Pharmacokinetics and Routes of Administration

Sublingual Administration of Drugs

  • Nitroglycerin:
    • Intense first-pass metabolism challenge.
    • Metabolites produce vasodilation in the heart right away; does not need to go through the liver to be activated.
    • Activates smooth muscle relaxation, increasing blood supply to the heart, relieving chest pain.
    • Patients often have congestive heart failure.
    • Taken sublingually for immediate relief.
    • If taken orally:
      • Extensive first-pass metabolism.
      • 60% plasma protein bound.
      • Excreted in urine as inactive metabolites.
    • Sublingual route:
      • Avoids first-pass metabolism.
      • Collected by major vein under the tongue, goes into systemic circulation.
      • Diffuses into capillary blood vessels, bypassing the liver.
  • Oral route (enteral) suffers from first-pass metabolism.

Intramuscular Administration

  • Aqueous solutions are rapidly absorbed.
  • Absorption affected by:
    • Dosage form design.
    • Local heating: Accelerates absorption.
      • Heat accelerates molecule movement.
    • Exercise: Increases blood irrigation, accelerating absorption.
    • Massage:
      • Not needed; apply local pressure instead.
      • Rubbing may alter kinetics and affect steady state release.
  • Insulin (usually subcutaneous):
    • Principles apply to subcutaneous route.
    • Exercise can increase insulin level peaks.
    • Schedule doses and injection sites carefully.
  • Fat distribution:
    • Subcutaneous fat in obese patients can hinder intramuscular or subcutaneous injections.
    • Needle length may not be ideal, leading to injection in the wrong space.
  • Oily solutions:
    • Create a deposit for steady drug release.
    • Delay drug release into the bloodstream.
  • Injection:
    • Similar to subcutaneous in aseptic techniques.
    • Different needle lengths for intramuscular vs. subcutaneous.
    • Drugs in aqueous solutions are rapidly absorbed in intramuscular space.
    • Absorption can be delayed with oily solutions or suspensions.
    • Intramuscular administration may better tolerate slightly irritant solutions compared to subcutaneous.

Subcutaneous Administration

  • Only non-irritant drugs should be used due to pain.
  • Rate of absorption is usually slow; less irrigated than muscle.
  • Particle size, protein complexation (e.g., insulin) can delay absorption.
  • Lidocaine (local anesthetic):
    • Adding epinephrine causes vasoconstriction.
    • Limits drug diffusion into the periphery.
  • Useful when slow, continuous absorption is desired.
  • Vaccines: Steady release is preferable; stimulates the immune system.
  • Insulin: Mimics normal hormone rhythm.
  • Formulation:
    • pH should be mostly isotonic.
    • Avoid severe pain or necrosis.
  • Rate of distribution depends on blood flow.
  • Vasoconstrictors (epinephrine) slow down absorption.
  • Heating, massage, or rubbing can increase absorption and distribution.

Other Parenteral Administrations

  • Intra-arterial:Drug put into a major artery in the body.
    • Used for chemotherapy or diagnostic agents; avoids liver metabolism.
    • Requires expertise.
  • Intrathecal: Drug put directly into cerebrospinal fluid.
  • Intrasynovial:Injected into the knee.

IV Sites

  • Central line: Major vein; allows larger volumes and irritant drugs.
    • Takes advantage of dilution factor.
  • Peripheral line: Smaller vein in periphery.
    • Feet, arms, hands.
    • Commonly used for IV therapy.

Intramuscular Sites

  • Muscles used for intramuscular administration.
  • Absorption rate: IV > Intramuscular > Subcutaneous.

Subcutaneous Sites

  • Upper arms, waist, buttocks, thighs.
  • Insulin: Mimics pancreas function.

