Drug Fate

Removing substances from the body

• Some substances are very difficult to eliminate – heavy metals such as lead and mercury

• The body very efficient at removing most unwanted substances such as drugs

Ways of drug elimination• Exhaling air – lungs function as

chemical exchange unit

• Also perspiration, saliva, feces and even mother’s milk

• Major job of eliminating drugs and other unwanted substances is done by the liver and kidneys

– Liver responsible for breaking down chemicals

– Kidney responsible for excreting chemicals, but some water soluble chemicals are directly filtered out and excreted by kidneys

The liver

• Largest organ in the body after skin

• Located high in the abdomen next to the stomach

• Function is to take molecules and modify them to new molecules– In this case, toxic chemicals

are modified into less harmful substances

• The liver receives 2 blood supplies– One from the digestive system– Second directly from the heart

Blood from the digestive system

• Drugs taken orally (alcohol) begin to be metabolized, or altered prior to being distributed to the sites of action

• Referred to as first-pass metabolism – drugs taken orally must be given at higher dosages than those injected

Metabolism in the liver

• Most lipid soluble substances cannot be filtered out and excreted by the kidneys. They pass through the kidneys and back into the bloodstream

• The liver must metabolize these substances into a form the kidneys can filter out

Metabolism through oxidation

• The liver produces enzymes that use oxygen to alter molecule structure

• These enzymes are called mixed function enzymes because they act on a variety of chemicals

• Drug interaction and mixed – function enzymes– Alcohol and barbiturates

Metabolism through conjugation

• Liver enzymes add chemicals to a drug molecule inactivating it by preventing its ability to be absorbed

• This is usually a second step in the metabolism process

• Oxidation occurs to alter the molecule, then conjugation inactivates the resulting molecule

Metabolism of Alcohol

• Ethanol (CH3CH2OH) is oxidized by P450 or alcohol dehydrogenase into acetaldehyde

• Acetaldehyde then conjugated by other enzymes (mainly aldehyde hydrogenase) into acetyl-coenzyme

• Acetyl-coenzyme conjugated into water, citric acid, carbon dioxide, and energy

Action of disufiram or antabuse

• Used to discourage alcoholics from drinking

• Acts during the conjugation phase

• It competes with acetaldehyde for the aldehyde dehydrogenase

• Levels of acetaldehyde rise because it isn’t being broken down as quickly

• Acetaldehyde is a toxin causing sickness and discomfort

Factors that effect liver metabolism

• Slowing metabolism by introducing a second drug that competes for the same enzyme

• Stimulating increased enzyme production due to past history

• Interspecies differences – animal research has to account for metabolic differences

• Age- enzyme systems not fully functional at birth – can be a problem

Drugs given to mother at delivery

• Anesthesia given to mother during birth; it crosses the placental barrier

• Mother’s liver metabolizes anesthesia – fetus can’t

• Umbilical cord cut; drug remains in baby for a long time

• Theophyline, a stimulant used to treat asthma

• Baby’s liver converts theophyline to caffeine, mother’s doesn’t

• Baby metabolizes caffeine very slowly

Kidney function

• Filters out chemicals metabolized by the liver and water soluble chemicals the liver cannot metabolize

• It does not act like a sieve or a swimming pool filter

Kidney function• Blood pumped through kidney at

high pressure• Most of the fluid in the flood and

substances in the fluid absorbed by the cell membranes of the kidneys

• Blood cells and large proteins are not absorbed

• Most of the fluid and substances reabsorbed back into the bloodstream

• Substances not absorbed are excreted in urine

– All lipid soluble substances diffuse back into the blood

– Needed non-lipid soluble substances, like glucose, are transported back into the blood

The role of diffusion in excretion• Water, drugs and other substances

diffuse through the pores in the kidney cells out of the blood

• Water is reabsorbed or diffuses back into the bloodstream faster than other substances

• Concentrations of drugs increase in the kidneys and decreases the concentration in the blood

• There now exists a concentration gradient

• If the drug has not been metabolized and if it is lipid soluble, it diffuses back into the bloodstream

• This is critical for nutrients and other needed substances to not be excreted

Reabsorption of alcohol

• One of alcohols effects is dehydration- it inhibits ADH or antidiuretic hormone that signals the kidneys to retain water

• Urination and dehydration increases as less water is reabsorbed and more alcohol is returned to the bloodstream

• Only reasonable way to decrease period of intoxication is drinking large amounts of water

Interaction of absorption and excretion

• Excretion curve• Absorption curve• Combine to form

“therapeutic window”• Therapeutic window –

a constant level that is high enough to be therapeutic, but not toxic