Pharmacology: Pharmacodynamics and Pharmacokinetics

• Pharmacology studies substances interacting with living systems through chemical processes, particularly binding to regulatory molecules.

Pharmacodynamics

• Focuses on the drug's actions on the body
• Determines the drug's classification and suitability for specific symptoms or diseases.

Pharmacokinetics

• Focuses on the body's actions on the drug
• Governs absorption, distribution, and elimination of drugs
• Important for choosing and administering drugs, especially for patients with impaired renal function.

Pharmacokinetic Processes

Absorption

• Allows the drug to enter the plasma from the administration site, either directly or indirectly.

Distribution

• Reversibly allows the drug to leave the bloodstream and enter interstitial and intracellular fluids.

Metabolism

• Biotransforms the drug via the liver or other tissues.

Elimination

• Removes the drug and its metabolites from the body through urine, bile, or feces.
• Knowledge of pharmacokinetic parameters enables optimal drug regimens, including route of administration, dose, frequency, and treatment duration.

Routes of Drug Administration

• Determined by the drug's properties and therapeutic objectives, such as the need for rapid onset, long-term treatment, or localized delivery
• Includes enteral, parenteral, and topical routes.

Enteral Route

• Safest, most common, convenient, and economical method
• Involves administering a drug by mouth through swallowing (oral), under the tongue (sublingual), or between the gums and cheek (buccal) for direct bloodstream absorption.

Oral Administration

• Advantages include easy self-administration and the availability of antidotes for toxicities or overdose, such as activated charcoal
• Complex absorption pathways and low gastric pH may inactivate some drugs
• Available in various forms, including enteric-coated and extended-release preparations.

Enteric-Coated Preparations

• Chemical envelope protects the drug from stomach acid, delivering it to the less acidic intestine
• Useful for acid-labile drugs (e.g., omeprazole) and drugs irritating to the stomach (e.g., aspirin).

Extended-Release Preparations

• Special coatings or ingredients control drug release for slower absorption and prolonged action
• Allows for less frequent dosing, improving patient compliance, and maintaining therapeutic concentrations longer than immediate-release forms
• Advantageous for drugs with short half-lives (e.g., morphine).

Sublingual/Buccal Administration

• Involves placing the drug under the tongue (sublingual) or between the cheek and gum (buccal)
• Advantages include ease of administration, rapid absorption, bypassing the GI environment, and avoiding first-pass metabolism.

Parenteral Route

• Introduces drugs directly into the body by injection
• Used for drugs poorly absorbed or unstable in the GI tract (e.g., heparin, insulin), for patients unable to take oral medications, or when rapid onset is needed
• Offers highest bioavailability, avoids first-pass metabolism and the GI environment, and provides the most control over dosage
• Disadvantages include irreversibility, pain, fear, tissue damage, and infections
• Major routes include intravenous, intramuscular, and subcutaneous.

Intravenous (IV) Injection

• Most common parenteral route
• Useful for drugs not absorbed orally, such as rocuronium
• Allows rapid effect and maximum control over drug amount
• Can be administered as a bolus for immediate full dose or as an infusion for lower peak concentrations and extended duration.

Intramuscular (IM) Injection

• Can be administered in aqueous solutions for rapid absorption or in depot preparations for slow absorption
• Depot preparations create a sustained dose over an extended interval as the drug precipitates and slowly dissolves at the injection site.

Subcutaneous (SC) Injection

• Provides absorption via simple diffusion, slower than IV
• Minimizes risks of hemolysis or thrombosis
• Provides constant, slow, and sustained effects
• Not suitable for drugs that cause tissue irritation
• Commonly used for insulin and heparin.

Intradermal Injection

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

Other Routes

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
• Inhalation is effective for gases and aerosols, benefiting patients with respiratory disorders by delivering drugs directly to the site of action
• Nasal route involves topical administration directly into the nose, often 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), bypassing the blood-brain barrier.

Topical Application

• Used when a local drug effect is desired.

Transdermal Route

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

Rectal Administration

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

Absorption

• Transfer of a drug from the administration site to the bloodstream
• Rate and extent depend on the environment, drug characteristics, and route of administration, influencing bioavailability
• Routes other than intravenous may result in partial absorption and lower bioavailability.

Mechanisms of Drug Absorption from the GI Tract

Passive Diffusion

• Driving force is the concentration gradient across a membrane
• Drug moves from high to low concentration areas
• Does not involve a carrier, is not saturable, and has low structural specificity
• Most drugs are absorbed this way
• Water-soluble drugs penetrate through aqueous channels, while lipid-soluble drugs move across lipid bilayers.

Facilitated Diffusion

• Involves specialized transmembrane carrier proteins that facilitate the passage of large molecules
• Does not require energy, can be saturated, and may be inhibited by competing compounds.

