EVERYTHING (Exam 1).pdf

One Health- unifying approach that aims to sustainably balance and optimize health of people animals and ecosystems Antimicrobial resistance, zoonosis, climate change impacts, food safety and defense, human animal bond, policy, vector borne disease Stakeholders: INTERNATIONAL QUADRI...

One Health- unifying approach that aims to sustainably balance and optimize health of people animals and ecosystems Antimicrobial resistance, zoonosis, climate change impacts, food safety and defense, human animal bond, policy, vector borne disease Stakeholders: INTERNATIONAL QUADRIPARTITE: WHO, WOAH, FAO, UNEP!!!!!! Federal: ○ USDA-FSIS: Meat, egg products, poultry, food defense ○ USDA-APHIS: Approval + use of biologics (Vax) in animals USDA controls Federal Meat inspection organization ○ US Fish and Wildlife ○ CDC: Human Health protection ○ FDA: Seafood, milk and shell egg inspection Center for veterinary medicine (within FDA): approval and use of animal drugs, residue tolerations, pet food composition, enforces penalties for drug violations ○ EPA State: ○ Dept of agriculture, dept of health, vet diagnostic labs, public health labs, Endemic (enzootic), epidemic (epizootic), pandemic (panzootic), sporadic disease Epidemiological triad: Agent, host, environment Chain of infection (Agent → reservoir → portal of exit → transmission → portal of entry → susceptible host) Lyme, avian influenza, salmonella, west nile, toxocara, baylisascaris procyonis Other: Q-fever, influenza virus, cryptosporidiosis, lepto, rabies Horizontal (aerosol, direct transmission, fomite, vector, oral) vs. vertical transmission (in utero, in ovo, breast milk) Biosecurity Principles (risk assessment, separation of healthy animals from infectious agent, cleaning and disinfection) Surveillance QUARANTINE (new, returning, not sick + seperate) VS ISOLATION (sick n separate) Regular veterinary care (Vet’s role in public health): provide care for sick animals, disease prevention (vaccinations) Reference intervals Methods to Stop Zoonosis: W.A.S.H. (Wash avoid safety health) Entry(PPE, wash, disinfect equipment) ←> Transmission (biosecurity)←> Source (prevention + treatment, animal health BODY PARTS/REGIONS Directions (dorsal, ventral, rostral, cranial, caudal, axial, abaxial, proximal, distal, lateral, medial, palmar, plantar, solar) Perineum (anal triangle, urogenital triangle) Divisions of the trunk: pectoral, cranial (xiphoid + hypochondriac) Middle (umbilical, lateral) Caudal (inguinal, pubic) (+umbilicus and costal arch) Common sx sites → ○ Ventral midline, paracostal, flank, inguinal parapreputial (Cat/dog) ○ Paralumbar fossa, flank (equine, bovine, small ruminants) Anatomical planes Transverse, dorsal, median, sagittal, parasagittal X-Ray Physics Cathode (-) → source of e-, thermogenic emission (hot), tungsten filament, focusing cup Anode (+) → e- driven across tube to strike tungsten disc (anode), brehmstrahlung (braking radiation) x-rays released as e- slows down and releases energy mAs = #e- = #X-ray photons (intensity) = image DENSITY ○ As mA increases, time decreases kVp = energy of e- (voltage) = x-ray energy= penetration = image CONTRAST X-rays cause IONIZATION!!!!! Adverse effects ○ Deterministic- increasing dose results in increasing severity after THRESHOLD is reached ○ Stochastic- random, radiation induced cancer → No dose threshold DNA Damage ○ Direct damage X-ray can break piece of DNA backbone Single strand break = fixable/replaceable Double strand break = harder to repair → risk for mutation/cancer ○ indirect damage Water reactive oxygen species (OH- + H30+ +e-) Radiation safety: Time, distance (Inverse square law), shielding (PPE (protects from SCATTER), dosimeter) (ALARA) Collimator = beam adjuster = decreases scatter Homeostasis- regulation of variables inside the body to maintain a stable internal environment (mostly)negative feedback loops Receptor(detects stimulus/change), control center(compares current variable to normal range - usually brain), effector (produces response to force variable back to normal range) Exercise example ○ CARDIAC OUTPUT: (CO=HRxStroke volume of 1 systole) = amount of blood ejected from both ventricles in 1 minute Hyperthyroidism example ○ Many body systems affected, esp heart: Tachycardia Baroreceptor reflex ○ Stretch response (walls of carotid and aorta that detect changes in BP) ○ Brain centers receive stimulus and activate sympathetic/parasympathetic signals  Sympathetic: if BP too low (along w/ adrenal glands and constriction of vessels) Parasympathetic if BP too high to decrease HR ○ Effectors (Heart and vessels) - increase or decrease CO to bring arterial back to normal range within seconds Severe Hemorrhage The Cell (organelles): Cell membrane ○ Semipermeable, peripheral/integral proteins, phospholipid bilayer Nucleus ○ Genetic info (Chromatin - euchromatin/heterochromatin) ○ Nucleolus (synthesize RNA) ○ Nuclear envelope - double membrane Ribosomes ○ Protein synthesis Endoplasmic reticulum (Cisternae = flattened membrane sacs) ○ Smooth - detoxification, synthesis of steroid hormones ○ Rough - synthesize membrane and secretory proteins. Usually continuous with outer membrane of nuclear envelope Golgi apparatus - more cisternae ○ Packages, condenses and modifies proteins ○ Secretory granules Lysosomes ○ Rich in hydrolytic enzymes (proteases, nucleases, lipases) → latent ○ Responsible for degrading macromolecules ○ Ingests material via phagocytosis or pinocytosis; Autophagy within cell Peroxisomes ○ Has a crystalline core, contains catalases and oxidases ○ Abundant in hepatocytes → synthesis of bile acids ○ Abundant in proximal convoluted tubules (kidney) → breakdown of excess purines to uric acid Mitochondria ○ Powerhouse of the cell (Oxidative phosphorylation, citric acid cycle, beta-oxidation of fatty acids) ○ Two membranes → Inner and outer mitochondrial ○ DNA and ribosomes are contained in the mitochondrial matrix Cell inclusions ○ Glycogen - glucose storage (long term)  ○ Lipids - nutritive, provide energy for cellular metabolism ○ Pigments Hemosiderin - iron storage complex Melanin - contained in melanocytes Lipofuscin - “age pigment” Cytoskeleton ○ Microfilaments (ACTIN) Involved in endo/exocytosis, migratory activity, muscle contraction ○ Intermediate filaments Protecting epithelial cells, anchoring organelles, maintain cell shape + integrity Keratin, desmin, lamin ○ Microtubules Vesicular transport, major component of centriole, cell elongation/ movement, cilia + flagella, Intercellular junctions ○ Tight junctions - apical part of intestinal epithelium prevent passage of water soluble proteins ○ Zonula adherens - basal part of intestinal epithelium Held together by transmembrane protein linker and a bundle of actin filaments ○ Desmosomes (macula adherens) - found in epidermis Held together by transmembrane protein linker plus intracellular electron dense plaque (intermediate proteins attach to plaque - hairpin loop) ○ Hemidesmosomes Adhere cells to basement membrane (Basal lamina) ○ Communicating (Gap) Junctions Intercellular space bridged by interlocking transmembrane proteins Allows passage of inorganic ions + water soluble molecules IN CARDIAC MUSCLE  Specializations (usually in epithelial cells’ free surface) ○ Cilia: Move material over cell surface ○ Microvilli: increase surface area of cells → primary role is molecular absorption CARDIO!!!! Heart Anatomy and how blood flows thru heart R+L atrium, R+L ventricle, Aorta, Anterior/posterior vena cava, Tricuspid Valve, Pulmonary valve, bicuspid valve, Aortic valve Sinoatrial node, av node, bundle of His, L+R bundle branches, purkinje fibers Heart rhythm - ANS modulates HR (Extrinsic system) ○ Sympathetic - L+R atrium, SA node, AV node, L+R ventricle ○ Parasympathetic - L+R atrium, SA node, AV node…limited innervation of ventricles Intrinsic system (SA node, AV node, bundle