Category: Patient Care-26 What is caused by loss of a large…
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Cаtegоry: Pаtient Cаre-26 What is caused by lоss оf a large amount of blood or plasma?
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DRUG EXCRETION Drug excretiоn = remоvаl оf drug аnd/or metаbolites from the body Major Routes of Excretion Kidney (primary organ) Most clinically important route Other routes Bile → feces Lungs → exhaled air (volatile substances) Milk Saliva Sweat Tears Chemical Properties Affecting Excretion Lipid-soluble (non-polar) drugs Poorly excreted by kidneys in unchanged form Require metabolism → more hydrophilic compounds Exception: Lungs preferentially eliminate non-ionized, lipophilic volatile drugs Hydrophilic (polar) drugs More easily excreted May be eliminated unchanged in urine Drug Clearance (CL) Definition Volume of plasma cleared of drug per unit time Total clearance Sum of all organ clearances: Renal + hepatic + pulmonary + others Renal Excretion (Key Mechanisms) Glomerular Filtration Occurs at glomerulus → Bowman’s capsule Mechanism: Passive filtration of free (unbound) drug Influencing factor: Only unbound drugs are filtered Effect: ↑ drug excretion Tubular Secretion Occurs in proximal tubule Mechanism: Active transport from peritubular capillaries → tubular lumen Features: Can secrete protein-bound drugs (after dissociation) Saturable process (competition possible) Effect: ↑ drug excretion Tubular Reabsorption Occurs mainly in distal tubule Mechanism: Passive diffusion back into blood Influenced by: Lipid solubility Degree of ionization Effect: ↓ drug excretion Urine pH and Drug Excretion (Ionization & Trapping) Core Principle Ionized drugs = trapped in urine → excreted Non-ionized drugs = reabsorbed → retained Alkalinization of urine (↑ pH) Example: NaHCO₃ Effect on drugs: Acidic drugs e.g., salicylic acid, phenobarbital Become ionized ↓ tubular reabsorption ↑ excretion Basic drugs e.g., amphetamines, TCAs Become non-ionized ↑ reabsorption ↓ excretion Acidification of urine (↓ pH) Example: NH₄Cl Effects are opposite: Basic drugs → ionized → ↑ excretion Acidic drugs → non-ionized → ↑ reabsorption Ion Trapping Strategy used in drug toxicity management Goal: Alter urine pH to trap drug in ionized form Promote renal elimination Elimination Parameters & Concepts Elimination Half-life (t½) Time required for 50% reduction in plasma drug concentration Depends on: Clearance (CL) Volume of distribution (Vd) Drug Elimination Patterns First-order kinetics (most drugs) Constant fraction eliminated per time Rate depends on concentration Zero-order kinetics (saturation) Constant amount eliminated per time Occurs when elimination pathways are saturated Steady-State Concentration (Css) Achieved when: Rate of drug administration = rate of elimination Key point: Usually reached after ~4–5 half-lives Clinical relevance: Determines stable therapeutic drug levels during continuous dosing Question: A 24-year-old patient with salicylate overdose is treated with sodium bicarbonate infusion; which mechanism best explains the resulting increase in renal drug excretion?
BIOAVAILABILITY Definitiоn Frаctiоn оf аn аdministered drug dose that reaches systemic circulation unchanged• Compares non-IV routes to IV (reference = 100% bioavailability)• Quantified using Area Under the Curve (AUC) Key concept AUC reflects total systemic exposure• IV administration bypasses absorption barriers → standard reference Factors affecting bioavailability Route of Administration IV = 100%• Oral = variable (first-pass + absorption limits) Dosage Form Solutions > suspensions > tablets > coated/extended-release• Faster dissolution → higher bioavailability Lipid Solubility ↑ Lipophilicity → ↑ membrane absorption → ↑ bioavailability• Facilitates passive diffusion First-Pass Metabolism (major determinant) Inverse relationship with bioavailability• Metabolism before systemic circulationSites:– Liver (major)– Gut wall enzymes– Gut microbiota Clinical significance:• Extensive first-pass → very low oral availability• Example: nitroglycerin (oral ineffective) Enterohepatic recycling = Drug cycles between intestine ↔ liver Absorbed from intestine → portal vein → liver → Excreted into bile → back to intestine → reabsorbed again Effects:• ↑ Bioavailability• ↑ Duration of action• ↑ GI exposure → ↑ risk of GI adverse effects Question: A drug is given orally, but only a small fraction reaches systemic circulation because it is extensively metabolized in the liver before entering the bloodstream; what is this phenomenon called?
