Physico-Chemical Properties and Drug Action

What are the different places a drug can go to once it distributes within the blood?

• liver (metabolism)

• kidney (excretion)

• site of action

• CNS

ADME stands for:

Absorption

Distribution

Metabolism

Excretion

What 2 processes does a drug have to go through when given orally?

1. dissolution

   • into aqueous environment of GIT

2. crossing the bio membrane

   • to reach the blood stream

   • requires lipophilic properties

What plasma protein mainly helps the lipophilic drug form a water soluble complex to allow for passage through the blood?

albumins

T/F: bio membranes are mainly lipophilic

TRUE

A drug that is very lipophilic with have (good/poor) absorption but (good/poor) dissolution.

good, poor

If polar FGs dominate in a drug, the drug will have (good/poor) absorption thru the membrane, but (good/poor) dissolution.

poor, good

What functional groups increase the polarity and dissolution of drugs?

• very polar groups

  • hydroxyl groups

    • alcoholic hydroxyl (aliphatic)

    • phenolic hydroxyl (aromatic)

  • aliphatic amines

  • COOH, amides, imides, CN, NO2, sulfonamides

How does a hydroxyl group affect the polarity of a drug?

• very polar → increases solubility of 5-6 carbons

How does an amino group affect the polarity of a drug?

• very polar, increases solubility of 5-6 carbons

• quaternary amines form ammonium salts → soluble due to charge

How does a carboxylic acid affect the polarity of a drug?

• weakly polar → increases solubility of 2-3 carbons

• acidic FG

How does a cyano group affect the polarity of a drug?

• weakly polar → increases solubility of 2-3 carbons

How does a nitro group affect the polarity of a drug?

• weakly polar → increases solubility of 2-3 carbons

How do amides affect the polarity of a drug?

• weakly polar → increases solubility of 2-3 carbons

How do imides affect the polarity of a drug?

• weakly polar → increases solubility of 2-3 carbons

How do sulfonamides affect the polarity of a drug?

• weakly polar → increases solubility of 2-3 carbons

What are functional groups that increase the lipophilicity of drugs?

• alkyl groups

• phenyl groups

• halogen groups (I >Br >Cl>F)

• ester: more carbons = higher lipophilicity

How does an ester group affect the lipophilicity of a drug?

• more carbons makes esters more lipophilic → better absorption

How do ethers affect the lipophilicity of a drug?

• very weakly polar

• more lipophilic than alcohol

How do alkyl groups affect the lipophilicity of a drug?

• very lipophilic → due to more carbons

• better absorption

Ho

How do aromatic radicals affect the lipophilicity of a drug?

• very lipophilic → highly absorbed

How do halogens affect the lipophilicity of a drug?

• increases the lipophilicity of a drug

• the bigger the atom → more lipophilic

• I >Br >Cl>F

What is the role of albumin?

• binds to lipophilic drugs to form a water soluble complex compatible with the aqueous medium of the blood

• complex is reversible

What is the makeup of albumin?

• water soluble protein rich in 2 types of AAs:

  • hydrophobic AAs

    • Leu

    • Phe

    • Trp

  • basic AAs

    • Arg

    • Lys

Drug binding to albumin occurs through what 2 types of reversible interactions?

1. hydrophobic interactions w/ lipophilic AAs

   • the major force for binding

2. ionic interactions with basic AAs

T/F: ibuprofen will bind strongly to albumin because it is both lipophilic and acidic.

TRUE

T/F: only a small amount of the lipophilic drug is primarily bound to albumin

FALSE

• 99% primarily bound to albumin

Explain the concept of drug-drug interactions by displacement.

• drugs can displace one another because:

  • drug binding to plasma proteins is NONselective

  • # of binding sites with similar physicochemical characteristics can compete with

• results in a change of the free drug concentration of both drugs leading to increased toxicity of the drugs

Drug A and B both have strong plasma protein binding. If the two drugs are concurrently taken and each have equal affinity to plasma proteins, what will happen?

• each will displace the other by ~50%

  • leads to increasing the amount of free concentration of both drugs in plasma

  • result: excessive action and/or toxicity

If Drug A has a higher affinity than Drug B and are taken concurrently, what will happen?

• drug A will take most of the binding sites on albumin

• drug B will still have a higher concentration than normal