of His, bundle branches, purkinje fibers) RESPIRATORY Upper airways - obstructions and noises All the structures cranially to the trachea: nostrils, nasal passages, nasopharynx, and larynx ○ Sense of smell, thermoregulation, defense, air pathway, and swallowing Clinical examples → obstruction of upper airways ○ Brachycephalic Obstructive Airway Syndrome (BOAS) → Mostly brachycephalic dogs ○ Left Laryngeal hemiplegia in horses (roarers) Lower airways - disturbances in ventilation All structures caudally to the larynx, including the trachea and the lungs → The pleura and thorax are key structures ○ Air pathway, defense, and gas exchange Clinical examples ○ Asthma → Obstruction of lower airways ○ Pneumothorax → Restrictive lung disease GASTROINTESTINAL GI WALL: Secretion, absorption, motility 1. Cephalic - chewing, swallowing, gastric secretions accumulate before food enters stomach 2. Gastric - Swallowed food activates gastric activity in stomach 3. Intestinal - occurs in duodenum as a response to arriving chyme and moderates gastric activity via hormones and nervous reflexes Types of digestion in monogastric organisms ○ Luminal enzymatic digestion Gastric and pancreatic juices contain hydrolytic enzymes to break down nutrients ○ Brush border enzymatic digestion Enterocytes in small intestine release other hydrolytic enzymes that further cleave macronutrients into absorbable micronutrients GI Diseases (Issues): Periodontal Disease (most common), Vomiting(active expulsion from stomach), Regurgitation(passive burp from mouth/esophagus), diarrhea (osmotic, secretory or exudative) RENAL: Upper: ○ Kidney - formation and excretion of urine, regulates composition & volume of body fluid  NEPHRONS Bowman’s capsule, proximal tubule, nephron loop, distal tubule, collecting duct Filtration, secretion, reabsorption, excretion Lower - filling, emptying, voiding = ANS + Sphincters ○ Bladder - apex, body, neck, detrusor muscle, smooth muscle sphincter, urethralis muscle Male - prostate + ductus deferens ○ Ureter + Urethra DISEASES: ○ AKI Pre-renal: hypotensive, heart failure Renal: NSAID toxicity Post renal: Obstruction ○ CKD (GFR and/or tubular function) REPRO SYSTEM: Sexual Steroid Hormones → synthesized by cholesterol Properties of steroid hormones ○ Lipophilic ○ Diffuse freely through cell membrane ○ Intracellular receptors ○ Triggers gene transcription and synthesis of proteins Production of Testosterone and Estrogen → GnRH (Has negative feedback loop) ○ GnRH from hypothalamus → Signal pituitary to release LH and FSH → diffusion to sexual structures for synthesis of hormones MALES ○ Male Basic Structure Testes - Produce testosterone (Interstitial compartment), in charge of spermatogenesis (seminiferous tubule) Epididymis - Sperm mature and further develop here Scrotum - Protects and supports the testes, serves as a temp sensor and cooling system Accessory sex glands - Responsible for the production of fluid secretions that form the seminal plasma of the semen Penis - External genital, serves as male copulatory organ ○ HORMONES LH in males stimulates Leydig cells to produce testosterone, FSH stimulates Sertoli cells for spermatogenesis; Testosterone → Produced by Leydig Cells in testes  Development of primary (testicle descent, spermatogenesis, enlargement of the penis and testes) and secondary male sex characteristics (muscle growth, bone thickness, hair darkening) Male behavior and libido (heat detection, mounting) Powerful anabolic effect FEMALE ○ Female Basic Structure Ovaries - Produce estrogen and progesterone, Folliculogenesis and oogenesis Uterus - Responsible for the nourishment of the embryo or fetus Vagina - Receptacle for male penis Vulva - External genital, female copulatory organ, last part of birth canal ○ HORMONES in women LH stimulates THECA cells to produce testosterone → FSH stimulates GRANULOSA cells to convert testosterone to estrogen (Cells become more sensitized to gonadotropins, and estrogen production increases rapidly) Estrogen → Produced by Follicular Cells in ovaries Induces estrus or heat behavior Induces ovulation Progesterone → Produced by Luteal Cells in ovaries (corpus luteum) (Placenta is source during pregnancy) Production of Progesterone ○ After ovulation, the ovarian follicle(s) form a corpus luteum (CL) → CL is formed by Lutein cells → All lutein cells of the CL produce progesterone (prepares endometrium for potential pregnancy) LH pulses keep the CL viable = luteotropic; FSH and LH pulses are sufficient to initiate follicular waves; Diestrus ends with the regression of CL (luteolysis) Maintains secretory activity of endometrial glands of the uterus Decreases uterus tone and increases cervix tone Prepares the uterus for pregnancy Prepares mammary gland during late pregnancy for lactation ○ Estrous Cycle A series of sequential and predictable hormonal, morphological, and behavioral events that occur b/w one estrus and the next estrus in a non-pregnant animal Estrus Stages: Ovulation → Drop in estrogen Metestrus → Drop in estrogen, rise in progesterone Diestrus → Considered corpus luteum stage; Progesterone at its highest, estrogen at its lowest Proestrus → Estrogen rises, progesterone drops  Estrus → Estrogen peaks for ovulation to occur, (Heat behavior) Progesterone at its lowest, period in which a female is receptive to mating MUSCULOSKELETAL Support, movement, protection Muscle, bone, joints, cartilage, tendons (M-B), Ligaments (B-B) SARCOMERE (functional unit) ○ Actin + myosin ○ Z-line, m-line, A/I bands, H band Skeletal Smooth Cardiac Striated non-striated Striated voluntary involuntary involuntary Multiple nuclei, troponin 1 center nucleus, no troponin 1 center nucleus, troponin Heat, movement, skeletal stability, protection Peristalsis, constriction/dilation Coordinated heart beats Limited healing capacity Viable smooth muscle cells can undergo Little regeneration ability beyond childhood  -satellite cells/mesenchymal cells can mitosis to replace damaged tissue -no satellite cells, proliferate + fuse to make more skeletal -myocardial scars form from fibroblasts and muscle CT -scarring and CT interfere w/ regeneration -Myofilament < myofibril < muscle fiber < Gap Junctions, “Myocardium” fascicle < muscle - Dense Bodies (attach thin+intermediate Same organization as skeletal muscle, -sarcomere filaments) branched, cross-striated -Heat, movement, skeletal stability, protection -walls of hollow organs, erector pili, pupil -INTERCALATED DISCS: desmosomes + -Depends on nervous system only muscles Gap junctions -can remain contracted for long period w/o - Depends on ANS, local stimuli, hormones, fatiguing, wavelike contractions catecholamines -depends on ANS+ hormones Epithelium Avascular, adhered by cell junctions, function associated w/morphological structure. Attached to basement membrane Basement Membrane = basal lamina + Reticular lamina ○ Basal lamina = lamina lucida + lamina densa Functions: ○ Protection - underlying tissue from injury/pathogens ○ regulation/exchange - of molecules between underlying tissues + compartments ○ Secretion - hormones into vascular system, Sweat, mucous, enzymes (delivered by ducts) Endocrine - secretes hormones released into interstitial fluid, diffused into blood stream and delivered to cells w/ receptors for that hormone, coordinating regulation and integration of body responses  Exocrine - release contents thru duct/duct system that ultimately leads to the external environment Mucous, sweat, breast milk, saliva etc. Characterized by method in which they secrete product ○ Unicellular: individual cells scattered thru epithelium (EX: Goblet cells in intestine) ○ Multicellular: Merocrine - (most common) - exocytosis of secretory vesicles → lumen Holocrine - death of entire cell which sloughs off and releases contents to lumen Apocrine - release of budding vesicles that contain contents and apical