HPU2303 Human processes 3

HEALTH SCIENCE

Causes of cellular injury

• Hypoxia

• Chemical agents

• Physical agents

• Infectious agents

• Genetic causes

What is inflammation?

• Primary defense mechanism of the immune system to tissue injury and infection.

What are the benefits of inflammation?

• Limits and controls tissue damage

• Prevents infection by contaminating microorganisms

• Initiates and promotes adaptive immune response

• Initiates healing

Mechanism of cell injury

• Hypoxic injury

• impact of 02 and 02 derived free radicals

• Alteration in calcium homeostasis

Neutrophils are ?

• Predominantly phagocytes in the early inflammatory site

• Arrives at the site 6-12 hours after the initial injury

• Short lived at the site, becomes pus then removed by the lymphatic system.

Hypoxic injury steps

• Lack of 02 in the cells

• Anerobic metabolism

• insufficient ATP

• Failure of NA+ -K+ pump and NA+ and CA2+ exchange in the cell

• Intracellular accumulation of Na+ and Ca2+ and diffusion of k+ out of cell

• Cellular swelling

• Membrane damage

• Cell death

  (ATP - adenosine triphosphate is a molecule that stores and releases energy in cells).

What impact does 02 derived free radicals have on cells?

• Normally small number of free radicals produced during ATP- adenosine triphosphate production from partially reduced 02 molecules called ROS-reactive oxygen species

• Antioxidants clean up these molecules before they undergo chemical reaction.

Characteristics of free radicals

• an atom that is electrically uncharged

• unstable

• prone to stealing or donating charge from other molecules

• capable of chemical bonding with proteins, lipids and carbohydrates.

Apoptosis

• Normal cellular function

• Programmed cell death that causes self-destruction

• Normal cell

• condensation of chromatin

• membrane blebs ( bulges in the membrane that break off)

• cellular fragmentation

• Apoptosis

• phagotosis

Necrosis

• Common form of cellular death

• arises in response to pathophysiological process

• severe cellular swelling and breakdown of the organelles

• normal cell

• reversible injury or recovery

• swelling of endoplasmic reticulum and mitochondria

• membrane blebs ( bulges in the membrane that break off)

• Breakdown of plasma membrane and nucleus - leakage of contents

Benefits of inflammation

• Limits and controls tissue damage

• Prevents infection by contaminating microorganisms

• Initiates and promotes adaptive immune response

• Initiates healing

Inflammatory mediators - histamine

• Act on blood vessels

• Cause vasodilation and increased vascular permeability

Inflammatory mediators - Leukotrienes

• produce histamine like effects

• stimulate more prolonged responses than histamine

• therefore, important in later stages of inflammatory process

Inflammatory mediators - prostaglandins

• cause increased vascular permeability, pain and fever

• produced when enzyme cyclo- oxygenase converts arachidonic acid to prostaglandin

Inflammatory mediators - Cytokines

• Group of proteins that provide a means of communication for inflammatory cells

• Can be pro inflammatory or anti inflammatory

• Cytokines that strongly influence inflammation- interleukins and tumor necrosis factor alpha (TNF-a)

Inflammatory mediators - Chemotactic factors

• cause directional movement of cells towards the site of injury

• Two main chemotactic factors - neutrophil chemotactic factor and eosinophil chemotactic factors, attracts neutrophils and eosinophils

Inflammatory mediators - Platelet activating factors

• cause platelet activation

• increases vascular permeability

Cytokines- Interleukins

• can be pro - inflammatory and anti- inflammatory

• Endogenous pyrogen, causes fever

Cytokines- TNF-a

• pro inflammatory

• induces fever

Interleukins Mnemonic - Hot T-bone steak

IL-1 = Fever (HOT)

IL - 2= stimulated T cells

IL-3=stimulates bone marrow

IL - 4 = stimulates igE production

IL- 5 = stimulate igA production

IL 6 = stimulates aKute - phase protein production

Inflammatory mediators

• Histamine

• Leukotrienes

• Prostaglandins

• Cytokines

• Chemotactic Factors

• Platelet activating factor

• Interleukins

• TNF-a

Pathogens and Antigens

Pathogens - foreign agent

• Bacteria

• Infection eg Staphylococcus

• Food Poisoning eg Salmonella

• Fungi eg Candida

• Protozoa eg amoeba

• Parasites eg worms

• Pathogens introduce foreign proteins into the body called antigens

• Antigenic receptors on T cells and B cells recognize these foreign objects and aims to remove them from the body.

