#d001x

Clearance

Total clearance = hepatic clearance + renal clearance

Also clearance depends on blood flow (Q) and extraction ratio (E)

Therefore total clearance = Qh*Eh + Qr*Er

Volume of Distribution (Vd)

Apparent volume of plasma required to contain drug in plasma

An average 70kg man has 2.7L of plasma but Vd is often much larger than 2.7L (plasma volume is 0.039L/kg) because in reality drugs redistribute to peripheral compartment

Since concentration = amount/volume and the amount and Vd of a drug is known, the concentration can be determined. Then that concentration can be used with plasma volume to determine how much of the drug is actually in the central compartment

E.g. 25mg of ranitidine is given, Vd = 1.4L/kg = 98L in a 70kg man

C = 25mg/98L = 0.255mg/L

Since plasma volume is 2.7L:

0.255mg/L = amount of drug in plasma / 2.7L

Amount of drug in plasma = 2.7L * 0.255mg/L = 0.69mg

Therefore, only 0.69mg of 25mg ranitidine given is in plasma

Protein Bound

A higher % of protein binding decreases clearance and decreases Vd

However, half life and kel (elimination constant) remain the same

Phases

Drug concentration decreases sharply during the distribution phase, then more slowly during the elimination phase (though both happen together)

The end of the distribution phase is when concentration in tissues (Ct) reaches maximum and Vss (steady state volume) is reached

The equation for the blue line is represented by the equations (A and alpha representing distribution phase and B and beta representing elimination phase, in which alpha is usually larger than beta)

Receptor Superfamilies

Ligand gated

Membrane bound

Control ion flow across the membrane

Associated with synapses

Called “fast neurotransmitters“

G protein coupled

Membrane bound

Pass signal across membrane

Signal proteins released into cell – complex pathways

Called “slow neurotransmitters“

Tyrosine kinase linked

Membrane bound

Ligand binding causes receptor dimers

Dimers act as enzymes

Associated with cancer

Nuclear receptors

Not membrane bound

Found in nucleus; ligand must enter the cell in order to bind

Control gene expression

Ligand types

Full agonist: upgoing sigmoidal curve, reaches Emax = full effect

Partial agonist: upgoing sigmoidal curve, reaches only a fraction of Emax, tend to bind to same position on receptor as full agonist = compete with full agonist

Antagonist: downgoing sigmoidal curve, binds to same receptor as agonist but causes no response; there are competitive and non-competitive antagonists

Inverse agonist: receptor has inherent activity called constituent activity; inverse agonist causes the activity to drop to zero ; downgoing sigmoidal curve with intercept > 0

Drug discovery

Target based

Begins with a drug target aka protein, develop drug to bind to that protein

Protein binding assay measures how well drug binds to protein, and this is an in vitro test

More predominant method due to advanced molecular biology

Advantages

Relatively simple

Rapid lead optimization

Disadvantages

 Protein may turn out to be ineffective relatively late (usually phase II)

Low efficacy

Phenotype based

Begins with a lead based on phenotype

Slow lead optimization

High efficacy, less likely to turn out ineffective later

Methods of Determining Protein Structure

Two methods: X-ray crystallography and nuclear magnetic resonance

Resolution measured in angstrom; the lower the angstrom, the higher the resolution

The Ramachandran plot can be used to validate protein structures

D-amino acids, unlike L-amino acids almost certainly have an incorrect protein structure

X-ray crystallography

More common method, 3/4 of protein structure determination

This course is crazy. I’m only one class in and I’m learning so much cool stuff. This is pretty exciting!

Pharmacophore = the minimal component of a class of drugs to achieve biological activity

Ephedrine

Emperor Shen Nung, father of agriculture, used Ma Huang for anti-tussive and decongestant properties.

The active ingredient in Ma Huang is ephedrine which is a vascoconstrictor and a stimulant

Ephedrine may be an alkaloid and its pharmacophore is:

Comes from natural source

Has a base nitrogen

Has a level of complexity (subjective)

It is a phenethylamine (class)

It has a stereoisomer or diastereoisomer called pseudoephedrine (sudafed), also a decongestant and stimulant, from which if you remove one alcohol group, you get methamphetamine

Phenethylamine

Examples: ephedrine, pseudoephedrine, methamphetamine, phentermine, fenfluramine

Its pharmcophore is:

Benzene ring

Two-carbon bridge

A nitrogen

Used as vasoconstrictors (therefore decongestants) and stimulants

Because they cause energy without food, also used as diet pills, such as phentermine and fenfluramine

Fen-phen

A diet pill that combines fenfluramine and phentermine

Withdrawn because it caused congenital heart defects (might have been just fenfluramine though)

Morphine rule

Benzene ring

Quaternary carbon

Two carbon linker

Tertiary amine