VL2: Introduction to Pharmacokinetcs

Transfer of a drug from its site of administration to the

bloodstream

Movement of the drug from bloodstream to the interstitial and intracellular fluids throughout the body

Biotransformation of the drug molecules by the liver or other tissues

Elimination of the drug and its metabolites from the body in urine, bile, or feces

1. Eternal Application

   • Oral

   • Sublingual

   • Rectal

2. Paraternal Application (Injections)

   • Intravenous

   • Intramuscular

   • Subcutaneous

3. Others

   • Inhalation

   • Transdermal

   • Topical

Pros

• -  Most common, safest and the most convenient route.

• -  Self-medication is possible, economical.

• -  Low risk of systemic infections.

• -  In case of drug overdose or accidental poisoning, the drug can be

  removed quickly by gastric lavage or induced vomiting.

  Cons

• -  Onset of action is delayed.

• -  Changes in absorption rate or absorption extent due to food effects.

• -  Low pH of stomach may inactivate some drugs.

• -  Drugs are subjected to first-pass metabolism. (Enteric-coated

  preparations).

• -  Low pH of stomach may inactivate some drugs.

• -  Not suitable for patients with persistent vomiting

Sublingual = Placement under the tongue

Buccal = Placement between cheek and gum

Pros

• Rapid onset, convenient (suitable for emergency), Self-medication is possible, low incidence of infection, bypass of the harsh gastrointestinal environment, avoidance of first-pass metabolism.

Cons

• -  Limited to certain types of drugs (Not suitable for hydrophilic drugs, drugs with large molecular weight, irritant drugs or drugs with unpleasant taste).

• -  Not suitable for large doses of drugs.

• -  Not suitable for patients with dry mouth.

• -  Drugs have short duration of action. Frequent administration may be

  necessary.

Pros

• Suitable for patients who are vomiting, unconscious, or unable to

  swallow.

• Partial avoidance of first-pass metabolism, bypasses destruction by

  stomach acid.

• Suitable for drugs that cause stomach irritation.

• Can be used to produce local or systemic effect.

• Cons

• Inconvenient and uncomfortable for chronic use.

• Not suitable for drugs that cause local irritation in the rectum.

• Not suitable in case of persistent diarrhea or certain rectal diseases.

• Rectal absorption is often erratic and incomplete (Not suitable for

  drugs with low TI).

Pros

• Most suitable for unconscious patients and emergency cases that

  require a rapid onset of action.

• Used for drugs that are poorly absorbed from the GI tract and for

  agents that are unstable in the GI

• Have the highest bioavailability, drugs are not subjected to first-pass

  metabolism or harsh GI environments.

• Provide the most controllable drug dose delivery to the body.

  
  

  Cons

• Irreversible, self-medication requires training.

• May cause pain, fear, local tissue damage, and infections.

Pros

• Rapid effect: Drug is immediately introduced into the systemic

  circulation (most suitable for emergency cases).

• Maximum control: Allows for the highest degree of control over

  drug levels in the blood, especially for drugs not absorbed orally.

• Flexible dosing: Can be delivered as a bolus for immediate effect or

  through an infusion to maintain drug levels over time.

• Dilution of Irritating Drugs: Substances that may cause irritation when administered by other routes are diluted quickly in the

  bloodstream.

• Suitable for high-molecular-weight proteins and peptide drugs. Ideal

  if dosed in large volumes.

Cons

• Irreversibility: Once administered, the drug cannot be "recalled,"

  unlike oral drugs.

• Risk of Contamination: Bacteria or other infectious agents can be

  introduced if sterile techniques are not followed.

• Potential for Adverse Reactions: Rapid delivery of high drug

  concentrations can cause complications such as hemolysis or toxic

  effects of the drug.

• Need for Monitoring: Patients must be closely observed for any

  unfavorable drug reactions, and infusion rates must be carefully

  managed. Self-administration is unsafe.

• Unsuitable for oily substances and suspensions.

Pros

• Suitable for rapid absorption or sustained release: Aqueous solutions of drugs are absorbed quickly into the bloodstream while oily and specialized depot formulations allow for slow and extended release of drugs.