cytoplasm of cell apex Cytocrine - secretory material is transferred from one cell to another Simple Stratified Squamous Areas w/ passive diffusion of gasses Mesothelium, alveoli, Bowman’s capsule, endothelium = walls of Withstand mechanical/chemical stress + injury vessels Oral cavity, epidermis (keratinized), esophagus, vagina Cuboidal Kidney tubules, secretory ducts of pancreas, ducts of exocrine glands, thyroid follicles Lining of excretory ducts of glands  Columnar Areas w/ lots of secretory/absorptive activity Large ducts of exocrine glands Duct lining, villi of small intestine Often have apical modifications: cilia/microvilli other TRANSITIONAL - lower urinary tract Always stratified, Full bladder- cells appear more flat Empty bladder-cells appear more round PSEUDOSTRATIFIED - “respiratory epithelium” often ciliated, almost always simple (1 layer) Connective Tissue Develops from the mesodermal layer (mesenchyme) Mesenchymal cells can differentiate into different cells depending on where they are in the body. All CT is derived from mesenchyme CT Consists of: Cells ○ Macrophages phagocytic In blood = monocyte, in CT = macrophage (same thing different name) ○ Mast Cells Histamine (vasodilation - allergies) and heparin(blood coag, wound healing), inflammatory response to injury or allergies ○ Adipocytes Storage for fat + lipids, produce variety of hormones Adipose tissue when found in large numbers White - single large droplet of lipid…less active, fat storage Brown - multiple small lipid droplets, high activity, found in young kids or hibernating animals ○ Leukocytes Lymphocytes - adaptive immunity response  Neutrophils - rare in CT unless in inflammatory states Plasma cells - prominent where pathogens enter (GI + resp tract). Derived from B-lymphocytes Extracellular matrix (fibers + GS) ○ Fibers - produced by fibroblasts Collagen Type I - found in every CT Type II - Hyaline + elastic + body of eye Type III - Reticular fibers, healing wounds, smooth muscle, fetal skin Elastic Interwoven w/ collagen to prevent tearing from excess stretching Thinner than collagen Reticular Composed to type III collagen In loose CT, boundary between CT + epithelium, adipocytes, small vessels, nerves + muscles, wound healing, scar formation, LYMPHATIC TISSUE stroma support ○ Ground substance - aqueous gel of glycoproteins/proteoglycans. Space between cells and fibers Types of CT Loose CT ○ Areolar: vessels, lamina propria, mucous membranes, subcutaneous tissue ○ Adipose: White/brown ○ Reticular: Lymphatic tissue, liver, spleen, framework of soft organs, framework for which other cells attach Dense CT ○ Regular- tendons, ligaments, aponeuroses ○ Irregular - capsules surrounding lymph Cartilage - avascular, specialized CT, Lacunae house chondrocytes, surrounded by perichondrium ○ Hyaline Most common (type II collagen) Low friction surface, lubrication of synovial joints, distributes force JOINTS, nose, trachea ○ Elastic Elastin present in matrix, dense network of branching fibers External EAR, external acoustic meatus, epiglottis, larynx ○ Fibrocartilage Orderly arrangement of type I collagen, no perichondrium, Attaches tendons to bone Intervertebral discs, cardiac skeleton, pubic symphysis, tendons  Bone ○ Compact ○ Spongy Lymph Blood ○ Erythrocytes (CO2, O2, hemoglobin), gas exchange, regulate pH ○ Plasma Water - 92% Proteins (albumin, globulin, fibrinogen, etc.) Responsible for COLLOID OSMOTIC PRESSURE Derived from liver, Transport, defense, blood clotting Other solutes (electrolytes, glucose, nutrients, vitamins, gasses, regulators) ○ Leukocytes Granulocytes (cytoplasmic granules) Neutrophil ○ Phagocytic, contain lysosomes Eosinophil ○ Lysosomes contain histamine, bradykinin ○ Immune response against parasites and allergies Basophils ○ Granules contain histamine, bradykinin ○ Inflammatory and allergy response Monocytes (round nuclei) Lymphocytes ○ T-lymphocytes Bone marrow→ thymus (to mature) Cytotoxic immune response (specific response) ○ B-lymphocytes Bone marrow → lymphatic tissue (to mature) Plasma cells produce antibodies (antibody mediated response, specific response) Monocytes ○ Migrate to tissues to form macrophages ○ Phagocytosis of foreign material/cell debris BONE Specialized CT with mineralizing matrix ○ Organic: Type I collagen + unmineralized ground substance ○ Inorganic: Calcium hydroxyapatite Surrounded by periosteum - contains osteogenic cells for healing Endosteum = contains endosteal cells can become osteoblasts WOLFF’S LAW - states that bone in a healthy animal will adapt to the loads under which it is placed. If loading on a particular bone increases, the bone will remodel itself over time to become stronger to resist that sort of loading Types of Bone: Long, Short, flat, irregular ○ Long bones: Epiphysis, metaphysis, diaphysis Osteoprogenitor Cells (osteogenic) - stem cells that arise from embryonic mesenchyme ○ Osteoblasts - build bone, become trapped in matrix (lacunae) to become osteocytes ○ Osteoclasts (multiple nuclei) - break down bone, phagocytic Bone organized into osteons within the compact bone ○ Lamellae = rings of matrix ○ Osteocytes live in lacunae and can communicate with each other through canaliculi ○ Central (haversian) Canals connected to each other by perforating (Volkman’s) canals Bone formations ○ Intramembranous Ossification (flat bones like facial bones and skull bones) 1. Mesenchymal cells gather and become osteoblasts 2. Osteoblasts form ossification center 3. Osteoblasts secrete osteoid that calcifies within a few days 4. Osteoblasts become osteocytes when trapped ○ Endochondral Ossification (long bones) 1. Chondrocytes lay hyaline cartilage template 2. Osteoblasts are delivered via vessels 3. Osteoblasts lay bone collar around shaft area and prevents diffusion to chondrocytes (who then DIE) 4. Primary ossification center formed in (future) medullary cavity by osteogenic cells 5. Chondrocytes continue to grow on ends of bone while medullary cavity expands and remodels  6. Secondary ossification center formed in epiphysis to allow more growth and development after birth 7. Hyaline cartilage remains at growth plate and articular surfaces until done growing a. resting/germinal zone → proliferative zone → Hypertrophic zone → calcification zone → ossification zone 8. Epiphyseal line forms at epiphyseal plate Bone Repair ○ Initial formation of fibrocartilage ○ Replacement with a temporary callous of woven bone ○ Fracture forms hematoma → Fibrocartilaginous (soft) callus forms → Hard (bony) callus forms → Bone is remodeled CELL INJURY AND REPAIR Necrosis - membrane rupture, INFLAMMATION, protein denaturation, dead contiguous cell ○ Nucleus degradation Pyknosis - Shrunk, round dark Karyorrhexis - fragmented Karyolysis - Dissolution  Apoptosis - Cell shrinkage, fragmentation, NO INFLAMMATION ○ Initiation phase Intrinsic: mitochondrial Extrinsic: death receptor initiated ○ Activation Caspase (3!!!) Cascade (breaks down DNA - endonuclease) Condensation of cytoplasm and chromatin into apoptotic bodies Macrophage eats apoptotic bodies TYPES OF NECROSIS Causes Gross appearance Histological appearance Coagulative Ischemia, free radicals, toxins, Grey/white (unless mixed w/ Outline of necrotic cell = preserved burns, x-rays, Nutritional (WMD blood) acidophilic/eosinophilic cytoplasm = Vit E + selenium deficiency) Depressed compared to Nuclear changes surrounding tissue -Pyknosis - Shrunk, round dark -Karyorrhexis - fragmented -Karyolysis - Dissolution Caseous Toxins of certain Cheese, milk curds, dry greasy, Granular stains purple microorganisms (tuberculosis) breaks easily Loss of cell outline, normal tissue architecture Liquefactive Ischemia, free radicals, toxins, CNS! Clear spaces with or without pink burns, x-rays Abscesses/cavities containing staining yellowish fluid Proteinaceous precipitate in necrotic Necrotic tissue converted to