Drug Action Final

X axis (dose)

Usually plotted as log concentration for a bigger sigmoidal shape

Y axis (response)

The measured effect, from molecular to organism level (ex. Cell death, muscle contraction)

sigmoidal curve

Shows a minima effective dose, a steep rise in effect, and a plateau where higher doses yield no greater response (higher linear between 16-84%-most linear at mid point) important for accuracy in determining quantitative data

Potency

Inversely related to the dose or concentration needed to produce an effective

curve shifted to the left means

Higher potency

curve shifted to right means

Lower potency

Efficacy (Emax)

the maximal possible effect, seen as plateau of the curve

ED50

The dose producing a response in 50% of the population (quantal) or 50% of the maximum effect (graded)

LD50

The dose causing death in 5"% of the population (cells, animals)

therapeutic index

Ratio of LD50 to ED50, or TD50 to ED50

Log vs linear

Log allows you to see bigger changes/you can see more on the graph

Dose and concentration are

Inversely proportional to potency

Left shift

More potent and a lower dose needed

More efficacious if

Graph goes up higher

Dose response curves compare

Log of dose vs degree of response

therapeutic index

LD50/ED50

The farther apart the graphs are the better

Adding an antagonist will do what to the potency of a drug

Decrease it

To make a sigmodial curve from quantal data

Add up the area under the curve and turn it into a sigmodial curve

Additivity

Agonist and agonist 2

Synergy

Agonist and agonist 3

potentiation

Agonist and 0 inactive compound 2

Agonist and another substance

Increase the potency

Selective

Selective drug action refers to a drug preferentially binding to one type of receptor or tissue over others, often dose-dependent (e.g., selective beta-blockers).

A matter of degree (quantitative). A drug binds with higher affinity to Target A than Target B, but may still affect B at higher doses.

Specific

Specific drug action implies an ideal, absolute binding to only one, exclusive target, resulting in a single effect, which is rare in practice. (maybe some monoclonal antibodies?)

•Specificity: An "all-or-nothing" (qualitative) concept. A drug binds to one, and only one, specific receptor, producing one effect with zero unintended, off-target interactions23

Adverse effect

Unintended, undesirable, often unpredictable harmful effect

Side effect

Predictable effect that can have be therapeutic

Teratogenic effects

Effect of drugs on the child in utero

• Teratogenic effects of drugs cause structural or functional congenital malformations (birth defects) by interfering with embryoo-resis, early in pregnancy (e.g., first 8 weeks).

- Fetal alcohol syndrome - leading teratogen in the U.S.

• Fetopathic effects of

drugs occur later, causing functional impairment or growth restriction.

• Fetal Valproate Syndrome: Caused by the antiepileptic drug sodium valproate, resulting in physical and mental disabilities, including neural tube defects.

Idiosyncratic drug reactions

• Adverse effects that cannot be explained by the known mechanisms of action of the offending agent, do not occur at any dose in most patients, and develop mostly unpredictably in susceptible individuals only.

(1) immune-mediated hypersensitivity reactions

(2) reactions involving unusual nonimmune-mediated individual susceptibility, often related to abnormal production or defective detoxification of reactive cytotoxic metabolites (as in valproate-induc er toxicity)

(3) off-target pharmacology, whereby a drug interacts directly with a system other than that fozwhich it is intended

Competitive antagonist Effect on agonist response:

Rightward shift of the dose-response curve

No change in Emax (maximum effect)

Increasing the agonist concentration can overcome the antagonist

Why: They compete for the same binding site; more agonist can displace the antagonist.

Non‑competitive antagonist Effect on agonist response:

Decrease in Emax

No shift in EC50 (or only minimal)

Increasing agonist concentration cannot overcome the block

Why: They bind allosterically or irreversibly, reducing the number of functional receptors.

Additive response (two agonists) Effect on agonist response:

Combined effect = sum of each drug's individual effect

Example: Drug A gives 20% effect, Drug B gives 30% → together ≈ 50%

Why: They act through similar or independent pathways that simply add up.

Synergistic response (two agonists) Effect on agonist response:

Combined effect is greater than the sum of individual effects

Example: A = 20%, B = 30%, together = 90%

Why: One drug enhances the other's efficacy or amplifies downstream signaling.

Potentiation (inactive substance + active agonist) Effect on agonist response:

An inactive substance increases the effect of an active drug

Example: Drug A has no effect alone, but increases Drug B's effect → B's response is amplified

Why: The "inactive" agent modifies metabolism, clearance, receptor availability, etc.

