pharm & toxico sec 5

Most of the drug leave the body via

urine passing through the kidneys as unchanged drug or as polar metabolites

How else can drug leave the body?

sweat, bile, lungs, milk

What is one specificity about lipophilic drugs

they do not get eliminated efficiently by the kidneys.

What process is needed to eliminate lipophilic drugs

lipophilic drugs get converted into polar drugs to be eliminated efficiently

What does drug metabolism involves

the enzymatic conversion of a drug to a metabolite

2 drug metabolism outcome

- creation of pharmacologically active metabolite

- Toxin formation

Where does the drug metabolism occur?

in the liver

Which group of enzymes are used for drug metabolism

cytochrome P450

P450 pathway

Transforms the Fe3+ ion contained in P450 into Fe2+ by using NADPH- P450 reductase.

Forms a Fe2+ OOH-DH complex

production + release of complex

What does the OH group on the derivative phase of P450 pathway

It's point of attack of the phase 2.

The OH group serves as a attachment point for bulk group.

What does phase 1 and phase 2 of the P450 pathways increases

water solubility

What does the P450 forms?

It forms an inactive and excretable product.

What is the function of aspirine

inhibits platelet function and ant-inflammatory activity.

what happens when the aspirin is altered by drug metabolism

it gets hydrolyzed to salicylic acid -> no antiplatelet activity but only anti-inflammatory

renal excretion, 2 ways to eliminate

drug crosses the glomerular filter of the kidney

transported from peritubular capillaries to the tubules by active transport.

what is the specificity about lipid-soluble drugs in the elimination process

lipid-solubles drugs are reabsorbed passively by the diffusion across the tubules back to the tubules.

what is the specificity with weak acid in the elimination process

due to the pH partition, the WA is excreted faster in the alkaline urine.

What processes poison goes through when we are exposed to it

absorption, distribution, elimination, and metabolism.

therapeutic poisons at low doses

botulinum toxin, ivermectin

4 ways to get across the cell membranes

- diffuse through lipids

- diffuse through aquaporins

- through carrier molecules

- pinocytosis

What route is important for the transport of macromolecules

Pinocytosis

Which passage routes are important for the pharmacokinetic mechanisms

lipid and carrier-mediated protein

What does the lipid solubility influences

-rate of absorption from the guts

- penetration into the brain and other tissues

- extent of renal elimination

What's pH partition?

- Weak acid = accumulate in the high pH areas

- Weak bases = accumulate in the low pH areas

What does urinary acidification leads to?

increase of excretion of weak bases = decreases excretion weak acids

What does urinary alkalinisation leads to?

decreases excretion of weak bases = increase excretion of weak acid

Consequences of increase of plasma pH

weak acid drugs to be extracted from the CNS into the plasma

Consequences of decrease of plasma pH

weak acid drugs would be concentrated in the CNS= increase of neurotoxicity

carrier-mediated drug transporter is important in these locations:

- renal tubule

- biliary tract

- blood-brain barrier

- gastrointestinal tract

What does the carrier-mediated transport involve and how they act?

involve a transmembrane protein which binds one or more molecules or ions

changes conformation and releases them on the other side of the membrane

Where are P-glycoprotein found?

- renal tubules

- microvessels in brain

- gastrointestinal tract

What's the role of P-glycoprotein?

absorption, distribution, and elimination of drugs.

Important in the multidrug resistance in cancer cells.

physiological role: elimination of env. toxins

Albumin

Protein in plasma that binds with many acidic drugs.

Albumin binding depends on:

- concentration of free drug

- affinity for binding sites

- concentration of proteins

What is one of the consequences of lipid - soluble drugs prescription?

Accumulation of body fat.

How are the environmental contaminants metabolized?

Poorly metabolized

If ingested regularly, it gets accumulated in the body fat.

Chloroquine

drugs used to treat rheumatoid arthritis with high affinity for melanin.

Differences between brain capillaries and peripheral capillaries.

peripheral capillary: made of endothelial cells with small gaps (allows the drugs to pass through the gaps)

brain capillary:

Made of highly packed endothelial cells.

( Drugs with LOW lipid solubility cannot pass through)

drug absorption

passage of drug from site of administration into plasma

Which drug does not need to enter the plasma before reaching the site of action?

bronchodilator aerosol

Where does the inhaled drug gets eliminated

expired air

What's the issue with oral administration

easily absorbed from the intestines.

oral administration: which drugs are poorly absorbed

strong acids and bases = fully ionized.

What affects the gastrointestinal absorption?

- gastrointestinal motility

- particle size and formulation

- splanchnic blood flow

- physiochemical factors

splanchnic blood flow

higher the blood flow near intestines the greater the absorptions

Forms of administration

- cutaneous administration

- nasal sprays

- eye drops

- inhalation

- oral / rectal

- intravenous

How is the distribution measured

volume distribution

When is Vd is high

when distributed into muscles and fat

Vd is low when

drugs retained in blood

what does Vd test for

Volume of fluids requires to dissolve a dose of drug.

Drug with low Vd

Insulin -> retained in plasma

Drug with high Vd

Morphine -> retained in fat tissues