Principles of Drug Action: Chemical Basis of Drug Metabolism

The flashcards are designed to cover essential concepts, processes, and implications of drug metabolism based on the given lecture notes.

What are the principles of ADME in pharmacokinetics?

Absorption, Distribution, Metabolism, and Excretion

What happens once the drug is across the gut wall?

Drug enters blood vessels

Absorption

Mechanisms of how drugs enter the body

Distribution

Pathways that determine the drug's spread throughout the body (tissues and organs)

Metabolism

Focus on how drugs are broken down (primarily in the liver)

Excretion

Mechanisms involved in removing drugs from the body (via urine or stool)

What type of cells are lining blood vessels?

Loose-fitting

What happens once drugs enter the blood vessels?

Rapid distribution to tissues and organs

What causes uneven distribution around the body?

Due to the uneven blood supply

What happens to blood concentration after absorption?

Drops rapidly

Why does blood concentration drop rapidly after absorption?

due to distribution, macromolecular binding, and storage in fat tissue (e.g. barbiturates) or bone

What do brain barriers hinder?

Polar drugs from entering the brain

What are brain barriers made of?

tight-fitting cells line the capillaries in the brain

What can brain barriers increase?

The polarity of peripherally acting drugs to reduce CNS side effects

What is the purpose of drug metabolism?

Major mechanism for terminating drug activity

What is done to enhance removal of drug?

altering or adding functional groups

Are drug metabolites active or inactive?

Inactive

Are prodrugs active or inactive?

Inactive

What is the primary organ involved in drug metabolism?

The liver

What does the term 'first-pass effect' refer to?

The percentage of orally absorbed drug that is metabolized in the liver before distribution to the rest of the body.

What organelles are found within the liver?

Microsomes, cytosol, mitochondria

Can drugs absorbed by other routes avoid the first pass effect?

Yes

What are the two main categories of drug metabolism?

Phase I and Phase II reactions

What characterizes Phase I metabolism?

It includes oxidation, reduction, and hydrolysis of drugs.

What do phase I metabolism add?

a polar handle to the molecule; enhance water solubility

Identify a major enzyme involved in Phase I oxidation reactions.

Cytochrome P450

What does Phase II metabolism involve?

Conjugation, where endogenous compounds are added to the drug molecule.

Which type of drug metabolism typically results in more polar metabolites?

Phase I metabolism

What does Phase II metabolism add?

endogenous compounds to the drug molecule

What can’t enzymes involved in metabolism can’t select?

xenobiotic and endogenous compounds

Purpose of xenobiotic metabolism

To convert lipophilic substances into more polar derivatives that are excreted more rapidly

Integrated Nature of Metabolism

Multiple sequential reactions are often required; May be competing pathways operating

What is Cytochrome P450 involved in?

Catalyze Oxidation/Reduction

What do Cytochrome P450 contain?

heme molecule bound to an iron atom

What are drugs that can affect the activity of P450?

Phenobarbitone & Cimetidine

What are foods that can affect the activity of P450?

grapefruit juice, brussel sprouts & cigarette smoke enhance activity

Oxidation of Aromatic Rings

Unsubstituted phenyl rings are primarily hydroxylated at the para position

In oxidation of aromatic rings, there is the phenyl ring primarily hydroxylated?

Para position

What happens to oxidation if an aromatic ring with substituated positions?

Aromatic ring that is less sterically hindered

What happens to oxidation if an aromatic ring with electron withdrawing substituents?

No hydroxylation occur

What must the carbon atom of an oxidation of aromatic ring have?

Hydrogen attached

What must oxidation of alkenes have?

there must be at least one hydrogen atom available

What happens if there is no hydrogen in oxidation of alkenes?

Can’t undergo alkene oxidation

Oxidation of Aliphatic and Alicyclic Carbon Atoms

The terminal methyl group in the chain (the omega, ω position). The penultimate (i.e., next to last) carbon atom in the chain (the omega-1, ω -1 position)

Oxidation of Carbon Atoms Adjacent to Double Bond

Includes benzylic carbon atoms, allylic carbon atoms, carbon atoms adjacent to an imine bond, or a carbonyl bond (e.g., ketone, amide, ester)

Allylic Oxidation

Aliphatic carbon directly attached to alkene or non-aromatic double bond

oxidative deamination

removal of amine group

oxidative N-dealkylation

removal of alkyl group from N

N-oxidation

N-Oxide

What is the primary route of oxidative metabolism for aromatic nitrogen?

N-oxidation since they cannot undergo oxidative deamination or oxidative N-dealkylation

Quaternary heterocyclic

can undergo N-dealkylation, but not oxidative deamination or N-oxidation

Oxidative Deamination

This primarily occurs with primary amines; however, it can also occur with secondary amines

Oxidative N-Dealkylation

This metabolic transformation can occur with secondary or tertiary amines or amides

What type of metabolism occur for secondary/tertiary amine/amides?

Oxidative N-Dealkylation

What will N-Dealkylation of tertiary amines produce?

secondary amines

What will N-dealkylation of secondary amines produce?

primary amines

N-Oxidation

A direct oxidation of the nitrogen atom as opposed to an adjacent carbon atom

How are N-Oxidation based on?

The presence or absence of a hydrogen atom

What are carbon sulfur groups susceptible to?

sulfur dealkylation, desulfuration, sulfur oxidation

Oxidative Dehalogenation

This type of oxidation can remove halogens from aliphatic chains and aliphatic rings, but not from aromatic rings

Oxidation of FGs with Carbon-Oxygen Bonds

Either present within the structure of a drug molecule or added as a result of the oxidation of hydrocarbon rings and chains, it can undergo oxidation to produce aldehydes, ketones, and carboxylic acids

Reduction

Involve a gain of hydrogen by the reduced functional group