Partial agonist Effect on agonist response:

Produces a submaximal response even at full receptor occupancy

In the presence of a full agonist, it reduces the overall response (acts like an antagonist)

Why: It has lower intrinsic activity; it competes with the full agonist for receptors.

If therapeutic index ratio is 3 that means

You need to increase the dose 3 fold to increase toxicity

Mechanism based adverse effect

Based on MOA, adverse effects you would expect to occur

Side effects are

Generally expected and less concerning

Adverse reactions may be

(Not always) unexpected and always pose significant health risks

First pass metabolism

A large amount of drug administered gets metabolized by liver which reduced the amount that's left to actually work in the body

Core Mechanism:

• Occurs primarily in the liver and GI tract

• Involves Cytochrome P450 (CYP) enzymes

• Drugs absorbed through intestinal wall

• Transported via portal vein to liver

• Active drugs converted to metabolites.

P-glycoproteins (proteins attached to sugars) MDR1-ABCB1

Efflux transporters (limits drug availability)

Goal of Metabolism

Enhance elimination by increasing water solubility, polarity, ionization

Phase I rxns

Introduce new functional groups or unmasks a functional group to help make drug more water soluble

Phase II Rxns

• Phase II Rns

• -attachment of mainly water soluble ionizable groups to the xenobiotic or the Phase I transformed drug

• T water solubility and renal elimination

• although sometimes via the bile & enterohepatic recirculation

• Phase I Rn followed by Phase II -or-Phase Il followed by Phase I Rxn

Extra hepatic microsomnal enzymes

Oxidation, conjugation

Hepatic microsomal enzymes

oxidation and conjugation

hepatic non-microsomal enzymes

acetylation, sulfation, GSH, alcohol/aldehyde dehydrogenase, hydrolysis, ox/red

Xenobiotics

Foreign substances (the body works to eliminate)

Metabolism (biotransformation)

1) Active drug → inactive drug

2) Active drug → active metabolite drug or toxic metabolite

3) Inactive drug (pro-drug) › active drug

4) Un-excretable drug → excretable drug***

• Why and how are drugs eliminated from the body?

Why the body eliminates drugs:

To terminate drug action

To prevent accumulation and toxicity

To maintain homeostasis by clearing foreign chemicals

How elimination occurs:

Metabolism (biotransformation) — mainly in the liver

Converts lipophilic drugs → more hydrophilic metabolites

Makes them easier to excrete

Excretion — mainly via the kidneys

Also via bile, feces, lungs, sweat, breast milk

• What role does renal function play?

Renal function is one of the biggest determinants of drug clearance.

Kidneys eliminate drugs by:

Glomerular filtration (free drug only)

Tubular secretion (active transport)

Tubular reabsorption (passive, depends on lipophilicity & urine pH)

If renal function decreases:

Drug clearance ↓

Half‑life ↑

Risk of toxicity ↑

Dose adjustments often required (especially for hydrophilic drugs)

• Are all drugs metabolized? How does a metabolite differ from a parent drug?

No. Some drugs are excreted unchanged (e.g., lithium, gentamicin).

Parent drug vs. metabolite:

Parent drug: original administered compound

Metabolite: product formed after enzymatic modification

May be inactive, active, or toxic

Prodrugs require metabolism to become active (e.g., codeine → morphine)

• What is phase I and phase II metabolism? What enzymes are involved in each?

Phase I metabolism

Purpose: Introduce or expose a functional group Reactions:

Oxidation

Reduction

Hydrolysis

Major enzymes:

Cytochrome P450s (CYPs) — especially CYP3A4, CYP2D6, CYP2C9, CYP1A2

Esterases

Alcohol/aldehyde dehydrogenases

Outcome: Slightly more polar metabolites; sometimes active.

Purpose: Conjugate drug with a large, polar group Reactions:

Glucuronidation

Sulfation

Acetylation

Methylation

Glutathione conjugation

Major enzymes:

UGTs (glucuronidation)

SULTs (sulfation)

NATs (acetylation)

GSTs (glutathione transferases)

Outcome: Highly polar, inactive metabolites → easily excreted

• What is first-pass metabolism and how does it affect drug administration?

Definition: Metabolism that occurs before a drug reaches systemic circulation, primarily in the liver and intestinal wall.

Consequences:

↓ Bioavailability

Oral doses must be higher than IV

Some drugs cannot be given orally (e.g., nitroglycerin)

Affected routes:

Oral (major)

Rectal (partial)

Sublingual, IV, IM, transdermal bypass first‑pass

• Why can metabolism differ between patients or within the same patient?