liquid area Leukocytes present and produce hydrolytic enzymes Wet Gangrene Infection Red+black WET tissue Coagulative + liquefactive combo Distal extremities or dependent parts of organs Dry Gangrene Loss of blood supply resulting in Dry, leathery, hard, coagulative necrosis. MUMMIFICATION (no bacterial Distal extremities or dependent involvement) parts of organs  Fat Enzymatic, traumatic, idiopathic, White, opaque, granular Shadowy outline w/ blue or purple nutritional (yellow fat dz, (calcification) in areas of necrosis stealitis) Adipose tissue with saponification Cell regeneration vs. repair ○ Regeneration Dead cells replaced by identical cell type Best chance of regaining homeostasis Requires progenitor cells and underlying supportive tissue is still in place ○ Repair Dead cells must be replaced by another cell type (like fibrous scar tissue) Homeostasis is hopefully restored or nearly restored Occurs if loss of progenitor cells and/or loss of underlying supportive tissue Liable cells ○ High capacity for regeneration, tissues regenerate for lifespan of host ○ EPITHELIUM, mucosa, bone marrow EX: parvo Stable cells ○ Regenerated when stimulated: hormones, growth mediators other factors (broken bone) ○ Regeneration capabilities vary between cell types ○ Organs, BONE, nerves ○ Extent of injury affects prognosis and long term healing EX: aflatoxin in horses Permanent cells ○ Limited to no regenerative abilities, healing occurs by replacement with scar tissue which can inhibit long term function ○ MYOCARDIUM, skeletal muscle, CNS cells EX: Snakeroot (horses) NEURO STRUCTURE MAIN FUNCTIONS EXTRA STUFF Spinal cord Sensory and motor info conduit between - Gray matter = nerve cell bodies PNS and brain - Dorsal horn (afferent info to cord) - Ventral horn (efferent info from cord) Sensory input, reflex circuits, somatic + - intermediate zone integrate sensory info w/ descending autonomic motor output inputs from brain to shape efferent output - White matter = nerve axons covered in myelin - dorsal column carry sensory info via ascending tracks - ventral + lateral columns carry sensory and motor info via ascending + descending tracts (respectively) Medulla Oblongata Cardiovascular + respiratory control, - Cranial nerves pass through here! auditory + vestibular input, brainstem - Tracts travel from motor cortex to the spinal cord and carry reflexes axons of motor neurons that command movement - 2 medullary pyramids → command movement Pons Respiratory + urinary control, eye - MANY transverse pontine fibers movement, facial sensation, motor control -most descending axons from cortex synapse in the pons and enter cerebellum Cerebellum Receives ascending and descending info - Receives descending inputs from the forebrain for intentions about intention of movement and of movement + ascending inputs from the spinal cord about the coordinates accurate movement position of the body in space (proprioception) - Damage results in ataxia Motor coordination, motor learning, , equilibrium, proprioception, Midbrain Acoustic relay, control of eye (movement, - Conduit for all nerve tracts passing between the forebrain and lens, pupillary light reflex) hindbrain Tectum (Dorsal) (superior colliculus, inferior colliculus) Tegmentum (Ventral) (red nucleus, substantia nigra) Thalamus Sensory + motor relay to cerebral cortex, Relay station for sensory, somatic, vision, hearing (part of diencephalon) regulation of cortical activation, visual input Hypothalamus Autonomic +endocrine control (w/ pituitary) Motivational drives= hunger, thirst, sex (part of diencephalon) motivated behavior Basal nuclei Modulates motor planning and initiation Located in basal forebrain gray matter (within cerebral cortex) Cerebral (cortex) Sensory perception, cognition, learning, Process+integrate thoughts, perceptions, voluntary actions, memory, motor planning, voluntary memory, emotion, consciousness movement, language - Gyri (folds to increase surface area) - Sulci (fissures that separate gyri) Grey Matter - exterior White Matter - interior (myelinated) BONUS STRUCTURES!! - Amygdala + hippocampus = memory + emotions - Retina, optic nerve, olfactory bulb Meninges Wrapper of Brain and spinal cord, contains Dura mater - tough outermost layer CSF arachnoid mater - middle layer, CSF contained in subarachnoid space pia mater - delicate vascular membrane closest to brain/spinal cord  CSF Suspends brain + spinal cord Fills subarachnoid space Formed by ependymal cells in choroid plexus (located on floor of lateral ventricles and roof of 3rd + 4th) Neuro embryonic Development Fertilization→ zygote forms→ cleavage (blastocyst + morula) → Gastrulation (formation of 2 germ layers endoderm, mesoderm, ectoderm) - Endoderm = generate lining tissue of various spaces - Mesoderm = muscle and connective tissue - Ectoderm = integumentary and nervous system Precursor to brain + spinal cord = neural tube 1. Begins w/ central region of ectoderm w/ the formation of neural plate 2. Neural plate border bends dorsally and 2 ends join at neural border to form neural crest 3. Neural tube closure disconnects neural crest from ectoderm 4. Neural crest becomes PNS 5. Notochord degenerates as part if intervertebral discs 6. Somites become axial skeleton and skeletal muscle NERVOUS TISSUE CNS: Brain + Spinal Cord ○ Brain: Gray matter: “exterior” part of cerebrum and cerebellum Consists of nerve cell bodies (soma) White matter: “interior” part of cerebrum and cerebellum Consists of myelinated axons grouped in tracts and myelin producing oligodendrocytes ○ Spinal Cord Gray matter: “interior” of spinal cord (H-shaped) Ventral (efferent) → cell bodies of motor neurons. Axons = ventral roots Dorsal (afferent) horns → interneurons receive sensory info from dorsal root ganglia White Matter: “exterior” of spinal cord Central canal lined with ependymal cells + CSF PNS: Ganglia, cranial nerves, spinal nerves, peripheral nerves ○ Somatic: Voluntary functions ○ Autonomic: Involuntary Sympathetic: Fight or flight Parasympathetic: rest and digest  Enteric: uses combo of sympathetic and parasympathetic to digest Neuron ○ Prominent nucleolus ○ Many free surface ribosomes and well-developed rough endoplasmic reticulum (active protein production) These areas of cytoplasm contain Nissl Bodies (clumps of free ribosomes and RER) ○ Cell body aka Soma ○ Dendrites: Signal reception + processing from other neurons, external environments Many dendrites allow 1 neuron to receive and integrate info from many other cells ○ Axon: Synapse! Receive, integrate and send info Longer than dendrites, originates from axon hillock Axolemma, axoplasm Terminal button contacts other neuron/cell to initiate impulse at that cell Synapse = Neuron to neuron may be covered in myelin sheaths that are created by Schwann cells (PNS) or Oligodendrocytes (CNS) Node of Ranvier = space between schwann cells, express transport proteins Types of Neurons: ○ Uni(pseudo)polar: fused axon and dendrite, MOST SENSORY NEURONS ○ Bipolar: 1 axon, 1 dendrite ○ Multipolar: 1 axon, several dendrites  Synapse = information transferred neuron to neuron (gap) ○ Unidirectional ○ Electrical signal from presynaptic cell is transmitted as a chemical signal (neurotransmitter) that affects the postsynaptic cell ○ Types of connections between axon and other nerve cells: Axodendritic, axosomatic, axoaxonic Peripheral Nerves: Communicate between sense organs, effectors and CNS ○ Nerve fibers + schwann cells covered by endoneurium ○ Nerve fibers (myelinated and/or unmyelinated) collected into fascicles (fibroblasts, macrophages, collagenous + reticular cells) ○ Fascicles covered by perineurium (CT + epithelium cells) ○ Bundles of fascicles covered by epineurium (thick CT sheath) - isolate axons in peripheral nerves Epineurium>nerve>perineurium>fascicles>endoneurium>neurons Neuroglial (Glial) cells (CNS): Metabolism and support