PARENTERAL ROUTES OF ADMINISTRATION Intrаvenоus (IV) Injectiоn Mechаnism Drug is directly intrоduced into systemic circulаtion Bypasses all absorption barriers (GI tract, skin, tissue interstitium) Immediate systemic distribution Advantages No first-pass metabolism Avoids hepatic enzymatic degradation before systemic circulation No GI influence Not affected by pH, enzymes, or food interactions Protein drug compatibility Proteins bypass GI enzymatic degradation Immediate effect Direct vascular entry → rapid pharmacodynamic response Use in critical states Effective when GI absorption is unreliable (coma, seizures) 100% bioavailability Entire dose reaches circulation Large volume administration Venous system tolerates higher fluid loads Disadvantages Irreversibility Cannot stop absorption once administered Sterility requirement Direct bloodstream access → high infection risk Requires technical skill Vascular access needed Local vascular injury Endothelial irritation → inflammation (phlebitis) Possible pain, bleeding, tissue irritation Intramuscular (IM) Injection Mechanism Drug deposited into skeletal muscle Absorption occurs via: Capillary diffusion (fast component) Lymphatic uptake (slow component) Advantages Relatively rapid absorption Slower than IV due to tissue diffusion barrier Useful in emergencies/unconscious patients Easier access than IV No venous cannulation required High bioavailability But less than IV due to partial tissue uptake variability Depot formulations Oily preparations form tissue reservoirs → sustained release Disadvantages Volume limitation (≤ 5 mL) Limited muscle capacity and diffusion area Bleeding risk in anticoagulated patients Muscle hematoma due to vascular injury Local tissue injury Pain, inflammation Fibrosis with repeated injections Possible sterile abscess formation Intradermal (ID) Site Dermis (highly vascular but small volume capacity) Uses Vaccines Allergy/sensitivity testing Limitations Very small volume (≤ 0.5 mL) Local inflammatory reactions common Subcutaneous (SC) Site Subcutaneous connective/adipose tissue Example Insulin (slow, predictable absorption) Advantages (SC & ID) Easier than IV access Suitable when slow systemic absorption is desired Can be used when IV access is not necessary Disadvantages Limited volume SC ≤ 2 mL, ID ≤ 0.5 mL Local tissue reactions Pain, irritation Inflammation and fibrosis from repeated exposure Variable absorption Influenced by local blood flow Inhalation Route Mechanism Drug delivered to respiratory tract Absorbed across: Nasal mucosa Bronchial epithelium Alveolar-capillary membrane (systemic delivery) Advantages Rapid onset Large surface area + high vascularity (alveoli) Local effects Bronchodilation (e.g., airway smooth muscle relaxation) Nasal decongestion Systemic delivery Volatile anesthetics absorbed via lungs Disadvantages Irregular absorption Variable ventilation/perfusion matching Airway irritation Triggers cough reflex and bronchospasm Swallowing loss 일부 drug enters GI tract → altered absorption pathway Transdermal Administration Mechanism Drug diffuses through: Stratum corneum → epidermis → dermis → systemic circulation Lipophilic drugs favored due to skin barrier properties Advantages Non-invasive and convenient Controlled systemic delivery Steady absorption over time Reversible Drug exposure stops upon patch removal Disadvantages Variable absorption Affected by: Skin thickness Temperature (increases perfusion) Local blood flow Skin irritation Contact dermatitis Local inflammation at application site Question: A drug is injected into skeletal muscle where it is absorbed through capillary diffusion and lymphatic uptake before reaching systemic circulation; which route of administration is being used?
