Pharmacology: Dynamics & Kinetics

• Pharmacology is the study of substances interacting with living systems through chemical processes, especially binding to regulatory molecules. This can activate or inhibit normal body processes.

Pharmacodynamics

• Pharmacodynamics refers to the actions of a drug on the body.
• These actions determine a drug's classification and suitability for treating specific symptoms or diseases.

Pharmacokinetics

• Pharmacokinetics refers to the actions of the body on the drug.
• These processes govern absorption, distribution, and elimination.
• They are crucial for selecting and administering drugs, especially in patients with impaired renal function.
• Knowledge enables clinicians to design optimal drug regimens, including route, dose, frequency, and duration.

Pharmacokinetic Processes

• Absorption is the entry of a drug into plasma from the administration site.
• Distribution involves the reversible movement of a drug from the bloodstream into interstitial and intracellular fluids.
• Metabolism is the biotransformation of a drug by the liver or other tissues.
• Elimination removes the drug and its metabolites from the body via urine, bile, or feces.

Routes of Drug Administration

• The route depends on the drug's properties and therapeutic goals such as rapid onset, long-term treatment, or localized delivery.
• Major routes include enteral, parenteral, and topical.

Enteral Administration

• It involves administering a drug by mouth and it is the safest, most common, convenient, and economical method.
• The drug can be swallowed (oral), placed under the tongue (sublingual), or between the gums and cheek (buccal).

Oral Administration

• It offers ease of self-administration, and antidotes like activated charcoal can counteract toxicities or overdose.
• Oral drug absorption can be complex. Low gastric pH may inactivate some drugs.
• Available oral preparations include enteric-coated and extended-release forms.

Enteric-Coated Preparations

• These protect drugs from stomach acid, delivering them to the less acidic intestine.
• They are useful for acid-labile drugs like omeprazole and those irritating to the stomach, such as aspirin.

Extended-Release (ER) Preparations

• ER medications have special coatings or ingredients that control drug release for slower absorption and prolonged action.
• Benefits include less frequent dosing, improved patient compliance, and sustained therapeutic concentrations.
• Advantageous for drugs with short half-lives, such as morphine (oral half-life of 2-4 hours).

Sublingual/Buccal Administration

• Sublingual route is placement of drug under the tongue. Buccal route is placement of drug between the cheek and gum.
• Offers ease of use, rapid absorption, bypasses the GI environment and avoids first-pass metabolism.

Parenteral Administration

• Introduces drugs directly into the body via injection.
• Used for drugs poorly absorbed or unstable in the GI tract, when patients can't take oral medications, or when rapid action is needed.
• Has the highest bioavailability, avoids first-pass metabolism and the GI environment.
• Allows most control over the delivered dose, but is irreversible and may cause pain, tissue damage, and infections.
• Major routes include intravenous (IV), intramuscular (IM), and subcutaneous (SC).

Intravenous (IV) Injection

• Most common parenteral route and useful for drugs poorly absorbed orally, like rocuronium.
• Permits rapid effect and maximum control over drug amount.
• Bolus injection delivers the full drug amount almost immediately and IV infusion delivers it over a longer period resulting in lower peak plasma concentrations and increased duration.

Intramuscular (IM) Injection

• IM drugs can be in aqueous solutions (absorbed rapidly) or depot preparations (absorbed slowly).
• Depot preparations suspend the drug in a nonaqueous vehicle. The drug precipitates at the injection site and dissolves slowly for sustained release.

Subcutaneous (SC) Injection

• Provides absorption via simple diffusion, slower than IV.
• Minimizes risks of hemolysis or thrombosis, and may provide constant, slow, sustained effects.
• Not for drugs that cause tissue irritation due to potential pain and necrosis. Common drugs include insulin and heparin.

