BIOL122 - Pharmacology & Pathology Review
Fundamentals of Pharmacokinetics
Pharmacokinetics describes the specific processes that determine what happens to a drug once it enters the body. It consists of four distinct phases known by the acronym ADME: Absorption, Distribution, Metabolism, and Elimination.
Absorption identifies the passage of a drug from its specific site of administration into the bloodstream.
Except for drugs administered intravenously, medications must generally cross cell membranes to enter the circulation.
Factors that affect the rate and extent of absorption include the nature and thickness of the absorbing surface, the blood supply to the area, the chemical structure and molecular size of the drug, the solubility of the drug (water-soluble versus lipid-soluble), and the preferred pH of the drug.
Distribution refers to the movement of unmetabolised drug through the blood and various tissues.
This process is influenced by plasma proteins (such as albumin), blood flow, the volume of body water, and adipose tissue.
Distribution is also affected by drug interactions involving plasma proteins and physiological barriers, including the blood-brain barrier. Lipid-soluble drugs are notably relevant for their ability to pass through the blood-brain barrier.
Plasma Proteins and Albumin play a critical role in drug transport. Some drugs bind to these proteins while circulating.
Changes in the concentration of plasma proteins can directly alter the amount of free drug present in the system.
A vital principle of pharmacokinetics is that only free drug (unbound) is available to be excreted.
Metabolism involves the chemical modification or transformation of drugs within the body, primarily to increase water solubility to assist in later excretion.
The liver serves as the major organ for drug metabolism.
While most medications are deactivated during metabolism, some specific drugs are activated by these processes.
First-pass metabolism is a critical consideration for oral medications.
After absorption from the gastrointestinal tract, oral drugs enter the hepatic portal circulation and travel to the liver before reaching systemic circulation.
Consequently, a portion of the drug may be metabolised or transformed before ever reaching the systemic bloodstream.
A greater degree of first-pass metabolism results in reduced oral bioavailability.
Elimination is the process of irreversible loss of a drug from the body.
Drugs can be excreted via several routes, but only free drug can be excreted.
Some drugs undergo a process where they are excreted through the liver into bile and subsequently reabsorbed via the gastrointestinal tract, which can prolong the action and clearance time of the drug.
Bioavailability and Administration Routes
Bioavailability is defined as the rate at which an administered drug reaches systemic circulation or its specific area of effect.
A fundamental concept of bioavailability is that not all of an administered dose necessarily reaches systemic circulation or the site of action.
Intravenous (IV) medications possess the highest possible bioavailability () because the entire dose is placed directly into the systemic circulation.
Bioavailability for other routes depends on factors including absorption efficiency and the extent of first-pass metabolism. For oral drugs, bioavailability is specifically influenced by gastrointestinal absorption and hepatic first-pass metabolism.
Lifespan Pharmacology: Pregnancy
Pharmacology changes across the lifespan because physiological differences alter the ADME processes. Standard adult doses may be inappropriate for pregnant, pediatric, or elderly patients.
Physiological changes in pregnancy that may affect absorption include nausea, vomiting, decreased gastric acid production, increased mucus production, and decreased intestinal motility.
Although increased cardiac output and blood flow could theoretically increase absorption, no significant overall effect on oral drug absorption has been observed in pregnant patients. Studies on other administration routes during pregnancy remain relatively few.
Distribution changes during pregnancy occur because of increased cardiac output and circulating blood volume.
Increased blood volume leads to reduced plasma concentration of hydrophilic (water-soluble) drugs because they are distributed through a larger volume of fluid.
Increased total body adipose tissue leads to reduced plasma concentration of lipophilic (lipid-soluble) drugs as they distribute into fat stores.
Albumin production is reduced, which results in a greater concentration of free drug. This may necessitate monitoring of free drug concentrations and adjustments to medication doses.
Metabolism changes during pregnancy are highly variable. Activity levels of various hepatic enzymes may increase or decrease, which is particularly significant for drugs with a narrow therapeutic range.
Elimination changes during pregnancy include an increase in the Glomerular Filtration Rate (GFR) by approximately .
Changes also occur in renal tubular secretion and reabsorption.
The impact of increased GFR on drug clearance cannot be generalized to every medication and must be considered individually.
Lifespan Pharmacology: Neonates and Children
Children are physiologically distinct from adults, and drug handling capabilities evolve with age and development.
Absorption in children is influenced by gastric acid levels, which do not reach adult levels until approximately of age. This affects the absorption of acidic drugs. Children also exhibit reduced gastric motility and have thinner skin than adults.