DRUG METABOLISM Overview Drug metаbоlism = enzymаtic cоnversiоn of drugs into more hydrophilic (wаter-soluble) compounds to facilitate excretion. Hydrophilic drugs → often excreted unchanged Primary site: liver (highest enzyme concentration) Secondary sites: kidneys, intestine, lungs, plasma Mechanism of Drug Fate Outcomes Active → inactive metabolite (most common) Example: phenobarbital Active → toxic metabolite Example: acetaminophen (NAPQI formation) Active → active metabolite Same or different effect (e.g., diazepam) Inactive prodrug → active drug Examples: codeine, clopidogrel Phases of Metabolism Phase I (Non-synthetic) Functional group modification (oxidation, reduction, hydrolysis) Mainly via CYP450 system Often introduces or exposes polar groups Phase II (Synthetic / Conjugation) Addition of polar moiety (glucuronidation, sulfation, acetylation, etc.) Produces highly water-soluble metabolites Usually inactivates drug Cytochrome P450 System Heme-containing enzyme family on smooth ER Major role in drug detoxification and metabolism Located mainly in liver, also intestine, lungs, kidneys Multiple isoforms classified by: Family (number) → e.g., CYP3 Subfamily (letter) → e.g., A Specific enzyme → e.g., 4 → CYP3A4 CYP450 Functional Importance Single isoform can metabolize multiple drugs Single drug can affect multiple isoforms Major source of drug-drug interactions CYP450 Enzyme Modulation Inhibitors Decrease CYP activity → ↓ metabolism ↑ drug levels → ↑ toxicity risk Example: cimetidine Inducers Increase CYP activity → ↑ metabolism ↓ drug levels → ↓ therapeutic effect Example: phenobarbitone Factors Affecting Drug Metabolism Genetic variation Polymorphisms (e.g., slow vs rapid acetylators) Enzyme induction/inhibition Drugs, food, environmental agents Liver function Hepatic impairment ↓ metabolism Age Neonates and elderly → reduced metabolic capacity Question: A 62-year-old patient on multiple chronic medications develops signs of drug toxicity shortly after starting cimetidine; which of the following mechanisms best explains this drug interaction?
T½ (HALF-LIFE) & ELIMINATION KINETICS Definitiоn Time required fоr plаsmа drug cоncentrаtion to decrease by 50% after stopping administration t½ is independent of dose (in first-order kinetics) Clinical relevance Determines drug duration of action Influences dosing interval Controls time to reach steady state (Css) Determinants of Half-life t½ ∝ Vd / Clearance Clearance (CL): Inverse relationship; ↓ CL → ↑ t½ Volume of distribution (Vd): Direct relationship; ↑ Vd → ↑ t½ Plasma protein binding (PPB); ↑ PPB → ↓ free drug → ↓ clearance → ↑ t½ (indirect effect) First-Order Elimination Kinetics Definition; Constant FRACTION of drug eliminated per unit time Key featuresRate proportional to concentrationNon-saturable pathwayst½ constant Clinical implicationPredictable eliminationMost drugs follow this pattern Zero-Order Elimination Kinetics Definition: Constant AMOUNT of drug eliminated per unit time Key featuresSaturable metabolism (enzyme capacity limited)Rate independent of concentrationt½ NOT constant (variable) Clinical implicationSmall dose increases → large toxicity riskNonlinear pharmacokinetics High-yield drugsPhenytoinAlcohol (ethanol)WarfarinAspirin (high dose)TheophyllineTolbutamide Steady-State Concentration (Css) Definition: Rate of drug administration = rate of elimination Key principlesReached after ~4–5 t½≈ 97% of Css achieved at this pointSame rule applies for drug elimination after stopping therapy Dose-response relationshipFirst-order: doubling dose → doubles Css (predictable)Zero-order: doubling dose → disproportionate increase (unpredictable toxicity) DeterminantsDepends on dose and clearanceIndependent of half-life (affects only time to reach Css) Clinical Significance Therapeutic effect: Marks onset of full drug response (especially first-order drugs) Dose optimization: Guides maintenance and adjustment strategies Loading dose Rapidly achieves target plasma concentration Avoids waiting multiple t½ Not dependent on clearance for timing Maintenance dose Maintains Css over time Given intermittently or by infusion Adjusted based on clearance Therapeutic drug monitoring (TDM) Maintains drug levels between toxic and subtherapeutic range Important for narrow therapeutic index drugs Key drugs: gentamicin, digoxin, phenytoin, theophylline Question: A patient is taking a drug that demonstrates zero-order elimination kinetics; which of the following best describes its pharmacokinetic behavior?
