Pharmacodynamics and Pharmacokinetics Principles

• The lecture discusses the principles of pharmacodynamics and pharmacokinetics.
• The objectives are to identify major drug absorption routes, explain the influence of protein and tissue binding on drug distribution, and discuss mechanisms involved in the elimination of drugs.

Drug Absorption

• Systemically administered drugs can be absorbed directly from the site of administration (e.g., skin) or from a distant site (e.g., oral).
• Drugs must be dissolved in body fluid, regardless of the administration site.
• Drugs need to cross the epithelial barrier at the absorption site to enter the bloodstream.

Factors Controlling Drug Absorption

• Drug solubility and dissolution rate are factors
• Concentration contributes to drug absorbtion.
• Circulation and surface area at the site of absorption influences the process

Routes of Systemic Administration

• Drug administration can be achieved through oral, nasal, inhalation, otic, ocular, topical/transdermal, parenteral, and/or rectal/vaginal routes
• Oral administration includes tablets, capsules, disintegrating tablets, buccal tablets, sublingual tablets, mini tablets, effervescent tablets, thin films, medicated gums, granules, troches, lozenges, solutions, suspensions, emulsions, elixirs, and buccal sprays.
• Nasal administrations utilize drops and sprays
• Inhalation administrations consist of dry powders and liquid sprays
• Otic administrations include topical, intratympanic, and intracochlear applications
• Ocular administrations encompass solutions, emulsions, suspensions, ointments, contact lenses, implants, inserts, and intravitreal applications.
• Topical/Transdermal administrations use ointments, creams, lotions, gels, sprays, and patches.
• Rectal/Vaginal administrations employ suppositories, enemas, tablets, pessaries, gels, creams, foams, and sponges.
• Parenteral administrations are done via intramuscular, subcutaneous, intravenous, and intradermal injections.

Oral Route

• The oral route is the most common, preferred, and safest.
• Stomach pH (1-3) influences oral route.
• The stomach is a site of drug dissolution and degradation.
• Little absorption occurs in the stomach due to the limited time drugs spend there.
• The small intestine, with an enormous surface area (6-7 m in length), is the major site of absorption.
• The large intestine (1.5 m) is mostly involved in water and electrolyte absorption from feces.
• Oral route is subject to the first-pass effect.

Buccal or Sublingual Route

• Involves placing a drug under the tongue or crushing and spreading it in the buccal area.
• Absorption is quick.
• This route avoids first-pass metabolism.
• Suitable for drugs destroyed by stomach acid and enzymes.
• Facilitates rapid absorption of lipophilic drugs via transcellular diffusion.
• This route is unsuitable for bitter-tasting drugs.

Rectal Route

• Administered rectally via suppository or retention enema.
• Limited absorption due to the lower surface area.
• In pediatrics, this route is advantageous
• Largely avoids first-pass metabolism.
• Slow, incomplete, and irregular absorption are disadvantages.
• Possible irritation of the rectal mucosa.

Parenteral Routes

• In subcutaneous injections, absorption is slow, which prolongs action.
• Intramuscular injections are the most common parenteral route, allowing fairly rapid absorption
• Intravenous injections are the most rapid but also dangerous.
• Intraperitoneal injections involve injecting into the abdominal cavity.
• Intradermal injections are under the epidermis and are used for some vaccines.

Transdermal Route

• Drug absorption occurs through intact skin.
• It can be facilitated by carriers and devices.
• This route provides fairly constant drug delivery.
• Nicotine and fentanyl patches, as well as hormone therapy, use this method
• Iontophoresis uses the local electric current to drive ionic drugs across the skin.

Nasal Route

• Drug absorption occurs through the nasal mucosa.
• Rapid drug absorption is observed.
• Attractive for small proteins and other macromolecules not suitable for oral administration.
• The disadvantages are limited surface area and doses.
• Long-term use can damage the nasal lining.

Pulmonary Route

• The drug is inhaled by mouth into the lungs.
• Absorption occurs via passive diffusion across the alveolar epithelium.
• Drugs must reach the terminal bronchioles and alveoli to be effectively absorbed.
• Particles less than 5 µm in diameter are preferred.
• The dosage form, retention, and clearance are potential problems.