Intradermal Injection

• Intradermal injection is injection into the dermis, the more vascular layer of skin under the epidermis.
• Used for diagnostic determination and desensitization

Oral Inhalation and Nasal Preparations

• Provides rapid drug delivery across mucous membranes of the respiratory tract and pulmonary epithelium.
• Effects are almost as rapid as IV bolus.
• Effective for respiratory disorders like asthma or COPD, minimizing systemic side effects.
• Nasal route involves topical administration directly into the nose, used for allergic rhinitis.

Intrathecal/Intraventricular Administration

• Introduces drugs directly into the cerebrospinal fluid when local, rapid effects are needed in the central nervous system (CNS).

Topical Application

• Used when a local drug effect is desired.

Transdermal Administration

• Achieves systemic effects by applying drugs to the skin, usually via a transdermal patch.
• Absorption rate varies with skin characteristics and drug lipid solubility.

Rectal Administration

• Minimizes liver biotransformation because 50% of rectal drainage bypasses portal circulation.
• Prevents drug destruction in the GI environment.
• Useful if the drug induces vomiting, if the patient is already vomiting, or is unconscious.
• Absorption can be erratic and incomplete; many drugs irritate the rectal mucosa.

Absorption of Drugs

• Absorption is the transfer of a drug from the administration site to the bloodstream.
• Rate and extent depend on the absorption environment, drug's chemical properties, and route of administration.
• Non-intravenous routes may result in partial absorption and lower bioavailability.

Mechanisms of Absorption

• Drugs absorb from the GI tract via passive diffusion, facilitated diffusion, active transport, or endocytosis.

Passive Diffusion

• Driving force is the concentration gradient across a membrane.
• The drug moves from high to low concentration areas.
• Doesn't involve a carrier, is not saturable, and shows low structural specificity.
• Most drugs absorb this way.
• Lipid-soluble drugs readily move, whereas water-soluble drugs penetrate through aqueous channels or pores.

Facilitated Diffusion

• Agents enter the cell through transmembrane carrier proteins for large molecules.
• This process doesn't require energy, can be saturated, and may be inhibited by competing compounds.

Active Transport

• Involves specific carrier proteins and is energy-dependent (ATP hydrolysis).
• Moves drugs against a concentration gradient and is saturable.
• Systems are selective and competitively inhibited by co-transported substances.

Endocytosis and Exocytosis

• Transports exceptionally large drugs across the cell membrane.
• Endocytosis engulfs a drug by the cell membrane. Exocytosis secretes substances out of the cell.
• Vitamin B12 is transported across the gut wall by endocytosis, neurotransmitters are released by exocytosis.

Factors Influencing Absorption

Effect of pH on Drug Absorption

• Most drugs are weak acids or weak bases, which pass through membranes more readily if uncharged.
• Weak acids release a proton (H+), forming a charged anion (A−). Weak bases (BH+) release a proton producing an uncharged base (B).

Blood Flow to the Absorption Site

• The intestines receive much more blood flow than the stomach, so absorption from the intestine is favored over the stomach.

Total Surface Area

• The intestine has a surface area about 1000-fold that of the stomach, due to microvilli, making absorption more efficient.

Contact Time at the Absorption Surface

• Severe diarrhea decreases absorption.
• Anything that delays transport from the stomach to the intestine delays absorption.

P-Glycoprotein Expression

• P-glycoprotein is a trans-membrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes.
• It transports molecules across cell membranes, pumping drugs out of cells which reduces drug absorption.
• Associated with multidrug resistance.

Bioavailability

• Rate and extent to which an administered drug reaches systemic circulation.
• Important for calculating drug dosages for non-IV routes.
• Determined by comparing plasma levels after a particular route (e.g., oral) with IV administration.

Determination of Bioavailability

• After IV administration, 100% of the drug enters circulation rapidly.
• Oral administration results in only part of the dose appearing in plasma.
• Plasma concentrations versus time are plotted, and the area under the curve (AUC) is measured.