RECEPTORS Overview Receptоrs = highly specific regulаtоry prоteins Bind drugs / endogenous ligаnds Trаnslate binding → cellular response Major role in drug selectivity & efficacy Intracellular Receptors Located in cytoplasm or nucleus Ligands: lipid-soluble drugs Steroid hormones Thyroid hormones Mechanism: Drug enters cell → binds receptor → gene transcription regulation Effect: Slow onset, long duration Ion Channel Receptors (Ionotropic) A. Non-gated (Leak) Channels Always open Allow ions to move along gradient Example: K⁺ and Na⁺ leak channels in cardiac muscle Maintain resting membrane potential B. Gated Ion Channels Mechanically (Stress) Activated Open due to physical force Examples: Sound wave transduction in ear Pressure/stretch receptors Voltage-Gated Open due to membrane voltage changes Example: Na⁺, Ca²⁺ channels during action potentials Critical in neurons + cardiac conduction Ligand-Gated Open when ligand binds → conformational change Fast synaptic transmission Examples: GABA receptors Glutamate receptors Nicotinic ACh receptors Key feature: Fast response (milliseconds) G-Protein Coupled Receptors (GPCRs) — Metabotropic Largest receptor family Structure: Extracellular ligand-binding site Intracellular G-protein (α, β, γ subunits) Gα subtypes Gαs → stimulates cAMP Gαi → inhibits cAMP Gαq → activates IP₃/DAG pathway Mechanism Ligand binds → G-protein activation → second messengers → cellular response Key Features Slower than ion channels Strong signal amplification Examples: Adrenergic receptors Muscarinic ACh receptors Enzyme-Linked Receptors Receptor directly linked to enzyme activity Often tyrosine kinase-based Mechanism Ligand binds → receptor dimerization Autophosphorylation → signaling cascade → gene/protein effects Example Insulin receptor (tyrosine kinase) Factors Affecting Receptor Binding 1. Selectivity / Specificity Each receptor binds specific ligands 2. Receptor Occupancy Max response may occur with
ENTERAL ROUTES OF DRUG ADMINISTRATION Orаl Rоute (PO) Cоre cоncept Drug is swаllowed аnd absorbed through gastrointestinal tract → systemic circulation. Advantages Easiest route; self-administration Highly convenient for long-term therapy Best patient compliance Absorption can be stopped (vomiting, spitting, purgation) Disadvantages First-pass metabolism (liver/GIT) → ↓ bioavailability Not suitable for emergencies (slow onset: ~30–90 min) Not suitable for protein/peptide drugs (acid + enzymes degrade) Not usable in vomiting or unconscious patients Poor tolerance for bitter/irritant drugs Food-drug interactions can alter absorption Sublingual & Buccal Routes Core concept Drug absorbed directly through oral mucosa → systemic circulation (bypasses GIT). Dosage forms Tablets Films Sprays Pellets Advantages Rapid onset (1–5 minutes) → useful in emergencies No first-pass metabolism Avoids gastric acid and digestive enzymes Can be stopped by removing drug (spitting) Suitable for some protein drugs No effect from food or GIT pH Disadvantages Not suitable for bitter/irritant drugs Limited surface area → not suitable for high doses Not usable in unconscious or vomiting patients Rectal Route Core concept Drug administered via rectum → absorption through rectal mucosa (suppositories/enemas). Dosage forms Suppositories Enemas Advantages Useful in emergencies (can be relatively rapid) Ideal for vomiting or unconscious patients Useful in pediatrics Avoids gastric irritation and food effects Can be used for drugs degraded by enzymes Disadvantages Patient discomfort → poor compliance Irregular and unpredictable absorption Not suitable for irritant drugs Partial first-pass metabolism (especially upper rectum drainage into portal circulation) Question: An elderly patient with acute chest pain is given nitroglycerin to be placed under the tongue for rapid symptom relief. Which advantage best explains the choice of this route of administration?