Active Transport

• Uses specific carrier proteins and is energy-dependent, driven by ATP
• Moves drugs against a concentration gradient, from low to high concentration
• Saturable and selectively inhibited by other co-transported substances.

Endocytosis and Exocytosis

• Used to transport exceptionally large drugs across the cell membrane
• Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell via vesicles
• Exocytosis is the reverse, secreting substances out of the cell through similar vesicle formation
• Example: Vitamin B12 is transported across the gut wall by endocytosis.

Factors Influencing Absorption

Effect of pH on Drug Absorption

• Most drugs are weak acids or bases
• Drugs pass through membranes more readily if uncharged
• For weak acids (HA), the uncharged form permeates membranes
• For weak bases the uncharged form (B) penetrates through the cell membrane
• Effective concentration of the permeable form is determined by pH and the drug's strength (pKa).

Blood Flow to the Absorption Site

• Intestines receive more blood flow than the stomach, favoring absorption from the intestine.

Total Surface Area

• Intestine's surface area, with brush borders and microvilli, is about 1000 times that of the stomach, making intestinal absorption more efficient.

Contact Time

• Rapid movement through the GI tract, as with diarrhea, reduces absorption
• Anything delaying transport from the stomach to the intestine delays absorption rate.

P-Glycoprotein Expression

• A transmembrane transporter protein responsible for transporting molecules, including drugs, across cell membranes
• Expressed in tissues like the liver, kidneys, placenta, intestines, and brain capillaries
• Transports drugs from tissues to blood, reducing drug absorption in areas of high expression
• It is associated with multidrug resistance.

Bioavailability

• Rate and extent to which an administered drug reaches the systemic circulation
• For example, 70% bioavailability means 70mg of a 100mg dose is absorbed unchanged
• Important for calculating drug dosages for non-intravenous routes.

Determination of Bioavailability

• Determined by comparing plasma levels after a particular route of administration (e.g., oral) with levels achieved by IV administration
• Area under the curve (AUC) measures plasma concentrations over time.

Factors Influencing Bioavailability

First-Pass Hepatic Metabolism

• When a drug is absorbed from the GI tract, it enters the portal circulation before the systemic circulation
• Rapid metabolism in the liver or gut wall reduces the amount of unchanged drug entering the systemic circulation
• Drugs with high first-pass metabolism require higher doses to ensure enough active drug reaches the target site
• Example: Nitroglycerin is primarily administered sublingually, transdermally, or intravenously due to high first-pass metabolism.

Drug Solubility

• Very hydrophilic drugs are poorly absorbed due to the inability to cross lipid-rich cell membranes
• Extremely lipophilic drugs are also poorly absorbed because they are insoluble in aqueous body fluids
• Drugs must be largely lipophilic with some aqueous solubility for ready absorption
• Reason why many drugs are weak acids or bases.

Chemical Instability

• Some drugs, such as penicillin G, are unstable in gastric pH
• Others, like insulin, are destroyed by degradative enzymes in the GI tract.

Drug Formulation

• Factors unrelated to drug chemistry, such as particle size, salt form, crystal polymorphism, enteric coatings, and excipients, can influence dissolution and absorption.

Drug Distribution

• Process by which a drug reversibly leaves the bloodstream and enters the interstitium and tissues.
• For IV drugs, the initial phase represents distribution
• Cardiac output, local blood flow, capillary permeability, tissue volume, binding to plasma and tissue proteins, and lipophilicity affect distribution from plasma to interstitium.

Blood Flow

• Rate varies widely; vessel-rich organs (brain, liver, kidney) have greater blood flow than skeletal muscles, adipose tissue, and skin
• Explains the short duration of hypnosis from propofol due to rapid distribution into the CNS.

Capillary Permeability

• Determined by capillary structure and drug chemistry
• Liver and spleen capillaries have large discontinuities, allowing large plasma proteins to pass through
• Brain capillaries are continuous with no slit junctions, forming the blood-brain barrier, requiring drugs to pass through endothelial cells or undergo active transport
• Lipid-soluble drugs penetrate the CNS readily, while ionized or polar drugs generally fail to enter.

Binding to Plasma and Tissue Proteins

Binding to Plasma Proteins

• Reversible binding sequesters drugs in a non-diffusible form, slowing transfer out of the vascular compartment
• Albumin is the major binding protein, acting as a drug reservoir
• Free drug concentration decreases due to elimination, bound drug dissociates from albumin, maintaining a constant fraction of total drug in the plasma.

Binding to Tissue Proteins

• Many drugs accumulate in tissues due to binding to lipids, proteins, or nucleic acids, or via active transport
• Tissue reservoirs prolong drug actions or cause local toxicity
• Ex: Acrolein causes hemorrhagic cystitis because it accumulates in the bladder.