of nerve cells ○ Astrocytes: (most abundant) Help form blood brain barrier Regulate interstitial fluid composition, structural support + organization of CNS Assist with neuronal development, replicates to occupy space of dying neurons ○ Ependymal cells: Line ventricles and central canal of cord. Make CSF ○ Microglia - Macrophages derived from monocytes Phagocytic, protects CNS from harmful substances/infectious agents ○ Oligodendrocytes Myelinates and insulates CNS axons → increase conduction velocity  ○ Pericytes Assist w/ blood brain barrier CELL TRANSPORT Passive transport ○ No energy used, only concentration gradients ○ Facilitated or simple diffusion EXAMPLE: Leak ion channels Primary Active Transport ○ ATP = energy source ○ Substrate binds to carrier protein and is passed through membrane EXAMPLE: Sodium potassium ATPase Secondary Active Transport ○ Energy used to generate concentration gradient which is then used to drive transport ○ Carrier and substrate bind to carrier protein to release them on opposite sides of membrane symport/antiport EXAMPLE: Proton pump (in mitochondria) ACTION POTENTIALS Electroneutrality principle: charges are equal on both sides of cell membrane but, within close proximity of cell membrane there is a higher accumulation of (+) charges outside and (-) inside ○ [K+] in ECF is 4mEq/L (CONSTANT) Electrogenic: Na+/K+ pump: cations generate negative resting membrane potential ○ 3Na+ Leave the cell, 2K+ Enter the cell ○ Generates more (+) charges outside than in which maintains overall negative electrochemical gradient ○ More K+ leak channels than Na+ Nernst Equation → EMF(mV) = (61/Z)log[X(out)/X(in)] ACTION POTENTIAL PHASES: Stimulus → graded potential → threshold reached → depolarization (Na+ influx(voltage gated)) → peak (Na+ start efflux (leak)) → repolarization (K+ efflux(voltage/leak channels)) → hyperpolarization (relative refractory period) → back to resting Vm Absolute refractory period: period which no stimulus can create another action potential Relative refractory period: follows absolute refractory period when only a super strong stimulus can create another action potential  All or None Principle:Stimulus results in no action potential or a full action potential. Action potentials are uniform in one kind of cell (all the same strength) Depolarization: Vm decreases, cell excitability increases ○ Influx of Na+ ○ Influx of Ca2+ ○ HYPERKALEMIA (symptom in horses is hyperkalemic periodic paralysis (HYPP)→tremors) Hyperpolarization: Vm increases, cell excitability decreases (Silences cells) ○ Efflux of K+ (slow voltage gated channel closing) ○ Efflux of Cl- ○ HYPOKALEMIA (symptom in cats = ventroflexion) In general, action potentials are unidirectional because upstream region has refractory period by before another action potential can be generated Saltatory conductions: ○ Myelin (schwann/oligodendrocytes) insulate, nodes of ranvier express gates/channels ○ Make signals pass through axons much faster and with less energy expenditure ○ Demyelination/myelin disorders: Guillain-barre(human), multiple sclerosis, genetic/congenital conditions, distemper Chemical Transmission (unidirectional): action potential arrives from axon→voltage gated ion channels allow Ca2+ to flow into cell which triggers neurotransmitter exocytosis →neurotransmitters diffuse across synaptic cleft →neurotransmitters bind to open ligand gated ion channels leading to the generation of graded/action potential ○ SNARE proteins - mediate fusion of vesicle w/ target membrane Botulism - flaccid paralysis Tetanus - spastic paralysis ○ Neurotransmitters leave synaptic cleft by: reuptake, broken down or diffusing away from synapse ○ Postsynaptic potentials Excitatory postsynaptic potentials (Na+ depolarizes membrane) Temporal - series of depolarizations from 1 synapse depolarize stepwise  Spatial - more than 1 synapse depolarize simultaneously Inhibitory postsynaptic potentials (K+ efflux or Cl- influx hyperpolarize cell) ○ Types of Neurotransmitters Ionotropic - open/block ion channels to change Vm Metabotropic - Act like hormones and are released to blood by endocrine glands → act on G-protein coupled receptors to modify Vm Both - based on cell receptor Small molecules Acetylcholine: excitatory in PNS and CNS Amino acids: in CNS + PNS → glutamate(CNS, excitatory), Glycine (Spinal cord, inhibitory), GABA (Brain, inhibitory) Biogenic amines: catecholamines (dopamine, norepinephrine, epinephrine), serotonin Gasses: nitrous oxide Neuropeptides Enkephalins: CNS (potent analgesic) Endorphins + Dynorphins: Body temp and reproduction Substance P: CNS (Pain and emesis) Electrical Transmission (can be bi-directional): Action potential arrives at presynaptic membrane of cell → ions/other molecules diffuse through connexons → action potentials is transmitted from presynaptic to postsynaptic membrane ○ Communicates through gap junctions (CONNEXONS) allowing for bi-directional flow of current without release into synaptic cleft ○ Cardiac muscle cells (systole), smooth muscle of intestine (peristalsis), few places in CNS NOREPINEPHRINE AND ACETYLCHOLINE RECEPTORS LIGANDS & DRUG TARGETS Receptors Ligands are complementary shapes to the protein binding site (lock-and-key) ○ Endogenous NTs; hormones → endogenous ligands ○ Drugs → exogenous receptors Examples: (going in direction of speed) ○ Ligand-gated ion channels (Ionotropic) → Activation of conductance Opens only when the receptor is occupied by an agonist Regulate the flow of ions through cell membrane; response occurs in seconds EXAMPLES: Local anesthetics – voltage-gated sodium channel Benzodiazepines 9BZDs) – GABA-gated Cl- channels Ligand-gated ○ Coupled to G-protein (Metabotropic) → Generation of second messenger → Activation of cell signaling 7 alpha helices spanning plasma membrane, Subunits - Alpha, Beta, Gamma G-protein regulated effectors: adenylyl cyclase, phospholipase C, plasma membrane ion channels selective for Ca2+, K+ Gs = stimulatory, Gi= inhibitory, Gq = stimulates PKC activity, Go = decreases Ca2+ currents EXAMPLES: Catecholamines, eicosanoids, lipid signaling molecule  1. Ligand binds to GPCR 2. GPCR undergoes conformational change 3. Alpha subunit exchanges GDP for GTP 4. Alpha subunit (w/ GTP) dissociate from beta-gamma subunits 5. Target protein relay signal (Gs, Gi, Go, Gq) via alpha or beta-gamma initiated 6. GTP hydrolyzed for GDP 7. ligand dissociates from receptor and GPCR returns to start (re-binds with alpha, beta, gamma) ○ Linked to tyrosine kinase enzymes (Metabotropic) → Activation of cell signaling Mediate response of insulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), cytokines  Enzyme catalyzes the phosphorylation of substrate protein → produces a biological response ○ Nuclear receptors → Activation of transcription and translation Glucocorticoid receptors (GR) are in the cytoplasm. Drugs combine with GR and then move to the nucleus. Thyroid Hormone (T3, T4) and estrogens are in the nucleus Receptor-drug complex increases binding of RNA polymerase, leading to transcription of target genes Response time can range from minute to hours → new proteins synthesized Prolonged treatment effect Non-Receptor examples: ○ Enzymes EXAMPLES: Cyclooxygenase - NSAID AChE - AChE inhibitors Dihydrofolate reductase - trimethoprim ACE inhibitors - Benazepril, enalapril ○ Carrier transporters (Membrane transport proteins) EXAMPLES: Na+/K+/2Cl- symport - site of action of furosemide (diuretic) Na+/K+ ATPase - Digitalis (cardiac glycosides) Na+/H+ pump - proton pump inhibitors ○ Nucleic Acid EXAMPLES:  Nucleic acids (antineoplastic drugs) Bacteria DNA (Quinolones) Chemical forces: ○ Binding forces - covalent (irreversible) > ionic > hydrogen > Van der Waals (reversible) Second Messengers ○ Relay signals ○ EXAMPLES: cAMP, cGMP, IP3, Ca2+, DAG ○ Role of Second Messengers Reception - Signaling molecule (hormone, mediator, drug, etc.) binds to specific receptors in the cell membrane Transduction - Intermediary or relay molecules generate an intercellular signal mediated by second messengers (calcium, IP3, cAMP, cGMP, and others) which involves specific cellular targets (effector proteins) Response - Cellular responses occur due to the action of the second messenger Receptor Regulation ○ Receptor Regulation or Supersensitivity Occurs b/c of long-term administration of an antagonist → leads to increase # of receptors → making cell more sensitive ○ Receptor Downregulation Caused by long-term exposure to agonists (chronic treatment with a pharmacological agonist drug or prolonged inhibition of metabolism of an NT) Decrease in total receptor number → endocytosis-internalization & subsequent degradation of the receptors → decrease cell’s sensitivity ○ Receptor Desensitization Reduced response to agonist drug due to over activation of a receptor (high doses, prolonged exposure to agonist) MECHANISM: loss of receptor through a decrease in G-proteins May occur in absence of significant changes in the number of receptors Efficacy vs Potency ○ Drug Efficacy: How much of a response a drug can produce Ligand-receptor pair → activates the receptor Emax → maximal response of drug ○ Drug Potency: How much can be given to be effective Potency varies inversely with dose; lower doses are required to produce a stated response, the more potent the drug Most potent drug → low EC50 Limiting factor for drugs to be administered in small amount Drugs with a high potency usually have a high affinity and occupy a significant proportion of receptors even at low concentrations; potency depends on affinity and efficacy of receptor  Selectivity vs Specificity ○ Selective drug Produces a single effect EXAMPLE: Heparin as anticoagulant ○ Specific drug Acts ONLY on one type of receptor/target → may produce multiple effects due to receptors in various organs EXAMPLE: Atropine Receptor-Drug Interaction Agonist ○ Drug possess affinity and intrinsic efficacy ○ Drugs bind to same site as endogenous ligand → primary agonist ○ Drugs bind to different region of the receptor → allosteric agonist Full agonist: produces maximum effect Partial agonist: produces less than maximal effect → if it occupies a significant fraction of available receptor population, it antagonizes action of agonist Direct acting vs. indirect acting vs mixed Antagonist ○ Interacts with receptor to inhibit the action of agonist without initiating any effect itself → have affinity, lack intrinsic activity ○ Antagonism by drug: Receptor antagonism Physiological antagonism: acetylcholine vs. norepinephrine Chemical antagonism: acid vs. alkali ○ Receptor antagonism Competitive: effects can be overcome by increasing dose of agonist drug; antagonist is acting reversibly at receptor site Non-Competitive: effects cannot be completely overcome regardless of dose → EITHER irreversible binding of antagonist at receptor OR interaction of the antagonist at site away from receptor (agonist doesn’t bind to) that prevents initiation of effect Inverse Agonist ○ Acts on same receptor as that of an agonist, but produces an opposite pharmacological effect of an agonist ○ EXAMPLES: H1 receptor antihistaminergic drugs; Beta-adrenergic receptor-blockers, carvedilol; Antipsychotic drugs (dopaminergic antagonist: D2 receptors); Antihypertensive (angiotensin antagonist: AT1 receptor antagonist)  Drug Receptor Theories ○ Occupancy Theory Binding of agonist to receptors → maximal response proportional to the drug-receptor complex D + R DR ○ Dose-Response Curve 3 Features: Threshold, Slope, Maximal response Graded dose-response relationships: Individual Doses of drug given to an individual usually result in greater magnitude of response as dose increases Graphs plot the response to a drug against its concentration Quantal dose-response relationships: Population % of population affected increases as dose increases; all-or-none Graphs plot the rate of an outcome occurring in a population against the drug dose Standard Safety Margin ○ Ratio between the amount of drug that is lethal to 1% of the population and effective in 99% of the population ○ LD01: amount of drug that is lethal in 1% of the population ○ ED99: amount of drug that is effective in 99% of the population  ○ FORMULA → ((LD1 - ED99)/(ED99)) *100 Therapeutic Index ○ Ratio between the amount (dose) of the drug that is toxic to 50% of the population (LD50) and the amount of the drug that is effective to 50% of the population (ED50) ○ Defined range of plasma concentration with desired intensity of therapeutic effect ○ Formula → TI = LD50/ED50 ○ LARGER TI IS A SAFER DRUG Therapeutic Window ○ G PHARMACOKINETICS → “What the body does to the drug” Pharmacodynamics: “what the drug does on the body” BIOAVAILABILITY: Amount of drug in systemic circulation in unchanged form ○ Relative Systemic Bioavailability → F (%) = AUC(t) / AUC (s) Drug Disposition: ○ “All processes involved in the absorption, distribution metabolism and excretion of drugs in a living organism.” ○ Influencing factors: physicochemical properties of drug, binding of plasma proteins, extravascular distribution, ion-trapping (ruminal fluid in ruminants), blood flow to elimination organs (liver and kidneys), activity of drug-metabolizing enzymes (hepatic microsomal metabolic pathways), efficiency of excretory pathways 4 processes: Absorption, Distribution, Metabolism and Excretion (ADME) ○ Absorption Movement of drug from site of administration to systemic circulation Interspecies variation in oral bioavailability because of GI physiology differences Affecting factors: Drug solubility and dissolution rate Particle size Formulation (sustained release preparation vs oral tablets) pKa of the drugs pH of gastric contents ○ Weak acids are absorbed more in the acidic environment of stomach (non-ionized) Salt form of drug Presence of food in stomach Henderson-Hasselbach Acids → [A-] < [HA] = greater absorption/unionized; [A-] > [HA] = less absorption/ionzied ○ pH-pKa = log {Base [A-] / Acid [HA]}  ○ pH-pKa = log {ionized / unionized} → weak acid Bases ○ pH-pKa = log {Base [B] / Acid [BH+]} ○ pH-pKa = log {un-ionized / ionized} → weak base ○ Distribution Drugs from the blood into tissue via bulk flow through the capillary pores or by simple diffusion Vd (Volume of distribution) = theoretical volume that contains the total amount of administered drug at a concentration equal to the plasma (estimation of drug distribution in a tissue) dose (mg) / Plasma concentration (mg/l) ○ Vd < 0.3 l/kg → drug has limited extravascular distribution ○ Vd > 0.7 l/kg → wide distribution of drug Apparent volume If drug concentration is high in plasma → high concentration in the vascular system If drug concentration is low in plasma → high in interstitial fluid or cellular fluid Factors that affect Metabolism Biological features of liver ○ Activity of drug metabolizing enzymes (DMEs) ○ Hepatic Volume/perfusion rate ○ Drug accessibility to hepatic metabolic site Physicochemical properties of the compound ○ (pKa, lipid solubility, molecular weight; drug binding to receptor) Rate of blood flow to tissue mass ○ organ perfusion [increase blood flow → more blood flow] High blood flow/mass ratio → brain, heart, liver, kidneys, and high endocrine glands – high distribution Intermediate ratio → muscle, skin Low ratio → adipose tissue, bone – limited distribution ○ Dehydration or illness/stress → decrease distribution Plasma-protein binding (hypoalbuminemia → more free-drug form present, leading to toxicity) ○ Albumin → important binding of acidic drugs ○ Weak bases → binds to alpha-1 acid glycoprotein ○ Charged drugs bind ionically → electrostatic attraction ○ Saturable (limited number of binding sites) Affinity of the drug for extravascular tissue components Route of administration  