Drug Distribution

• It involves reversible transfer of drug between the vascular and extravascular spaces.
• Drug distribution is uneven due to differences in regional pH, blood perfusion, protein and tissue binding, membrane permeability, and drug characteristics.
• Drug concentration in interstitial fluid (ISF) will be the same as free drug concentration in plasma once equilibrium is reached.
• Free drug in ISF may enter tissue cells, distributing more widely than if it remained in the plasma or ISF.

Apparent Volume of Distribution (Vd)

• A small Vd indicates that drugs mostly remain in plasma.
• A large Vd indicates that drugs distribute in plasma + ISF + ICF.

Protein Binding

• Reversible binding to plasma proteins (mainly albumin) forms drug-protein complexes.
• Binding depends on drug concentration, the number of available binding sites, and the association constant between drug and protein.
• Binding ranges from 0% to 99% and influences the half-life of the drug.

Tissue Binding

• Drug binding to tissue components can result in a large Vd.
• Tissue binding may be a slow process that becomes evident only after the drug has equilibrated in all fluids and reached a steady state.
• Tissue binding leads to "storage" such as in adipose (fat) tissue.
• The apparent volume of distribution for drugs that bind to tissue may be much higher than total body water.
• Tetracycline antibiotics deposit in teeth and bones due to chelation with divalent calcium.

Drug Excretion

• This is the primary route of excretion following drug conversion to polar metabolites.
• The kidneys produce urine (95% water) to excrete water-soluble materials.
• The nephron uses glomerular filtration, tubular reabsorption, and tubular secretion.
• The molecular sieve allows the filtration of molecules < 70 kDa.
• The kidneys receive 20% of cardiac output, with 20% of this converted to filtrate (urine).
• Renal plasma flow is 600 mL/min.
• A normal-functioning adult has a Glomerular Filtration Rate (GFR) of 120 mL/min.
• GFR is the volume of plasma filtered by the kidneys per minute (not the renal flow).

Tubular Reabsorption

• Involves the transport of essential substances from filtrate back into the peritubular capillaries, including glucose, amino acids, and ions (Na+, K+, Cl-, HCO3-).
• Active transport by specific carriers in the tubular epithelium.
• Concurrent water reabsorption from the filtrate returns approximately 98% of water filtered in the glomerulus back into the blood.
• Alkaline urine results in acidic drugs being more ionized, less reabsorbed, and more readily excreted.
• Urine acidifiers (ammonium chloride) or alkalinizers (sodium bicarbonate) are used to alter urine pH.
• Sodium bicarbonate injection increases renal excretion in pentobarbital (weak acid) overdose.

Tubular Secretion

• Reverses reabsorption.
• Cells of the tubular epithelium can remove certain molecules and ions from blood and secrete them into the filtrate.
• Solutes are more concentrated in filtrate due to water reabsorption, is energy-dependent, and uses active transport
• Carrier proteins bind the ionized form of the drug with organic anion and cation transporters (OAT & OCT).

Summary of Renal Excretion

• Excretion = Filtration – Reabsorption + Secretion

Excretion by Liver

• Facilitated via biliary excretion, which is when drugs in the liver conjugate to bile, empty to the duodenum, and gets eliminated via feces.
• Enterohepatic recirculation is a partial reabsorption of drugs excreted in bile, similar to orally administered drugs, and can increase half-life of the drug and cause potential toxicity.

Excretion by Other Organs

• Saliva follows a minor route where it is swallowed and drugs re-enter the GI tract.
• Breast milk has a lower pH (6.8) compared to plasma (7.4).
• Basic drugs like erythromycin have an 8-fold higher conc.
• Sweat is a minor route used for therapeutic and illicit drug monitoring.
• Lungs excrete volatile drugs (anesthetics, alcohol) - Breathalyzer test.
• Toxic metal secretion (like arsenic) can be detected in hair.

Review Points

• Routes and mechanisms of drug absorption
• Drug-protein binding and tissue deposition
• Principles of renal excretion
• Excretion by other organs