Week 1

Status quo

A drug could be “perceived” as disrupting homeostasis so body attempts to restore status quo

Tolerance

Reduced effects / reaction to drug following repeated use

Dependence

Baseline functionality becomes dependent on drug

• Not same as addition

• Examples:

  • coffee (can be dependent but not addictive)

  • morphine (can be be dependent and addictive or neither)

Tachyphylaxis

1. Decline in response to a drug with repeated administration

2. Physiological basis (i.e. nonrandom process)

Fade

Long term tolerance (decline in response with time)

Attenuation

Decrease of response at the receptor level

Desensitization

Decrease response to drug binding

Downregulation

Decreased expression of drug target 🎯

Sensitization

Also called reverse tolerance

• Increased response to a drug with prolonged use

• May be concurrent with tolerance

• Chronic use of antagonist may lead to receptor upregulation

Upregulation

Also called sensitization

Chronic use of antagonist may lead to receptor upregulation

Reverse tolerance

Also called sensitization

• Increased response to a drug with prolonged use

• May be concurrent with tolerance

• Chronic use of antagonist may lead to receptor upregulation

Supersensitivity

Abrupt removal of antagonist results in increased receptor activity

Biomarker

Genetics

Particularly important for newer cancer therapies

Example: V600E mutation in RAF-B is required to use vemurafenib for melanoma

Practice question 1

Downregulation

Practice question 2

Tachyphylaxis

Practice question 3

Dependence

Practice question 4

Reverse tolerance

Practice problem 5

Supersensitivity

ADR

Something bad happens when taking a drug

ADE

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Type A (ADR)

Adverse reaction that is based in its mechanism in action

Example: take too much of a drug and get negative effects

Type B (ADR)

Idiopathic

Example: take a drug and get a rash

FDA

Food & drug administration

ISMP

Institute for safety medical practices

Med/vaccineine errors

WHO

World Health Organization

Local case repot form LCR

CrCl (not chromium chloride)

Estimate kidney functions

FAERS

FDA adverse event reporting system

(Report if any ADRs)

Occupancy (in pharmacology context)

A drug living in a receptor

Fractional occupancy

Example: When a cell with a thousand of receptors has half of the receptors occupied

Downstream amplification

One binding event can produce more than one effect in the cell

Example: transduction

Spare receptors

When a cell is 100% occupied but there is still some spare receptors bc those receptors are not needed to reach 100%

Positive allosteric modulator

Increased the effect of allosteric

Negative allosteric modulator

Decreases the effect of allosteric

Potentiate

Make more potent

Isobologram

Looking how the activity of one drug and how it affects another drug

Analogy: You are lifting a box with another person. What happens if…

• the other person lifts the same upward motion ADDITIVE

• The other person holds the box in a way that some of her force pushes down on it as its being lifted ANTAGONISTIC

• With the other person you can rotate it while suspended so that you both get better handholds on the SYNERGISTIC

Synergistic (drug-drug context)

1 + 1 = 3

Getting more than what you bargained for

Usually a good thing

Antagonism (drug-drug context)

1 + 1 = 1.5

Preventing one drug from another from doing its job

-mechanistic detriment

Additive (drug-drug context)

1 + 1 = 2

Drugs leave each other alone

If you double occupancy you should expect…

Double the effect

Occupancy is usually directly proportional to…

Drug concentration

use the data to create a graded dose-response curve

Goes up but then hits a plateau

What information does this provide? What is the shape of the curve?

Full agonist

Hyperbolic

What is the approximate EC50

15.3

Fractional occupancy formula

f = [LR] / [Rt] = [L] / Kd + [L]

True or False

Due to downstream amplification, full biological response can be achieved at <100% occupancy

True

EC50 shifts left of KD and spare receptors exist

Why is fractional occupancy often higher than predicted for an agonist?

Because of downstream amplification (getting more bang for your buck)

Allosteric modulation

A drug can bind at an allosteric site and enhance receptor activity

• Alters affinity for the agonist

• Ability of the agonist to induce or stabilize conformational changes when activated

Positive allosteric modulators

• May Potentiate activity of agonist

• Allosteric modulators do not activate receptor in absence of agonist

The graph shows effect of three allosteric modulators. Describe their effects and label as positive or negative modulators

(Green is considered standard)

Green = agonist

Blue = allosteric modulator 1 and agonist

• Efficacy is increased (line is higher)

• Potency is unchanged (look at EC50)

• POSITIVE bc something increased

Red = allosteric modulator 2 and agonist

• Efficacy is unchanged (same height)

• Potency is increased (more to left)

• POSITIVE bc something increased

Why does the curve shift right at lower doses and shift down at higher doses?

