concentration-response relationship
• Response to drug based on concentration in body
• It is rare to know the concentration of a drug in the body, so we often talk
about a dose-response relationship instead

What are some examples of “responses” ?
Graded dose/concentration response curves

Y axis is physiological effect

EC50 or ED50: concentration or dose
needed to reach 50% of max effect

EMAX: maximal effect produced by the
drug
Potency: how much of a drug is needed
to produce a certain level of effect?
EC50 commonly used
Efficacy: how big is the effect?
Spare receptors

Maximal effect can be achieved with less than
100% of the receptors occupied

Occurs due to signal amplification by second
messenger pathways

EC50
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