Categories of Immunity

• Innate or nonspecific immunity

• Adaptive or specific immunity

• Innate or adaptive immunity are fully integrated in the body

Innate ( nonspecific ) Immunity

• Physical barriers such as skin and membranes

• Inflammation

• Chemical mediators

• White blood cells (Leukocytes) eg macrophages and phagocytes

• Fever

Adaptive (specific) Immunity

• Cell mediated immunity - T cells

• Antibody mediated Immunity - B cells

Innate Immunity - Chemical Mediators

• Histamine -

• Causes vasodilation, increased vascular permeability, attract white blood cells, stimulate phagocytosis

• Cytokines-

• Secreted by one cell, and stimulates a neighboring cell to respond

• regulate intensity and length of immune response

• Communication tool between cells

• Complement -

• Stimulate lysis of invading pathogen cells

• Interferons

• Anti - viral activity

Innate Immunity White Blood Cells

• White blood cells produced in bone marrow and lymphatic tissue

• Released into blood and transported around the body

• When a tissue is damaged it releases chemicals that attract white blood cells to a site of injury / invasion

• White blood cells

• Ingest foreign particles - phagocytosis

• Produce chemicals to attract other immune cells to local area

What cells make up white blood cells?

• Neutrophils - first cell to arrive at a site of insult, acute inflammation - phagocytosis

• Macrophages - most effective phagocyte, important in the later stages of inflammation and repair: help activate cells of the specific immune system (Antigen pressing cell)

• Basophils - immunosurveillance; produce histamine (allergy)

• Eosinophils - parasitic infection; allergy

• Natural Killer Cells - Can cause lysis of virus- infected cells or cancer cells

• B and T Lymphocytes- adaptive immunity

Adaptive Immunity

Specificity - ability to recognize a particular substance

Memory - ability to remember previous encounters with a particular substance and respond rapidly

Acquired during lifetime, depending on exposure

• fights invaders once innate immunity

Non-steroidal inflammatory drugs

Nsaids

Celebrex - Ortho

ibuprofen

Aspirin

Block the COX 1, 2

creates GI ulcers, renal damage to nephrons, stops clotting in blood

What comes from Mast cells

• Histamine

• Chemotactic factors

• Arachidonic acid

• Platelet activating factor

Paracetamol

Reduce the amount of opioids

Works with the cns

Antipyretic

reduces prostaglandins

What is the purpose of pain sensations?

• Motivates people to seek medical assistance.

• Encourages patients to adopt behaviors that enhance healing

• Teaches us to avoid environmental stimuli that cause harm.

What are the 3 main types of pain?

1. Nociceptive pain - produced by nociceptive stimuli. 2 subtypes; pain due to external damage and pain due to internal damage.

2. Neuropathic Pain - caused by injury or disease of the nervous system.

3. Psychogenic pain - severe persistent pain with no underlying pathology

What is acute pain?

Pain that lasts ess than three months

What is chronic pain ?

Pain that lasts longer than 3 months

What is referred pain?

Pain perceived as occurring in a region of the body distinct from the region in which the actual source of pain is located. An example of this is heart attack. The pain is felt in the shoulder or jaw but the cause is the heart.

What is Hyperalgesia?

An increased response to a stimulus that is normally painful.

What is allodynia?

Pain due to a stimulus that does not normally provoke pain. This condition often occurs in individuals with certain chronic pain disorders, such as fibromyalgia, neuropathic pain, or migraine.

What is the physiology of pain?

Tissue damage

Stimulate neurons

1st order neurons carry pain impulses from periphery to spinal cord

2nd order neurons carry it from spinal cord to thalamus

3rd order neurons carry it from thalamus to cerebral cortex

Pain awareness

What are 1st order neurons (nociceptors)

• Primary sensory neurons

• Responsible to detect sensations

• Runs from peripheral tissue through a peripheral nerve and terminates at dorsal horn of spinal cord.

• Stimulated by inflammatory mediators released at the site of injury

• Identified in every peripheral tissue

  • cutaneous nociceptors

  • musculoskeletal nociceptors

  • Visceral nociceptors

What are 2nd order neurons (spinothalamic tract neuron)

• Relay action potential from spinal cord to thalamus

• Activated by excitatory neuromodulators (Substance P)

• Cell bodies located in spinal cord. Axons cross the midline of the spinal cord and ascend along the length of the spinal cord on the opposite side.

• These axons project out of the spinal cord through brain stem and in the thalamus.

What is the 3rd order neuron (Thalamocortical neuron).

It relays information from the thalamus to cerebral cortex.

Descending pain pathway

• impulses from brain activates interneuron at dorsal horn of spinal cord

• Release endorphins (Endogenous opioids produced by body)

• Endorphins attach to opioid receptors

• Inhibit the release of excitatory neurotransmitters, inhibiting ascending pain pathway.

Clinical manifestations of pain

• Often experience an increase in heart rate, blood pressure, ventilation, nausea and vomiting, and sweating.

• Can be due to activation of sympathetic nervous system, elevating cardiovascular and respiratory responses

• Not universal in all individuals experiencing pain.