Epinephrine Auto-Injectors

  • EpiPen:
    • Designed for intramuscular injection in the thigh.
    • Decreases the symptoms of anaphylactic reaction.
  • Peak plasma epinephrine concentrations vary by muscle.
  • Study compared thigh vs. upper arm muscle.
  • Epinephrine administered from the syringe is still different from the EpiPen, even when administered to the thigh.
  • Intramuscular administration in the upper arm is not effective for anaphylactic reaction.
  • Subcutaneous fat in morbidly obese women can prevent needle from reaching muscle.

Rectal Administration (Enteral)

  • Useful for unconscious or vomiting patients, infants.
  • Glycerin suppositories stimulate defecation.
  • Rectum is highly irrigated.
  • Superior rectal vein: Deeper insertion; goes to liver (first-pass metabolism risk).
  • Inferior/middle rectal vein: Lower rectum; goes to periphery.
  • Assume 50% goes to liver, 50% to periphery.
    • Partial first-pass metabolism.
  • Drugs may irritate the mucosa.
  • Not the most pleasant route.
  • Useful for local effects (hemorrhoid relief).
  • Diastat (Diazepam) for rectal delivery, reduces seizures.
  • Diazepam:
    • An active ingredient also known under the brand name Diastat.
    • Sedative; downer of the central nervous system.
    • Binds to postsynaptic GABA receptors, calming neuronal activity.
    • Extensively metabolized in the liver to active metabolites.
    • 99% protein bound.
    • Suffers glucuronidation.
  • Dosage forms: Oral solution, IV administration, oral tablet, rectal gel, injectable solution.
  • Rectal gel (Diastat) is used as an anti-seizure medication (when oral ingestion is not possible).
  • 50% bypasses the liver.
  • Absorption can be irregular and incomplete.

Fraternities and Butt Chugging

  • Rectal administration of alcohol bypasses the liver; blood alcohol levels can be higher.
  • A very painful way to get drunk; high risk.

Oral Administration: Advantages

  • Safest, most economical, and practical route.
  • Convenient, and good systemic distribution.

Oral Administration: Disadvantages

  • Absorption may be variable, and there could be gastric irritation, leading to vomiting.
  • Not useful for vomiting patients, requires patient cooperation.
  • Drugs may be destroyed by gastric acidity; gut flora and mucosal enzymes can digest drugs.
  • Slower onset of effect, and may have drug dilution.
  • Broad spectrum antibiotics may need to be supplemented with florastor after use.
  • A balance needs to be struck between good and bad bacteria within the stomach.

Oral Administration

  • Pharmacology, and pharmaceutics play key roles in administering a particular drug.
  • Lipid-soluble drugs pass through membranes faster vs. water-soluble drugs.
  • Most absorption depends on passive diffusion.
  • Henderson-Hasselbalch equation:
    • Weak acids prefer low pH (unionized form).
    • Aspirin absorption is more favorable in the stomach, but intestine surface area overcomes this.
    • Most drugs absorbed in intestines regardless of being weak acids or bases.
    • Altering passage to intestines can affect absorption.

Gastric Emptying

  • Accelerated emptying increases absorption; delayed emptying decreases absorption.
  • Drugs can affect peristalsis.
  • Stomach content matters (e.g., chicken wings vs. water).
  • Medication instructions (with food or empty stomach) are important.
    • Aspirin/NSAIDs: With food to avoid upset stomach.
    • Coreg: With food to delay plasma peak concentration.
    • Spironolactone: With food.
    • Synthroid: Empty stomach due to food interactions.
    • Fosamax: Empty stomach; food impairs absorption.
    • Tetracycline: Empty stomach; food complexes impair absorption.
    • Amoxicillin, Lisinopril, Zyrtec: Doesn't matter.
    • Always take medication with a full glass of water.

Dosage Form Design

  • Enteric coating: Protects tablet from stomach acid to pass into the intestine.
  • Aspirin formulation can say enteric coated aspirin:
    • Prevents dissolution in the stomach (irritation reduction).
    • The film protects the tablet from the acidic pH of the stomach.
    • May resist dissolution in the intestine (formulation issue).
    • Aspirin is used to prevent heart attacks/strokes (blood thinning).
    • Very low dose administration.
    • Prophylactic treatment.
    • If plasma levels are not steady all the time, it will not provide full protection.
    • Generic brands must truly substitute branded when the formulation has enteric coatings.