• decreased potency (and efficacy)

• Decreased efficacy

Even though you are giving higher dose, you are running out of spare receptors

Learn it on your own

lecture time stamp: 1:23:44

Physiological receptor

Proteins that are receptors of endogenous regulator ligands (receptors your body makes)

Ligand

Binds to receptor

Constitutive Activity

Amount of activity receptor has by itself

Endogenous ligand

Ligand your body makes

Hyperbolic

Shape

Orthosteric

An agonist that binds to the same site of the receptor as the endogenous ligand

Allosteric

An agonist that binds to a different site on the receptor than the endogenous ligand

Potentiator

Allosteric potentiators bind to allosteric site and enhance activity of agonist

Agonists

Drugs that mimic the effects of the endogenous ligands (turn on the receptor)

Receptor Binding Sites

• A primary agonist that binds to the same recognition site as the endogenous ligand

  • Also called the orthosteric

• An allosteric agonist binds to a different site on the receptor than the endogenous ligand

Antagonists

Antagonists block or reduce the actions of agonists (drug or endogenous ligands)

Multiple mechanisms of antagonists

• Competitive: the agonist and antagonist compete for the same (or overlapping) binding site on the receptor

• Allosteric: binds to a different site on the receptor

• Chemical: binds to the agonist (and prevents the agonist from binding the receptor)

• Functional or physiological: indirectly inhibit cellular of physiological effects of agonist (such as by binding a different receptor)

Antagonists bind either reversible or irreversibly (or nearly irreversibly)

• Irreversible: often a covalent bond

• Pseudoirreversible: often several strong, intermolecular interactions

Descriptions of antagonist activity

• Competitive: orthosteric binding (reversible)

• Noncompetitive: insurmountable, because no amount of additional agonist can overcome its effect

  • Irreversible or pseudoirreversible binding, allosteric binding

• Uncompetitive: allosteric binding, inhibition requires simultaneous binding of the agonist

Partial agonists

Produce a partial (reduced) response relative to full agonist

Inverse agonist

Constitutive activity is key consideration- decreases receptor activity BELOW the baseline

Allosteric potentiators

Bind to allosteric site and enhance activity of agonist

Antagonists effect the efficacy or potency (or both) of agonists

• Competitive antagonists decrease the potency of agonists

• Allosteric and irreversible antagonists decrease potency and efficacy of agonist

• Allosteric potentiators increase the potency of agonists

Matching

Full agonists

Able to produce maximum response for a given population of receptors

Partial agonist

Able to produce a sub-maximal response for a given population of receptors

Orthosteric agonist

Binds to the same site on the receptor as the endogenous ligand

Allosteric agonist

Binds to different sites on the receptor as the endogenous ligand

Affinity (and Kd)

The measure of the strength of drug-receptor binding

Efficacy (and max response)

Relates to the ability of a ligand to bind to the receptor and cause change in receptor conformation → measured downstream response

Potency (and EC50/ ED50)

Expression of activity of a drug based on amount needed to produce a defined effect

Hormesis

Suppress (antagonize) response at higher dose rather than lower

Dose-response curve

Facilitate analysis and comparison of efficacy and potency. Asses the response of a receptors at given concentration of agonist

Quantal concentration-response curve

Look at graph slide 8

Quantal dose-response curve

Facilitate analysis of potency, efficacy, and toxicity at population level. Measures individual response to drugs

LD50

Kill half of humans

Frequency distribution

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Agonism

A ligand that binds to a receptor and activities it is an agonist. Full, partial, orthosteric, allosteric

Key parameter of Affinity

Kd ( [drug][receptor] / [drug]-[receptor] = Kd )

*the smaller the Kd, the higher the affinity

Key parameter of Efficacy

Maximum response, relative to endogenous agonist

Key parameter of Potency

EC50 or ED50

Generalization

Larger concentrations of drug generally produce larger effects of responses

Exception: agonists that exhibit Hormesis suppress response at higher doses

Comparing Efficacy & Potency

• Efficacy and potency vary for independently

Example: for a pair of drugs A and B that bind to the same receptor, drug A could be more effective and less potent, or more effective and more potent, etc.

• Differences in efficacy and potency between drugs may change based on context

B. Allosteric partial agonist

(Allosteric bc they bind in different sites, partial because it is 75 rather an 100)

Ligand (in pharmacology context)

Drug 🤝ligand

Dissociation constant (Kd)

stability of drug-receptor complex

The measure of dissociation is called Kd

Kd=[drug]*[receptor]/[drug—receptor](at equilibrium)

Drug + receptor is L + R Unbound state

Drug-receptor is LR Bound state

Solvated

Ligands have to be dissolved

Entropy (specifically pertaining to drug receptor binding)

Binding interactions between the drug and the receptor

Conformation

Form of steroisomerism

Affinity

The measure of the strength of drug-receptor binding

Irreversible and pseudo irreversible (specifically pertaining to drug-receptor binding)

Covalent interaction (sometimes)

Stabilization energy (specifically pertaining to drug-receptor binding)

Describes the strength between the binding interactions

Induced fit

Drug may cause receptor to change shape to facilitate binding

Intercalation

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Drug-receptor interaction process

1. Drug binds to the receptor (intermolecular or interionic interactions- hydrogen, van der wal, etc. or covalent bond)

2. The drug-receptor system produces a biological response