Pain management

• Non-steroidal anti- inflammatory drugs

• Opioids

• Adjuvant analgesics (steroids, antidepressants)

• Surgical approach - midline myelotomy (cuts the axons of the spinothalamic tract neurons crossing the midline of the spinal cord.

What does NSAIDS in COX 1 and 2 stand for?

Inhibit Cyclooxygenase enzymes, COX 1 and COX 2, which are involved in the conversion of arachidonic acid to prostoglandins

Examples of COX-2 inhibitors:

Celecoxib and Parecoxib

COX 1 inhibitors

Pain - aspirin inhibits both cox 1 and cox 2, mainly cox 1

Fever- Ibuprofen

Gut integrity - Celecoxib/ Parecoxib

Platelet aggregation - Meloxicam

COX 2 prostaglandins

Inflammation

Pain

Fever

Nonpharmacological management of pain

• massage

• Transcutaneous electrical nerve stimulation (tens)

• Heat therapy

• Cold Therapy

  • Cognitive Therapies- distraction. education, breathing techniques, relaxation

Nociceptors - pain

Pain receptors respond to extreme mechanical, chemical. Dull or ache

What is Psychogenic pain?

Psychogenic pain is physical pain that is caused, increased, or prolonged by mental, emotional, or behavioral factors, without evidence of physical injury or illness. It is a pain disorder associated with psychological factors. While psychogenic pain is not caused by clear physical pathology, it is a very real type of chronic pain. Some people also have chronic pain that’s not tied to an injury or physical illness, which is called psychogenic pain or psychosomatic pain.

What is Visceral Pain ?

Visceral pain is pain related to the internal organs. It is often vague, occurs intermittently, and feels like a deep ache or pressure. Unlike somatic pain, which occurs in tissues like muscles or skin, visceral pain is not well localized. It may be accompanied by symptoms such as nausea, vomiting, and changes in vital signs.

What is substance P?

Substance P is a neuropeptide that acts as a mediator of pain transmission in the central nervous system and during neurogenic inflammation in the periphery

Mast cell degranulation releases chemical mediators called?

• Histamine

• Tryptase

• Chymase

• Heparin

• Serotonin

Mast cell stabilizers

• Ketotifen

• Azelastine

• Cromolyn sodium

Cytokine - Interferon Alpha (IFNa)

Prevents viral replication and inhibits cell growth; secreted by virus-infected cells

Cytokine - Interferon beta (IFNβ)

Prevents viral replication, inhibits cell growth, and decreases the expression of major histocompatibility complex (MHC) class I and II molecules; secreted by virus-infected fibroblasts

Cytokine- Interferon gamma (IFNγ)

About 20 different proteins that activate macrophages and natural killer (NK) cells, stimulate adaptive immunity by increasing the expression of MHC class I and II molecules, and prevent viral replication; secreted by helper T, cytotoxic T, and NK cells

Cytokine - Interleukin-1 (IL-1)

Costimulation of B cells and T cells; promotes inflammation through prostaglandin production and induces fever acting through the hypothalamus (pyrogen); secreted by macrophages, B cells, and fibroblasts

Cytokine - Interleukin-2 (IL-2)

Costimulation of B cells and T cells and activation of macrophages and NK cells; secreted by helper T cells

Interleukin-4 (IL-4)

Plays a role in allergic reactions by activation of B cells, resulting in the production of immunoglobulin E (lgE); secreted by helper T cells

Cytokine - Interleukin-5 (IL-5)

Part of the response against parasites by stimulating eosinophil production; secreted by helper T cells

Cytokine- Interleukin-8 (IL-8)

Chemotactic factor that promotes inflammation by attracting neutrophils and basophils; secreted by macrophages

Cytokine - Interleukin-10 (IL-10)

Inhibits the secretion of interferon gamma and interleukins; secreted by regulatory T cells

Cytokine - Interleukin-15 (IL-15)

Promotes inflammation and activates memory T cells and natural killer cells

Cytokine - Lymphotoxin

Kills target cells; secreted by cytotoxic T cells

Cytokine - Perforin

Makes a hole in the membrane of target cells, resulting in lysis of the cell; secreted by cytotoxic T cells

Tumor necrosis factor α (TNFα)

Activates macrophages and promotes fever (pyrogen); secreted by macrophages

IgG 80–85% total serum antibody

Activates complement and promotes phagocytosis; can cross the placenta and provide immune protection to the fetus and newborn; responsible for Rh reactions, such as hemolytic disease of the newborn

IgM 5–10% Total serum antibody

Activates complement and acts as an antigen-binding receptor on the surface of B cells; responsible for transfusion reactions in the ABO blood system; often the first antibody produced in response to an antigen

IgA 15% Total Serum Antibody

Secreted into saliva, into tears, and onto mucous membranes to provide protection on body surfaces; found in colostrum and milk to provide immune protection to newborns

IgE 0.002% Total serum antibody

Binds to mast cells and basophils and stimulates the inflammatory response

IgD 0.2% Total serum Antibody

Functions as antigen-binding receptors on B cells

What is ADH?