Cons

• Slower absorption compared to IV: Drugs have slower onset of action compared to IV route, especially for depot preparations.

• Possible local side effects: Irritation or discomfort at the injection

  site may occur, especially with certain drug formulations.

• Not suitable for anticoagulants: Can lead to bleeding at the injection

  site.

Pros

• Constant and slow absorption: Allow for slower absorption

  compared to IV injections, leading to more sustained effects.

• Minimized Risk of Hemolysis/Thrombosis: Less risk of complications

  like hemolysis and thrombosis compared to IV injections.

• Self-administration is possible with lower risk (e.g, Insulin pen).

• -  Long-Term Drug Delivery: Certain SC devices, like implanted rods or

  pumps, can provide long-term effects, such as contraceptive

  implants or insulin pumps.

Cons

• Limited to Non-Irritant Drugs: SC is appropriate for drugs that do not cause tissue damage at the injection site (tissue irritation can lead to severe pain or necrosis at the site of injection).

• Involves administration of drug through the nose or mouth and into the lungs during respiratory inspiration.

• Especially useful for the local administration of drugs (gases, aerosols) into the respiratory tract (systemic side effects are minimized).

• Provides rapid delivery of drugs (Very rapid drug onset of action). Dose can be titrated.

• Suitable for achieving systemic effects by application of drugs to the skin, usually via a transdermal patch.

• Rate of absorption can be variable and onset can be delayed, depending on the physical characteristics of the skin at the site of application and lipid solubility of the drug.

• Convenient and painless, suitable for sustained delivery of drugs.

• When a local effect of the drug is desired (in certain conditions used for systemic effect)

1. Passive Diffusion

2. Facilitated Diffusion

3. Active Transport

4. Endocytosis

Driving Force: Concentration gradient (high to low)

Characteristics: No carrier involved, not saturable, low structual specificity

• Most drugs gain access to the body by this mechanism:

  Water-soluble: Move through aqueous channels or pores. Lipid-soluble: Easily cross lipid bilayers

Uses specialized transmembrane carrier proteins: Undergo conformational changes, allowing the passage of drugs into the interior of cells.

Characteristics: No energy required, can be saturated, inhibited by competing compounds.

Function: Facilitates entry of larger molecules from high to low concentration

Mechanism: Involves specific carrier proteins.

Characteristics: Energy-dependent (via ATP hydrolysis), can move drugs against concentration gradients (low to high), shows saturation kinetics.

Selectivity: Can be competitively inhibited by other substances.

Drugs that closely resemble the structure of naturally occurring metabolites are absorbed via this mechanism. e.g, levodopa (for Parkinson’s disease).

Endocytosis: Engulfs large drug molecules and transports them into the cell via vesicle formation. Examples: Insulin, Peptide antibiotics, vaccine antigens / mRNA, Vit B12.

Exocytosis: Reverse process; used to secrete substances out of cells. Example: Release of neurotransmitters like norepinephrine.

1. pH at the absorption site:

   • Weak acids: HA <-> H+ + A-

     Weak bases: BH+ <-> H+ + B

   • Uncharged forms of drugs diffuse through membranes more easily (faster absorption

     rates)

   • The ratio between the charged and uncharged forms of a drug is determined by the

     pH at the site of absorption and by the strength of the weak acid or base, which is represented by the ionization constant, pKa

1. Expression of P-glycoprotein:

• A family of transmembrane transporter proteins (belong to ABC transporters) that pump drugs out of cells, reducing absorption

• P-glycoproteins are associated with reduced drug absorption and resistance to multiple drugs

1. Blood flow at the absorption site:

• Intestinal blood flow is higher than stomach blood flow, favoring absorption in the intestine.

• In case of shock (marked reduction in blood flow) drug absorption from subcutaneous injections is markedly decreased

1. Surface area available for absorption:

• Intestinal surface area (due to microvilli) is 1000-fold higher than that of the stomach, enhancing drug absorption in the intestine

1. Contact time at the absorption surface:

• Short contact time (e.g., diarrhea) reduces absorption.

• Presence of food in the stomach both dilutes the drug and slows gastric emptying (Drugs taken with meal are generally

  absorbed more slowly)