NEUROTRANSMITTERS (NTS) Bаsic Chаrаcteristics оf Neurоtransmitters Definitiоn Chemical signaling molecules synthesized by neurons to transmit information across synapses Storage Stored in presynaptic vesicles within axon terminals (classic NTs) Release Mechanism Action potential depolarizes presynaptic membrane Voltage-gated Ca²⁺ influx Vesicle fusion → exocytosis into synaptic cleft Post-synaptic Effects Binding to receptors: Ionotropic receptors (ligand-gated ion channels) Fast, direct ion flow → rapid response Metabotropic receptors (GPCRs) Second messenger systems → slower, amplified, longer-lasting effects Functional Outcomes Excitatory (EPSP) → depolarization Inhibitory (IPSP) → hyperpolarization Modulatory → alters neuronal excitability and synaptic strength Termination Requirement Rapid inactivation essential to prevent continuous stimulation Termination of Neurotransmitter Action Neurotransmitters are cleared via three main mechanisms: a) Reuptake Transport back into presynaptic neuron via specific transporter proteins Fates after reuptake: Repackaged into vesicles for reuse Enzymatic degradation inside neuron b) Diffusion NTs diffuse away from synaptic cleft into extracellular space or blood c) Enzymatic Degradation (Synaptic Cleft) Breakdown by specific enzymes in extracellular space Rapid termination of signal Drug Targets in Neurotransmitter Pathways Pharmacologic agents may alter NT signaling at multiple steps: Synthesis inhibition or enhancement Storage disruption (vesicular transport interference) Release modulation ↑ or ↓ vesicle exocytosis Reuptake blockade Prolongs synaptic NT activity Enzyme inhibition Prevents NT degradation Receptor modulation Agonists / antagonists Signal transduction alteration Affects intracellular second messenger pathways Classification of Neurotransmitters A. Classical (Canonical) Neurotransmitters Synthesized primarily in neuronal cytoplasm Exception: norepinephrine partially synthesized in vesicles Acetylcholine (ACh) Ester-type neurotransmitter Monoamines (Biogenic amines) Catecholamines (from tyrosine) Dopamine (DA) Norepinephrine (NE) Epinephrine (E) Other monoamines Histamine (from histidine) Serotonin (5-HT, from tryptophan) Amino Acid Neurotransmitters Excitatory Glutamate (primary excitatory CNS NT) L-aspartate Inhibitory GABA (major inhibitory CNS NT) Glycine (spinal cord inhibitory NT) Modulatory amino acid: D-serine (NMDA receptor co-agonist) B. Non-Classical (Non-Canonical) Neurotransmitters Not stored in classic synaptic vesicles Can act in retrograde signaling (postsynaptic → presynaptic) Often diffuse or act intracellularly Neuropeptides Substance P Neuropeptide Y Somatostatin Endogenous opioids (endorphins, enkephalins) Vasoactive intestinal peptide (VIP) Endocannabinoids Retrograde signaling molecules Lipid-derived mediators Gasotransmitters Nitric oxide (NO) Diffuses freely across membranes Acts intracellularly (e.g., cyclic GMP pathways) Purinergic Neurotransmitters ATP Adenosine Appetite-Regulating Peptides Orexin Ghrelin Termination of Specific Neurotransmitters Acetylcholine (ACh) Rapid degradation in synaptic cleft by acetylcholinesterase (AChE) ACh → choline + acetate Choline is: Reuptaken into presynaptic neuron Recycled for ACh synthesis AChE Types True AChE (Cholinesterase I) Located in synapses and erythrocytes (RBCs) Pseudocholinesterase (Butyrylcholinesterase; ChE II / BCHE) Found in plasma and liver Broader substrate specificity (e.g., butyrylcholine) Dopamine (DA) Precursor to NE and E Termination pathways Reuptake via dopamine transporter (DAT) Repackaged into vesicles OR Degraded enzymatically Enzymatic degradation: Monoamine oxidase (MAO) Catechol-O-methyltransferase (COMT) Extraneuronal metabolism: Occurs in synaptic space via MAO & COMT Diffusion: Into surrounding tissues or circulation Norepinephrine (NE) & Epinephrine (E) Termination pathways Reuptake via norepinephrine transporter (NET) Repackaging into vesicles OR Enzymatic degradation Enzymes involved: MAO (intraneuronal) COMT (extraneuronal/synaptic space) Additional fate: Diffusion into tissues or bloodstream Question: A 62-year-old patient is found to have prolonged parasympathetic effects after exposure to a cholinergic agent, and symptoms improve after administration of a drug that inhibits acetylcholinesterase, which neurotransmitter termination mechanism is primarily being affected?
VOLUME OF DISTRIBUTION (Vd) Definitiоn Vd = аppаrent vоlume in which tоtаl drug amount would need to be uniformly distributed to achieve the same concentration as in plasma Reflects extent of drug distribution into tissues vs staying in plasma Formula: Vd = Amount of drug in body / Plasma drug concentration Core Interpretation Low Vd → drug remains mainly in plasma/blood compartment Example pattern: large, hydrophilic, highly protein-bound drugs High Vd → extensive tissue distribution (interstitial + intracellular compartments) Suggests lipid solubility or strong tissue binding Determinants of Vd Blood flow ↑ Blood flow → ↑ tissue delivery → ↑ Vd Highly perfused organs receive drug first (brain, liver, heart) Capillary permeability ↑ Permeability → easier tissue entry → ↑ Vd BBB restricts hydrophilic drugs → lowers Vd Drug physicochemical properties Molecular weight: ↑ MW → ↓ Vd (poor tissue diffusion) Lipid solubility: ↑ lipophilicity → ↑ Vd (membrane penetration) Ionization: ↑ ionized form → ↓ Vd (poor membrane crossing) Plasma protein binding (PPB) Main protein: Albumin Only free (unbound) drug is active, distributed, and cleared ↑ PPB → ↓ free drug → ↓ tissue diffusion → ↓ Vd Also acts as drug reservoir → prolongs duration & delays elimination Highly bound drugs (high clinical relevance): Warfarin, phenytoin Key clinical implications: Small PPB changes → large ↑ free drug → toxicity risk Liver disease → ↓ albumin → ↑ free drug effect/toxicity Drug–drug competition → displacement → sudden ↑ active drug fraction Tissue binding Drugs may accumulate in tissues (reversible or poorly reversible binding) Effect: ↑ Vd Prolonged action Delayed elimination Toxicity examples: Tetracyclines → bone/teeth → growth defects Aminoglycosides → kidney & inner ear → nephrotoxicity, ototoxicity Redistribution Drug moves from highly perfused organs → muscle/fat over time Leads to: Rapid onset (brain exposure) Rapid termination (fall in brain concentration despite drug still in body) Classic example: Highly lipid-soluble IV anesthetics (e.g., ultra-short barbiturates) → brief effect due to redistribution Question: A 58-year-old man with cirrhosis is started on warfarin therapy and is found to have hypoalbuminemia compared with baseline; what is the most likely effect?