Anti Diuretic Hormone

Treatment for syndrome of inappropriate anti diuretic hormone secretion (SIADH)

• Accurate assessment and monitoring of weight and fluid balance

• Fluid restriction 0.5-1L per day

• Increase sodium serum by no more than 8-10mmol/ L in the first 24 hours

• Identify cause and manage

Clinical manifestations of anti-diuretic hormone

• Dilutional Hyponatremia

• Low sodium osmolality and fluid retention due to excess ADH, leading to symptoms like nausea, headache, and confusion.

• Hyperosmolarity of urine

• Absence of conditions that can alter fluid volume status

Causes of Nephrogenic Diabetes Insipidus

• Renal diseases

• ADH unresponsive Kidney

• Drugs

Hyperaldosteronism

Happens one or both adrenal glands produce too much aldosterone

Causes of Neurogenic Diabetes Insipidus

• Tumours

• Trauma

• Surgery

What are the clinical manifestations of Diabetes Insipidus?

• Polyuria

• nocturia

• Continuous thirst

• Polydipsia

• Low urine concentration

• High to normal plasma osmolality

Nephrogenic form of Diabetes Insipidus

Caused by inadequate response of the renal tubules (KIDNEYS) to antidiuretic hormone.

Neurogenic (central form) of Diabetes Insipidus

Caused by the absence of antidiuretic hormone.

Vasopressin Receptor Antagonists

Block the effects of antidiuretic hormone, such as tolvaptan are newer agents that prevent the reabsorption of free water back into circulation.

Diabetes Insipidus

Is related to an insufficiency of antidiuretic hormone leading to polyuria and polydipsia.

Nursing Management of Diabetes Insipidus

• Maintenance of fluid and electrolyte balance

• Monitoring of vital signs, urine output

• Monitor level of consciousness and for signs of dehydration

• Fluid balance chart and daily weight

What is the function of the hypothalamus regarding hormones?

Controls - pituitary function

• thyrotrophin releasing hormone (TRH)

• Corticotrophin releasing hormone (CRH)

Pituitary gland releases

• Thyroid stimulating hormone (TSH)

• Adrenocorticotropic hormone (ACTH)

• Follicle stimulating hormone (FSH)

• Luteinizing hormone (LH)

• Growth hormone

• Anti diuretic hormone (ADH) by the posterior pituitary gland

Thyroid gland releases

• Thyroxine (T4)

• Triiodothyronine (T4)

• Calcitonin

Parathyroid releases

Parathyroid hormone

Adrenal cortex releases

• Aldosterone

• Cortisol

Adrenal Medulla releases

Catecholamines (adrenaline and noradrenaline)

what is one consequence of histamine release?

increased capillary permeability

Outline the features of the pain experience that are included in the sensory-discriminative aspect of pain

. - Intensity - The level of pain experienced, which can range from mild to severe.

• Quality - The characteristic of pain, whether it is sharp, dull, throbbing, or burning.

• Location - The specific area of the body where the pain is felt.

• Duration- The length of time the pain persists, which can be constant or intermittent

Explain why it is useful for the threshold for pain sensation to be lower than the threshold for tissue damage

It is useful for the threshold for pain sensation to be lower than the threshold for tissue damage because it acts as an early warning system, allowing the body to respond quickly to potential harm and avoid further injury.

Discuss the difference between hyperalgesia and allodynia.

Hyperalgesia refers to an increased sensitivity to pain in response to a painful stimulus, while allodynia is a condition where a non-painful stimulus is perceived as painful. These conditions highlight different mechanisms of pain processing.

Compare and contrast the properties of cutaneous high threshold mechanoreceptors and polymodal nociceptors

Cutaneous high threshold mechanoreceptors respond mainly to intense mechanical stimuli and are involved in detecting high levels of pressure or pain, while polymodal nociceptors are sensitive to a variety of damaging stimuli, including mechanical, thermal, and chemical, and primarily serve as pain receptors.

Explain why a skin laceration often causes two pain sensations separated in time

A skin laceration often causes two pain sensations separated in time due to the activation of both A-delta fibers, which transmit sharp, immediate pain sensations, and C fibers, which carry slower, dull, throbbing pain signals. This difference in transmission speed leads to the distinct sensations experienced.

Discuss why a painful stimulus applied to the right side of the body results in activation of the cerebral cortex on the left side of the body.

This phenomenon occurs due to the crossing of neural pathways in the spinal cord and brainstem, where sensory information from the right side of the body decussates (crosses over) to the left side of the central nervous system, leading to processing in the left cerebral cortex.