Lipophilicity

• Chemical nature strongly influences the ability to cross cell membranes
• Lipophilic drugs readily move across most biologic membranes, with blood flow being the major factor in distribution
• Hydrophilic drugs do not readily penetrate cell membranes and must pass through slit junctions.

Volume of Distribution

• Apparent volume required to contain the entire drug in the body at the same concentration measured in the plasma
• Calculated by dividing the dose by the plasma concentration at time zero (C0)
• No physiologic basis, but useful for comparing drug distribution with body water compartments.

Distribution into Water Compartments

• Plasma compartment: High molecular weight or extensively protein-bound drugs are trapped within the plasma, resulting in a low Vd (approximately 4 L in a 70-kg individual)
• Extracellular fluid: Low molecular weight but hydrophilic drugs can pass into the interstitial fluid but not into the intracellular fluid, distributing into about 14L in a 70-kg individual
• Total body water: Low molecular weight and lipophilic drugs can move into the interstitium and intracellular fluid, distributing into about 42 L in a 70-kg individual.

Determination of Vd

• Drug clearance is usually a first-order process, allowing Vd calculation
• First order means a constant fraction of the drug is eliminated per unit of time
• Analyzed by plotting the log of plasma drug concentration (Cp) versus time
• Plasma concentration extrapolated back to time zero determines C0
• Vd = Dose/C0.

Drug Clearance Through Metabolism

• Once a drug enters the body, elimination begins through hepatic metabolism, biliary elimination, and urinary elimination
• These processes decrease plasma concentration exponentially
• Most drugs follow first-order kinetics; some follow zero-order kinetics
• Metabolism produces more polar products for elimination
• Clearance estimates the amount of drug cleared from the body per unit of time
• Kidneys cannot efficiently eliminate lipophilic drugs, requiring metabolism into more polar substances in the liver via phase I and phase II reactions.

Drug Clearance Through Kidney

• Drugs must be sufficiently polar to be eliminated from the body through urine
• Patients with renal dysfunction are at risk for drug accumulation and adverse effects
• Involves glomerular filtration, active tubular secretion, and passive tubular reabsorption.

Glomerular Filtration

• Free drug flows through capillary slits into Bowman's space as part of the glomerular filtrate
• Glomerular filtration rate (GFR) is normally about 125 mL/min but can be diminished in renal disease
• Lipid solubility and pH do not influence passage, but variations in GFR and protein binding do.

Proximal Tubular Secretion

• Drugs not transferred into the glomerular filtrate leave through efferent arterioles and enter the proximal tubule
• Secretion occurs via two energy-requiring active transport systems: one for anions (weak acids) and one for cations (weak bases)
• These systems show low specificity, allowing competition between drugs.

Distal Tubular Reabsorption

• Drug concentration increases in the distal convoluted tubule, exceeding that of the perivascular space
• Uncharged drugs may diffuse back into the systemic circulation
• Manipulating urine pH to increase the ionized fraction of drug in the lumen minimizes back diffusion and increases clearance
• Weak acids are eliminated by alkalinizing the urine, while weak bases are eliminated by acidifying the urine (ion trapping)
• Ex: Bicarbonate is given to phenobarbital overdose patients to alkalinize urine, decreasing reabsorption.

Excretion by Other Routes

• Drug excretion can occur via the intestines, bile, lungs, and breast milk
• Drugs not absorbed or secreted into the intestines or bile are excreted in the feces
• Lungs eliminate anesthetic gases (e.g., desflurane)
• Elimination in breast milk may expose infants to medications and/or metabolites, causing side effects
• Excretion in sweat, saliva, tears, hair, and skin is minimal
• Total body clearance and drug half-life are important measures for optimizing drug therapy and minimizing toxicity.

Total Body Clearance

• The sum of all clearances from drug-metabolizing and drug-eliminating organs
• Calculated as: CLtotal = CLhepatic + CLrenal + CLpulmonary + CLother
• Hepatic and renal clearance are typically the most important.

Clinical Situations Resulting in Changes in Drug Half-Life

• Patients with abnormalities altering drug half-life require dosage adjustments
• Increased half-life occurs with diminished renal or hepatic blood flow (e.g., cardiogenic shock, heart failure, hemorrhage), decreased drug extraction (e.g., renal disease), and decreased metabolism (e.g., concomitant drug inhibits metabolism or hepatic insufficiency)
• These patients may require lower doses or less frequent dosing intervals
• Decreased half-life occurs with increased hepatic blood flow, decreased protein binding, or increased metabolism, necessitating higher doses or more frequent dosing intervals.