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.
Therapeutic range
Range of plasma drug concentration above the level needed for therapeutic effect, below level of toxic effects.
- Often measured as therapeutic index.
- Want a high therapeutic index!
Variations in drug metabolism
- Genetics
- Hepatitis or liver cirrhosis
- Kidney disease
- Newborns & geriatrics
- Interference / interaction by other drugs
