Drug Fate

1
Drug Fate
2
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

3
Ways of drug elimination

• Exhaling air lungs function as chemical
  exchange unit
• Also perspiration, saliva, feces and even
  mothers 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

4
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

5
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

6
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

7
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

8
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

9
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

10
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 isnt
  being broken down as quickly
• Acetaldehyde is a toxin causing sickness and
  discomfort

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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

12
Drugs given to mother at delivery

• Anesthesia given to mother during birth it
  crosses the placental barrier
• Mothers liver metabolizes anesthesia fetus
  cant
• Umbilical cord cut drug remains in baby for a
  long time
• Theophyline, a stimulant used to treat asthma
• Babys liver converts theophyline to caffeine,
  mothers doesnt
• Baby metabolizes caffeine very slowly

13
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

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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

15
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

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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

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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