Control of Plasma Levels

  • Capsule: Fast disintegration, causes quite a nice peak in plasma level.
  • Coated tablet: Coating prevents disintegration in the stomach, plasma level is more delayed in this case.
  • Capsules with pellets: Some pellets designed for immediate disintegration, some for slow disintegration.
    • Creates a plateau in the graph.
    • Results in a steady plasma concentration over time; desirable for behavior-affecting drugs.
  • The uniform tablet that combines droplets with both a fast and slow release is another route to accomplish the same objective.
  • Mini droplets are a similar formulation to the one listed just above.
  • You cannot cut a dosage in two when the area has core, because will expose the core and the control will be defeated.

Control Release Preparations

  • Sustain release, extend release, prolong action signify the same.
  • Solid oral dosage form designed with different rates of dissolution in the gastrointestinal fluids.
  • Reduces frequency of administrations.
  • Drugs with short halves, the duration can be prolonged with control releases.
    • Extended release will lead to less plasma peak concentration overall.
  • Definite Improvement of drug adherence.

Application of the Control Release

  • Solpidem will create an effect of the behavior of an individual.
  • Solpidem (Ambien) for insomnia:
    • Immediate release formulation helped patients fall asleep but woke up in the middle of the night.
    • The plasma levels would need the constant maintenance.
    • Control release formulation maintained plasma levels for a longer period of time.
    • For issues falling asleep, immediate-release is sufficient.
      • High gender difference.
      • Metabolism of 2.5 grams in the control release was handled differently across genders.
      • Not recommended for woman, due to incidents like car accidents occurring.
      • Females can take immediate release, for assistance to those having a hard time falling asleep.
      • Very high side effects of the drug can lead to various outcomes in women.
  • So the FDA is attempting to focus more on clinical study reviews on different demographics.
  • Extended release preparation (given every 24 hours) vs. multiple doses per day (every 8 hours):
    • If you are administering multiple doses a day there will always be plasma peaks, however if you have a plasma concentration that is extended you will achieve a more steady level.

Bioavailability

  • If 10 milligram are administered, sampling the patient and graph the graph, the area under the graph will tell you how much concentration makes it through the system.

Bioavailability: Advantages of controlled release preparations.

  • Enables higher doses to be given less frequently.
  • Maintain therapeutic concentration over prolonged periods.
  • Assumed to have less side effects.
  • Patient easily can take just one dose.
  • Drugs are water-soluble to be carried away by blood.
  • Extremely lipid-soluble compounds enter the lymph system (bypassing liver).
  • Gallbladder is attached to the liver.
    • stores large portion of bile.
    • Bile is able to help absorb fats.
      • released into the stomach.
      • Bile is very rich in cholesterol.

Hepatic Circulation

  • Bile, a high cholesterol compound helps disemulsify ages.
    • Some drugs have high affinity for Bile.
  • Recycling occurs that a very small portion is lost in the stools.
    • bile travels back to bladder.
    • liver does not not have to re-synthesize bile.
  • Morphine and Estrogen, both drugs have very high affinity for bile.
  • Anthero Hepatic circulation creates a continuous release in the intestine.
    • Prolonged half life.
  • Bacteria enzymes help release the attachment of the drugs in the bile.
    • the Estrogen will be released over the intestines, there will be free Estrogen released over period of time, and steady contribution will lead to plasma peaks.
    • if there does not exist Bacteria, the detachment will not occur and therefore will not be released. The effects are reliant on the bacteria.
    • Women who are take oral contraceptive pills, along side Bruxpantron can reduce the affects of the contraceptive pill, so therefore you should consider the alternative methods of control during this specific time-frame.
  • Probiotics are helpful for your gut, however, the affect on medication is not certain.