Factors Influencing Bioavailability

• Orally administered drugs undergo first-pass metabolism, in addition to chemical and physical characteristics of the drug.

First-Pass Hepatic Metabolism

• Drug is metabolized in the liver or gut wall.
• Reduces the amount of unchanged drug entering systemic circulation.
• Drugs should be given in doses sufficient to ensure that enough active drug reaches the desired site of action.
• For example, more than 90% of nitroglycerin is cleared during first-pass metabolism. Hence, it is primarily administered via the sublingual, transdermal, or intravenous route.

Solubility of the Drug

• Very hydrophilic drugs are poorly absorbed and drugs that are extremely lipophilic are also poorly absorbed, because they are insoluble in aqueous body fluids.
• Drugs must be largely lipophilic, yet have some solubility in aqueous solutions. This is one reason why many drugs are either weak acids or weak bases.

Chemical Instability

• Some drugs, like penicillin G, are unstable in gastric pH. Others, like insulin, are destroyed by GI enzymes.

Nature of Drug Formulation

• Particle size, salt form, crystal polymorphism, enteric coatings, and excipients can influence the ease of dissolution and alter absorption rate.

Drug Distribution

• Process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tissues.
• For IV drugs, the phase after administration represents distribution, with the drug rapidly leaving circulation and entering tissues.

Blood Flow

• The rate of blood flow to the tissue capillaries varies widely.
• Blood flow is greater to vessel-rich organs (brain, liver, and kidney) than to skeletal muscles. Adipose tissue, skin, and viscera have still lower rates of blood flow.

Capillary Permeability

• Determined by capillary structure and the chemical nature of the drug.
• In the liver and spleen, a significant portion of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass.
• In the brain, the capillary structure is continuous, and there are no slit junctions.
• Lipid soluble drugs readily penetrate the CNS because they dissolve in the endothelial cell membrane.

Binding of Drugs to Plasma Proteins and Tissues

• Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows transfer out of the vascular compartment.
• Albumin is the major drug binding protein.
• Many drugs accumulate in tissues, leading to higher concentrations in tissues than in interstitial fluid and blood.

Lipophilicity

• Lipophilic drugs readily move across most biologic membranes.
• Hydrophilic drugs do not readily penetrate cell membranes and must pass through slit junctions.

Volume of Distribution

• The apparent volume of distribution, Vd, is defined as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma.

Distribution into Water Compartments

• Drugs distribute into plasma compartment or extracellular fluid or total body water.
  • Molecular weight and protein binding affects ability to pass through slit junctions of capillaries.

Determination of Vd

• First order means that a constant fraction of the drug is eliminated per unit of time.

Drug Clearance Through Metabolism

• Once a drug enters the body, the process of elimination begins.
• The three major routes of elimination are hepatic metabolism, biliary elimination, and urinary elimination.

Drug Clearance Through Kidney

• Drugs must be sufficiently polar to be eliminated from the body.
• Removal of drugs from the body occurs most importantly via elimination through the kidney into the urine.

Glomerular Filtration

• Free drug flows into the Bowman space as part of the glomerular filtrate.

Proximal Tubular Secretion

• Secretion primarily occurs in the proximal tubules by two energy-requiring active transport systems: one for anions and one for cations.

Distal Tubular Reabsorption

• A drug may diffuse out of the nephric lumen, back into the systemic circulation.
• Weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine.

Excretion by Other Routes

• May also occur via the intestines, bile, lungs, and breast milk, among others.

Total Body Clearance

• The kidney is often the major organ of excretion. The liver also contributes to drug clearance through metabolism and/or excretion into the bile.

Clinical Situations Resulting in Changes in Drug Half-Life

• Patients who may have an increase in drug half-life include those with diminished renal or hepatic blood flow, renal disease and decreased metabolism.
• In contrast, the half-life of a drug may be decreased by increased hepatic blood flow, decreased protein binding, or increased metabolism.