Metabolism varies due to:

Genetics

CYP polymorphisms (e.g., CYP2D6 ultrarapid vs. poor metabolizers)

Age

Neonates: immature enzymes

Elderly: reduced liver mass & blood flow

Disease

Liver disease

Heart failure (↓ hepatic perfusion)

Renal disease (affects elimination → feedback on metabolism)

Drug interactions

Enzyme induction

Enzyme inhibition

Lifestyle

Smoking (induces CYP1A2)

Alcohol use

Diet (e.g., grapefruit inhibits CYP3A4)

Within the same patient

Acute illness

Inflammation (cytokines suppress CYPs)

Changes in other medications

• How does metabolism contribute to drug-drug interactions?

Enzyme inhibition

One drug blocks a CYP enzyme → ↑ levels of the other drug

Rapid onset

Example:

Fluconazole inhibits CYP2C9 → ↑ warfarin → bleeding risk

Enzyme induction

One drug increases enzyme expression → ↓ levels of the other drug

Slow onset (days-weeks)

Example:

Rifampin induces CYP3A4 → ↓ effectiveness of oral contraceptives

Competition for the same enzyme

Two drugs metabolized by the same CYP → slower clearance of both

Toxic metabolites

Example: acetaminophen + alcohol → ↑ NAPQI formation

Pharmacodynamic

Action at the site of action

Pharmacokinetics

drug movement through the body

Lipophilic non amino acids are absorbed by the bio membrane through

Passive diffusion

Alpha amino acids are absorbed through the bio membrane by

Active transport

Drugs bound to plasma proteins (albumin) must be

Lipophilic

Which barrier is thicker and only allows very lipophilic materials to get in

The blood brain barrier

Why are tertiary amines not strong polar groups

The third bond on the nitrogen takes away the ability to hydrogen bond

Albumins hydrophobic amino acids

Leu, phe, trp

Albumins basic amino acids

Arginine and lysine

What part of drug does the effect

The part not bound to albumin

Basic drugs with no ionic interactions with basic amino acids of albumin still

Bind to plasma protein for transportation through the blood

Major interactions of albumin

Hydroponic interactions with lipophilic amino acids

Minor interaction of albumin

Ionic interaction with basic amino acids

Antagonists have a

Higher affinity and lower or no activity

They need to be more lipophilic

3 targets of drug action

Receptors

Ion channels

Enzyme active sites

Binding of a drug to the site of action is affected by

Stereo-chemical isomers

Interaction forces

Lipophilicy

The more lipophilic a drug

The more strongly it binds to its receptor

Agonists posses

Affinity and intrinsic activity

Antagonists posses

Only affinity with no intrinsic activity

Bio-isosteres

The term bioisosteres refers to the replacement of an atom or functional group with certain number of electrons in the outer most shell with another atom or group with the same

number of electrons in the outermost shell.

Metabolism

How the body eliminates and/or deactivates the endogenous chemicals and foreign chemicals from the bodies after they exert their biological effect

Major site of metabolism

liver

Phase I metabolism

Creates a single polar group on the drug molecule

Phase II metabolism (conjugation)

Taking the polar group created in phase one and conjugate through covalent bonding with a very polar entity in the liver, such as glucuronic acid to produce a conjugate that is water soluble, and ready to be excreted in the urine

Most drugs metabolized by

Microsomnal metabolism

Microsomnal reactions are in the

Liver

Nonmicrosomal metabolism is

Anywhere in the body fluids

Microsomal reactions are all

Oxidation reactions

Microsomal reactions are catalyzed by

CYP450

CYP450

Fe2+ (ferrous) that oxidizes to Fe3+(ferric) and can reduce back to ferrous

Hydroxylation reactions

Adding a hydroxyl group to a carbon atom

Aliphatic: aliphatic hydroxylation

Aromatic: aromatic hydroxylation

Ous means

Less oxidized

Ic means

More oxidized

Preferred carbon in aromatic hydroxylation

Para

Preferred carbon in aliphatic hydroxylation

Last or second to last

Aliphatic hydroxylation occurs for carbon chains bigger than

Ethyl

The bigger the chain, the faster the reaction will be because the liver doesn't like having lipophilic entities around

How may hydroxylation reactions can occur for one molecule?

One

Primary and secondary amines are already strong polar groups and don't need to undergo

Dealkylation

Dealkylation results in

Aldehydes

Methyl: formaldehyde

Ethyl: acetyl aldehyde

Ethers are

Lipophilic

Oxidative deaminations goal is not to create a strong polar group, it is to

Terminate biological activity

Oxidative deamination needs

Primary amine

Connected to a secondary carbon

Oxidative deamination gives

A ketone

Dealkylation

removal of a an alkyl group from sulfur, nitrogen or oxygen.