Distribution in children is impacted by a higher blood volume relative to adults, potentially diluting hydrophilic drugs.
Conversely, children have lower adipose tissue levels than adults, which can lead to higher concentrations of lipophilic drugs.
The immature liver produces fewer plasma proteins (like albumin), leading to higher levels of free drug.
The blood-brain barrier is incomplete in young children.
Metabolism in children is slower at birth but increases relatively quickly during development. The liver remains functionally larger in proportion to body size until approximately of age.
Elimination in neonates is significantly lower; at birth, the GFR is approximately of adult levels. The GFR typically reaches adult levels between of age.
Lifespan Pharmacology: Elderly Patients
Ageing is associated with reduced gastric acid and decreased gastrointestinal motility, though these changes do not result in a significant overall effect on oral drug absorption. Evidence for other routes is limited.
Distribution changes in older adults include decreased blood volume, leading to increased plasma concentrations of hydrophilic drugs.
Older adults tend to have increased total body adipose tissue, which reduces the plasma concentration of lipophilic drugs.
Reduced albumin production results in higher free drug concentrations, necessitating monitoring and potential dose adjustments.
Metabolism in the elderly is characterized by a decrease in first-pass metabolism of approximately per year after the age of . Metabolism is highly individual and influenced by lifestyle factors.
Elimination through the kidneys (GFR) decreases steadily after the age of . This decline is highly variable and affected by individual health and lifestyle.
Pharmacodynamic changes in the elderly are drug-dependent. Notable examples include an increased physiological response to morphine and a decreased physiological response to beta blockers.
Adverse Drug Reactions and Interactions
An Adverse Drug Reaction (ADR) is a noxious, unwanted effect caused directly by a drug. The term "side effect" is considered outdated in this context.
An Adverse Drug Event (ADE) is distinct from an ADR because it is associated with a medication administration error rather than the drug's inherent properties. Examples of ADEs include the wrong dose, wrong route, or wrong drug.
ADR Categories (Type A through D):
Type A (Augmented): These represent an exaggerated or elevated effect of the drug. They are predictable, dose-dependent, and generally mild. Management typically involves reducing the dose.
Type B (Bizarre): These are not related to the normal pharmacological effect of the drug. They are unpredictable, not dose-dependent, and can be severe or fatal. They cannot be managed by simply reducing the dose.
Type C (Continuous/Chronic): These are associated with long-term medication use and include concepts like drug tolerance and dependence.
Type D (Delayed): These adverse effects may not manifest until a significant time after the medication has been discontinued, making them difficult to detect or prevent.
Drug-drug interactions are categorized as either pharmacodynamic or pharmacokinetic.
Pharmacodynamic interactions occur when one drug blocks or enhances the action of another drug.
Pharmacokinetic interactions occur when one drug alters the absorption, distribution, metabolism, or excretion (ADME) of another drug.
Introduction to Pathology
Pathology is defined as the study of changes in cells, tissues, and organs that underlie disease. It comprises four core aspects:
Aetiology: The cause or origin of the disease (the "why").
Pathogenesis: The mechanisms and processes through which the disease develops (the "how").
Morphological Changes: The structural changes occurring in cells, tissues, and organs due to the disease.
Clinical Manifestations: How the disease presents clinically, comprising signs and symptoms.
Signs and Symptoms are the two components of clinical manifestations.
A Sign is an objective finding that can be measured or observed by another person (Objective).
A Symptom is a subjective experience reported by the patient (Subjective).
Cellular Adaptation and Injury
Cells adapt to physiological states and pathological stimuli to maintain function. Stressors include injurious stimuli, nutrient deprivation, mutations, and injurious agents.
Major Cellular Adaptations:
Hypertrophy: An increase in the size of a tissue or organ resulting from the increased size of individual cells. No new cells are created; instead, there is increased production of intracellular components. This is the only adaptation method for permanent cells (cells that cannot divide). It can be physiological (response to hormones/growth factors) or pathological (ventricular hypertrophy due to high blood pressure).
Hyperplasia: An increase in the size of a tissue or organ caused by an increase in the number of cells. This occurs in stable and labile cells. It can be physiological (hormonal or compensatory after tissue resection, such as in the liver) or pathological (excessive hormone/growth factor action).
Atrophy: A reduction in the size of a tissue or organ caused by a decrease in both cell size and cell number. This can be physiological or pathological.
Metaplasia: A reversible change where one differentiated cell type is replaced by another differentiated cell type.
Cell Death occurs if cellular injury becomes irreversible. Forms of cell death include necrosis, apoptosis, and autophagy.