Rate of metabolism and excretion Blood-brain barrier A glial cell layer interposed between the capillary endothelium and nervous system Only non-ionized lipid-soluble drugs could penetrate this barrier Similar - ocular, prostatic, testicular, synovial, mammary gland, and placental barrier pH partitioning phenomenon – plasma pH > protected tissue pH (CSF) Selective transport mechanism → BBB processes glucose, l-amino acid, and transferrin transporters Drug efflux transport processes that remove drugs from protected tissues ○ P-glycoprotein associated with multidrug resistance protein 1 (MDR1) [encodes P-gp] → collie breeds ○ P-glycoprotein → ATP-binding cassette proteins EXAMPLE: Collie breeds are sensitive to ivermectin toxicity → compromised BBB ABC transporters Age-related → efflux transporters develop within 1st week of life In the intestines → low expressing in proximal part, higher expression in distal part In the placenta → dependent on placenta type At the BBB → (listed above with mutation of MDR1 gene) Drug Redistribution: Highly lipophilic drugs will distribute equally into the brain tissue and into body fat ○ Initial distribution to organs with high blood flow → later to less vascular tissues The body fat forms a “reservoir” from which the drug is slowly released back into systemic circulation May induce undesirable/secondary side effects Sinks/Storage - drugs binding to tissue or plasma proteins which cause slower release into systemic circulation ○ Metabolism (biotransformation of drugs) GOAL: MAKE DRUGS MORE WATER SOLUBLE FOR RENAL/BILIARY EXCRETION Liver → major metabolizing organ Essential to get rid of lipophilic xenobiotics Species variation influences drug metabolic rate Metabolite after biotransformation is KEY ELEMENT IN DRUG SAFETY Metabolite may be biologically active, have limited to no biological activity, or be toxic :( Affecting factors: Biological → hepatic volume/perfusion rate, activity of enzymes (drug metabolizing enzymes [DME]), drug accessibility to hepatic metabolic site;  Physicochemical → pKa, Lipid solubility, molecular weight Pathophysiological parameters influencing activity of DME ○ Age → young and old have lower expression levels ○ Gender → CYP450 iso-enzymes are involved in steroid hormone synthesis and deactivation → competition ○ Species → interspecies variation ○ Diet → Dietary constituents can induce (or inhibit) DME enzymes ○ Pathology → fever down-regulates phase 1 enzymes; organ-specific diseases (liver diseases/hepatitis) modulate DME function Phase I → Functionalism Phases: ○ Degradative reaction ○ Intro of functional group (-OH, -NH2, -SH, -O, -COOH) ○ Mainly microsomal ○ Metabolites formed may be smaller, polar/nonpolar/active/inactive Done by liver microsomal enzymes (membrane-bound) ○ End products are more water soluble → renal excretion Oxidation is the most important reaction Mediated by the microsomal mixed function oxidase system (Cytochrome P450) ○ Plays a significant role in the metabolism of drugs ○ Cytochrome is a pigment that exhibits a maximal absorbance wavelength of 450 nm when reduced ○ Mainly found in liver, kidney, lung, and intestine Other oxidation processes ○ Occurs in liver, kidney, and lung cells ○ Non-microsomal enzymes; do not require NADPH as a cofactor ○ Alcohol oxidation, Aldehyde oxidation, Xanthine oxidation, Amine oxidation, Aromatization ○ Various enzymes: Dehydrogenases, Flavin-dependent monooxygenases (FMO), Peroxidases, Aromatases Phase II → Conjugation Phases ○ Synthetic reaction ○ Conjugates phase I metabolite with glucuronic acid, sulfate, acetyl, methyl groups ○ Microsomal, Mitochondrial & Cytoplasmic ○ Metabolites formed are usually larger, polar, water-soluble, & inactive  Parent drug/phase I metabolite conjugates with endogenous substrate → deactivates Glucuronidation is a major conjugation reaction involving the transfer of UDP-glucuronic acid to a functional group Conjugation with ○ Glucuronic acid → UDP-GT: (uridine - 5 - diphospho) glucuronosyl-transferase ○ Glutathione → (GST), glutathione-S-transferase ○ Sulfate → (ST) sulfate transferase ○ Acetyl groups → different acetylases; Methyl groups → different methyl-transferases; Amino acid conjugation ○ Excretion with bile → high molecular weight ○ Excretion with urine → low molecular weight SPECIES DIFFERENCES ○ Cats deficient in glucuronidation enzymes ○ Pigs deficient in sulfation ○ Dogs deficient in acetylation processes ○ Guinea Pigs deficient in glutathione conjugation ○ BREED differences in specific CYTOCHROME ISOENZYMES Induction (ex. Barbiturates, phenytoin) of liver enzymes ○ Drugs metabolized at a higher rate ○ Decreased effectiveness of the treatment Inhibition (ex. Erythromycin, ketoconazole) of liver enzymes ○ Decreased metabolism ○ High concentration of drug → undesirable side effects ○ Excretion  Renal Vs. Biliary Biliary Important for excreting drugs of molecular weight > 300 and with high polarity Active transport of drugs and metabolites into bile Glucuronide conjugates into bile → enterohepatic circulation → degradation by microflora → excreted into feces If IM>SC>Oral>Rectal ○ Systemic Enteral Drugs administered to GI tract → provides local and systemic effects Oral (first-pass effect) ○ Bioavailability depends on pKa of drug, pH and surface area at site of absorption, vascularity, lipid solubility of drug ○ Advantages: Preferred safe choice, convenient, good absorption (if unionized) ○ Disadvantages: Relatively slow onset of effect, subjective to hepatic first-pass effect, Possible GI side effects, Drug interactions with stomach content, reduced absorption of drugs (if ionized) Enterohepatic recycling (extends half life) Mainly occurs in oral drugs  Drugs are conjugated to glucuronic acid in liver, carried in bile to the intestine, metabolized back into free drug by intestinal flora bacteria, and reabsorbed into plasma → extends half-life Hepatic first-pass metabolism (decreases bioavailability) Occurs in oral drugs (sublingual bypasses it) Drugs are metabolized in liver before going into systemic circulation Swallowed drug → Drugs are absorbed intact from the small intestine (digestive system) → Hepatic portal system → Liver → Rest of body Sublingual (avoids first-pass effect) Rectal (effective in vomiting/unconscious patients) Parenteral Benefits: Rapid absorption (IV>IM>SC), High bioavailability, no gastric effects Drawbacks: Requires skilled personnel, Sterilization is important, Possible injection reactions, Thrombophlebitis (clot at injection site) via IV Subcutaneous ○ Influenced by autonomic control over blood flow ○ Less absorption than IM ○ Not preferred route in dehydration/shock ○ Advantage: prolonged absorption Intramuscular ○ Rapid onset of action ○ Bioavailability varies depending on injection site, but high compared to SQ and oral ○ Adverse Effects: pain at injection site, abscess, infection, nerve damage, hematoma formation Intravenous ○ 100% bioavailability ○ Carefully injected to avoid anaphylactic shock Inhalation ○ Large surface area of lung epithelium → rapid absorption Intra-articular → into synovial fluids Intradermal → bleb into the skin, under epidermis Intraosseous → injection into bone marrow Intraperitoneal → large surface area ○ Local Topical Permeation depends on the lipid solubility of the drug  Absorption depends on blood supply to the area of the skin Less (systemic) adverse effects More convenient/good patient compliance Intranasal ear/eye drops Intra-articular → into joint/synovial space Intrathecal → into subarachnoid space (meninges) Epidural →into space above dura (meninges) Intramammary Intrauterine Intravaginal SYMPATHETIC AND PARASYMPATHETIC DRUG/RECEPTOR STUFF: Synapses ○ Both sympathetic and parasympathetics synapse in ganglion (always nicotinic →Acetylcholine is neurotransmitter)  Sympathetic → presynaptic = short, postsynaptic = long Parasympathetic → presynaptic = long, postsynaptic = short ○ Sympathetic postsynaptic neurotransmitters is Norepinephrine, (or epinephrine/noradrenaline) and receptors are ADRENERGIC (α and β receptors) ○ Parasympathetic postsynaptic neurotransmitters: Acetylcholine and receptors are MUSCARINIC Sympathetic: (α and β receptors) FIGHT OR FLIGHT ○ Ganglia lies close to the spinal cord. Presynaptic neurons are short and postsynaptic neurons are long ○ Motor structure-function → ANS and SNS are almost entirely separated in PNS ○ SNS and ANS are closely connected in CNS ○ Many organs are innervated by both sympathetic and parasympathetic each with a reciprocal effect (counteract but do not antagonize each other) ○ 1:20 post ganglionic fibers (1 signal from preganglionic can stimulate 20 post ganglionic) Parasympathetic: Parasympathomimetic/parasympatholytics = Cholinergic/anticholinergics ○ presynaptic neurons originate mostly from brainstem and sacral spinal cord ○ ganglia and postsynaptic neurons are usually in organ viscera Pupil dilation and constriction stuff → sympathetic and parasympathetic  Dim light → sympathetic neuron in cervical vertebrae → synapse in ganglion, release NE → stimulation of RADIAL muscle → mydriasis Bright light → parasympathetic neuron in edinger-westphal nucleus (midbrain) → ganglion releases Ach → stimulation of CIRCULAR muscle → miosis SYMPATHOMIMETICS AND SYMPATHOLYTICS (Adrenergics) Sympathomimetic= Adrenergic agonists Direct - acts directly on α and β adrenergic receptors Indirect - releases Norepinephrine from storage vesicles Mixed - directly stimulates adrenergic and releases norepinephrine from storage vesicles ○ Eye dilates (mydriasis), lungs dilate bronchioles, increase HR, increase vasoconstriction, GI, bladder, uterine relaxation Sympatholytics = Adrenergic antagonists Direct α-1 adrenergic receptor Indications Side effects Other AGONIST (Gq) Phenylephrine Mydriatic agent (used to dilate Vasoconstriction, hypertension Also used as  pupil) nasal drops for Hypotension decongestion Nasal congestion Methoxamine Hypotension during sx Vasoconstriction Not commonly used Phenylpropanolamine Urinary incontinence Tachycardia and hypertension Constricts inner bladder sphincter Direct α-2 adrenergic Indications Side effects Other receptor AGONIST (Gi) Xylazine Sedation/analgesia/premedication Sedation, muscle relaxation, ADVERSE EFFECTS: heart (particularly large animal) bradycardia, conduction disturbances, 2nd degree heart block TIVA in horses when combined with ketamine EMETIC IN CATS Dexmedetomidine Sedation/analgesia (cats and EMETIC IN CATS dogs) Treats emergence delirium following analgesia Medetomidine Sedation/analgesia (cats and dogs and horses) Brimonidine Glaucoma Increase aqueous humor outflow VASOCONSTRICTION Decrease aqueous humor production by vasoconstriction α adrenergic receptor Indication Side effects Other ANTAGONISTS Phenoxybenzamine Used before sx removal of Increases cardiac output, ADVERSE EFFECTS: Postural (nonselective, irreversible) pheochromocytoma to prevent prevents vasoconstriction in hypotension w/ reflex tachycardia hypertensive crisis peripheral blood vessels and arrhythmias, nausea, nasal Management of BPH stuffiness, inhibits ejaculation, Detrusor areflexia in dogs and aspermia cats Toxic for long term use: Mutagenic agent Prazosin BPH, Urinary retention, Hypotension, decreased ADVERSE EFFECT: reflex (α1 antagonist) Hypertension peripheral resistance tachycardia Yohimbine Reversal agent for Xylazine (α2 antagonist) Atipamezole (Antisedan) Reversal agent for (α2 antagonist) Dexmedetomidine and Medetomidine β adrenergic receptor Indication Side effects Other AGONIST (Gs) Isoproterenol Bradycardia, Heart block Vasodilation, increases cardiac β2 receptor targets uterus for (Nonselective, but prefers β1 output relaxation agonist) Uterine relaxation, (Tocolytic) ADVERSE EFFECTS: Tachycardia and arrhythmias, palpitations, ischemia Dobutamine CHF, Hypertension during sx Increases Cardiac Output Ionotropic agent (β1 agonist) Increases atrioventricular Exacerbates A-fib conduction Tolerance (tachyphylaxis) Terbutaline Bronchodilation Relaxes smooth muscle in ADVERSE EFFECTS: (β2 agonist) bronchial, uterine and vascular Tachycardia tissues Clenbuterol Bronchodilation Not for use in food animal: (β2 agonist) COPD/Asthma in horses residues cause anabolic effect in humans β adrenergic receptor Indication Side Effects Other ANTAGONIST (Gs) Propranolol Hypertension Peripheral vasoconstriction, Prototype for β1 antagonist (nonselective) bronchodilation, increased Adverse effects: anxiety, sedation, sodium retention, decreases bronchoconstriction, arrhythmias, glucose metabolism hypoglycemia Decreased ionotropic and chronotropic effect Atenolol Hypertension (β1 antagonist) Timolol Wide angle Glaucoma (β1 antagonist) PARASYMPATHOMIMETICS AND PARASYMPATHOLYTICS (Muscarinics) Parasympathomimetics: Direct: activates cholinergic receptors Indirect: inhibits cholinesterase inhibitors (to allow acetylcholine to remain in synapse for longer period of time) ○ Muscarinic M1 - (Gq) - ganglia and glands M2 - (Gi) - Myocardium + smooth muscle M3 - (Gq) - Smooth muscle and secretory glands, endothelium (kinda) ○ Vascular endothelium (NON-INNERVATED, but changes are expressed)  Ach binds M3 which causes Release of NO- → diffuses to endothelium to activate guanylyl cyclase (GTP to cGMP) → vasodilation ○ Less platelet aggregation, less smooth muscle growth, less neutrophil adhesion, lower BP (vasodilation) M4 - (Gi) - Smooth muscle and secretory glands M5 - (Gq) - CNS (all 5 subtypes) ○ Nicotinic Ligand gated ion channel (increases cell permeability to Na+) Nm - Neuromuscular junction, (depolarizes cells to cause CONTRACTION) Nn - Autonomic ganglia, CNS and adrenal medulla ○ Pupil constriction (Miosis), stimulates GI activity, Bronchoconstriction, decrease HR/BP, increase insulin release (lower [BG]) parasympatholytics: Direct Agonists Indication Side effects Other Pilocarpine Glaucoma, KCS Contraction of iris sphincter and (M3) ciliary muscle of iris Increase aqueous humor outflow Decrease aqueous humor production by vasoconstriction Bethanechol Urinary retention Bronchoconstriction, bradycardia, Do Not use with mechanical GI paralytic Ileus miosis, salivation/sweating, obstruction in GIT vomiting/diarrhea, urinary incontinence, neuromuscular Improves GI motility particularly in effects, uterine contraction esophagus (abortion) CNS effects at high doses Indirect Agonists Indication Side effects Other (Cholinesterase inhibitors) Organophosphates TOXIC!!!!!!! Profuse salivation, vomiting, Forms stable enzyme-inhibitor (irreversible AChE inhibitor) hypermotility of GIT, defecation, complex at esteric site urination, bradycardia, (phosphorylation) hypotension, bronchoconstriction, miosis, skeletal muscle Requires do novo synthesis of fasciculations, paralysis, enzyme) convulsions, death Neostigmine Myasthenia gravis (DUMBELLS) (reversible AChE inhibitor) Edrophonium Myasthenia gravis test VERY FAST ACTING (reversible AChE inhibitor) Revert neuromuscular blockade Antagonists Indication Side effects Other Atropine Competitive antagonist for Mad as a hatter (Disorientation) Rabbits resistant organophosphates Blind as a bat (mydriasis and cycloplegia) (atropinease Hot as a hare (increased body temp) enzyme…use Bradycardia, hypotension Red as a beet (skin flushing) glycopyrrolate instead) Dry as a bone (dry mouth, decreases secretions, anhidrotic effect) Full as a flask (urinary retention) Scopolamine Motion Sickness (Antiemetic) Smooth muscle relaxation ANATOMY Lymphatic System Ventral View of Abdomen: liver and SPLEEN Cardiovascular system Left Lateral View (lungs removed) Respiratory System Digestive System Ruminant Stomach Urinary System Endocrine System Repro - Male Repro - Female Muscular System Right lateral view  Left lateral view Skeletal system