Pharmacokinetics Flashcards
Pharmacokinetics
“the bodily absorption, distribution, metabolism, and excretion of drugs”
Hydrophilic drugs
Dissolve easily in water.
- Useful for easy transport in blood, urine, other body fluids.
- Useful for dissolving/absorbing oral medications.
Lipophilic (hydrophobic) drugs
Dissolve poorly in water.
- Useful for crossing cell membranes, blood-brain barrier.
- Useful for transdermal patches, skin creams.
Atoms and Polarity
CH (&CH2, CH3) groups are non-polar.
Atoms and Polarity
• OH (hydroxyl) and NH (& NH2: amine) groups are polar.
- C=0 (carbonyl) groups are somewhat polar.
Atoms and Polarity
• As a rule of thumb, one OH or NH can make up to 4 C atoms water-soluble.
• lonic groups are very hydrophilic too.
- Can make up to 8 or 9 C atoms water-soluble.
Ions, Polarity, and pH
• Many amines gain a proton at low or neutral pH to become positive ammonium ions
- Many drugs contain amines.
Ions, Polarity, and pH
Carboxylic acids lose a proton at neutral or high pH to become negative carboxylate ions.
- Less common in drugs than amines.
Ions, Polarity, and pH
Ions are much more hydrophilic than their neutral cousins.
- They have whole charges, instead of just partial ones.
Free base form
• Amines act as weak bases when they soak up a proton to become an ammonium ion.
• The neutral form of a drug is often referred to as the free base form.
- Passes through membranes (including blood-brain barrier) much quicker, but is less soluble in blood, causing unpredictable dosing.
- Most legal drugs are made as ionized salts.
• Not as free bases.
• lonized salts are more stable, usually solids.
pH affects solubility
• The pH at which half of the molecules of the drug become ionized is called the pKa.
- For drugs containing amines (most drugs) this means…
- Lower than that pH, the ammonium ion form will predominate.
- Higher than that pH, the neutral amine form will predominate.
- This matters a lot for some drugs, including local anesthetics that have different pKa’s.
Amine/ammonium ion ratio varies by pH
• Varies by a factor of 10 for each unit change away from the pKa.
- Taking lidocaine (pKa = 7.7) as an example…
•At pH 7.7 the amine/ammonium ion ratio is 1.
• At pH 8.7 the amine/ammonium ion ratio is 10.
• At pH 10.7 the amine/ammonium ion ratio is 1000.
• At pH 6.7 the amine/ammonium ion ratio is 0.1.
• At pH 4.7 the amine/ammonium ion ratio is 0.001.
Amine/ammonium ion ration varies by pH
• Drugs with a pKa close to physiological/blood pH (7.4) will have both amine and ammonium ion forms.
- amine form is more lipophilic,
dissolves better through membranes.
- Ammonium ion form more soluble/transportable in blood.
- Both aspects desirable to help the drug reach its target inside a cell.
Application: local anesthetics
• benzocaine is very soluble in membranes, almost completely insoluble in blood.
- Applied topically, never injected.
- Blocks pain only at the site where it is applied.
• Novocaine (Procaine) was common in 1950’s & 60’s.
- Dissolves well in blood, but does not cross cell membranes efficiently.
• Lidocaine & articaine dissolve well in blood AND cross cell membranes efficiently.
- These have replaced novocaine.
Routes of drug administration: Oral administration
• usually pills
- Convenient & cheap, but absorption is often variable.
• Enteric coated pills do not dissolve in stomach.
• May reduce stomach irritation, or keep the drug from being destroyed by strong acid.
• Sustained release pills dissolve more slowly.
- Drug is often encapsulated in tiny spheres.
- coatings dissolve at different rates so that the life of the drug is extended.
- Taking a pill once a day is easier to remember.
- Drug names with CD (circe diem), XL or SR at the end.
•egs. Cardizem CD, Toprol XL
•Enteric coated & sustained release pills are usually more expensive.
Routes of drug administration: Parenteral (injected)
• IV (intravenous)
- Expensive-must be sterile.
- immediate effect, complete absorption.
- drug must be soluble in blood (water).
- Otherwise crystals could lead to thrombus formation.
- rare exceptions, eg. Dilantin (phenytoin) is given IV to stop seizures, in a bolus buffered at high pH-painful!
• IM (intramuscular)
- Slower than IV, with more variation in absorption.
• SC (subcutaneous) is also slower.
- May be desirable, eg. with long-acting insulin.
Routes of drug administration: Transdermal patches and creams/oils
• Topically applied drugs must pass through relatively lipophilic layers of epidermal and subepidermal cells.
- Long-acting: drugs slowly dissolve through the skin.
- effective in comatose patients and patients who can’t swallow.
• Transdermal patch Egs.
- Nicotine (Nicoderm)
- Fentanyl (Duragesic)
• Pain control
- Nitroglycerine
• decomposes into active, nonpolar nitric oxide gas.
- Scopolamine
• Motion sickness
• Cream/oil Egs.
- Rogaine -for hair growth.
- Benzocaine -local anesthetic.
Bioavailability
• Catch-all term for how much of an (orally administered) drug is actually absorbed.
• May vary depending on..
- Taken on an empty stomach or with food.
- Taken with +2 ions (Ca2+, Mg2+, also Al3+).
• Can inactivate some drugs, eg. antibiotics tetracyline & Cipro.
• In antacids, milk.
- Gelatin capsule or tablet form.
- Size of drug crystals in tablets.
- Constipation or diarrhea in the patient.
Routes of drug administration: Other delivery modes
• Inhalation (respiratory)
- For asthma, COPD, emphysema.
• Not covered..
- Rectal suppository
• May be useful in patients who can’t swallow or who have chronic vomiting. may be problems with variable absorption.
Egs: Morphine, Compazine (an antiemetic).
- Vaginal suppository (vaginal infections).
- Ocular / conjunctival, otic (ear).
Drug transport from blood to tissues
- Normally pass out of capillaries by gaps between smooth muscle cells.
- Tight junctions between cells in capillaries at blood-brain barrier.
Serum albumin
A blood plasma protein with a pocket that reversibly binds/carries lipophilic drugs.
- Binding is reversible not permanent.
Serum albumin is too big to leak out of capillaries.
Cytochrome P450
Family of related enzymes (isozymes or isoforms).
- Work to make non-polar molecules more polar usually (but not always) by adding -OH groups.
- Found in endoplasmic reticulum of liver cells.
- Different members of the family recognize different kinds of target molecules.
Prodrugs
A few drugs are made as inactive precursors that are activated by enzymes in the body.
- The inactive precursor is called a prodrug.
- Variations in the activating enzyme can affect how the drug works/how effectively it is delivered.
Half life (T 1/2)
Time required for half of the drug to be inactivated (or removed) by the body.
