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CHAPTER TWENTY NINE 1 The Endocrine System A “communication” system for the body Major components of the endocrine system are: Hypothalamus Pituitary gland 2 The Endocrine System (cont.) Secondary components of the endocrine system are: Thyroid Parathyroid Pancreas Adrenal glands Gonads The pituitary gland controls the secondary components of the endocrine system During pregnancy, the placenta also acts as an endocrine gland 3 The Hypothalamus and Pituitary Gland Hypothalamus Part of the brainstem Controls the activity of the pituitary gland Pituitary gland About the size of a large pea Called the “master gland” because it controls many other glands Composed of anterior and posterior lobes Each lobe contains a number of hormones Hormones—chemical substances that regulate certain bodily functions 4 Hormones Transfer information and instructions from one set of cells to another Each hormone affects only the cells that are genetically programmed to receive and respond to its message Hormones are divided into two groups according to their structure: Steroids—slow acting, long lasting, and usually end in the suffix “-rone” (examples: testosterone, progesterone) Peptides and amines—made of proteins, fast acting, and short lived (examples: insulin, ADH) 5 Female Sex Hormones Estrogen—responsible for: Development of secondary sex characteristics Formation of osteoblasts Inhibition of osteoclasts Bone loss Progesterone—prepares lining of uterus for implantation of fertilized egg Replacement female hormones may be derived from animal, plant, or lab-modified sources 6 Female hormones Drug Products MOA: replaces estradiol in females Indications: menopausal Sx, prevent osteoporosis, Contraception, maintenance of pregnancy Generic Brand Indications Conjugated Estrogens Premarin ® Hormone replacement medroxyprogesterone Provera® Contraceptive Norgestrel Ovrette® Contraceptive Ethinyl Estradiol Estinyl® Hormone replacement Remember: Federal Law mandate for OC OC are contraindicated in women with a history of TE disorders, strokes and breast cancer DepoProvera is an IM injection used for birth control that lasts for 3 months 7 Male Sex Hormones Also called androgens or masculinizing hormones Primary male sex hormone is testosterone: Produced in the testes Stimulates the development of male sex organs Maintains secondary sex characteristics Progesterone—maintains healthy prostate Replacement male hormones are typically anabolic steroids 8 Male Sex Hormone Drug Products MOA: replaces testosterone levels in men Indications: hormone replacement therapy, treatment of anemia in cancer patient (no used for this anymore) Contraindications: history of liver disease, and prostate cancer Generic Brand(s) Testosterone Androgel®, Androderm® and as testosterone cypionate (IM injection) Nandrolone Durabolin ® Fluoxymesterone Halotestin® Oxymetholone Anadrol® Side effects: weight gain, muscle hypertrophy, viriziling effects, priapism, hepatitis and blood filled cysts in liver (oral more than IM), long term use results in sexual problems, gynecomastia Because of abuse in sports, federal schedule 3 9 Diabetes Mellitus A disorder of carbohydrate metabolism Type I DM Genetic factors involved Environmental factors (i.e. Coxsackie virus) Involves destruction of pancreas by the immune system Begins as children and young adults Patients are described as insulinopenic (i.e pancreas secretes almost no insulin) Patients are described as thin Blood abnormalities includes high blood glucose, high triglycerides level (VLDL), high blood levels of ketone Physical signs are extreme thirst, nocturia, hypertension and possible kidney disease. 10 Type II Diabetes Mellitus Genetic factors involved Environmental factors involved Involves the resistance of the body to the hormone, Insulin. Also described as Insulin resistance syndrome Signs and symptoms include those of Type I DM Metabolic Syndrome or Syndrome X Independent risk factor for cardiovascular disease Seen in men and women Biochemically marked by high blood glucose, cholesterol, trigycerides BMI>25 Hypertension of greater than 130 mmHg systolic Waistline of more than 40 in in men; 35 in in women 11 Therapy of Diabetes Insulin Regular insulin or short acting insulin Humulin R or Novolin R Humalog or Novolog Intermediate acting insulin Humulin N or Novolin N Mixture of intermediate acting /regular insulin Humulin 70/30 or Novolin 70/30 Novolog 70/30 Long acting insulin Lantus ® (insulin glargine) In general, insulin is the first line of therapy in type I DM In type II DM, oral drugs are tried first, ultimately insulin is required in this class of people as well 12 In general the dose of insulin in type I DM is about 0.5 units/kg of body weight which half of this dose given as long acting insulin and the other half is given as bolus dose with meals Type II DM patients are initiated on long acting or intermediate acting Insulin at bedtime. The dose is titrated according to fasting blood glucose and is determined by the patient’s endocrinologist 13 Oral Drugs for Diabetes Mellitus Type I DM patients can not be treated with most of these drugs Used in Type II DM Sulfonyureas Increases insulin secretion from the pancreas Should be given with food Avoid Alcohol Glipizide (Glucotrol®) Glyburide (Diabeta®) Tolbutamide (Orinase®) Glimepiride (Amaryl®) Biguanides Inhibits hepatic gluconeogenesis during fasting Metformin (Glucophage®) Caution: with people with kidney disease can result in a fatal reaction called Lactic acidosis 14 Meglitinides Similar to sulfonylureas Taken before a meal Repaglinide (Prandin®) Nateglinide (Starlix®) Thiazolidinediones Also known as the glitazones Increases insulin sensitivity in adipose tissue and muscles Pioglitazone (Actos®) Rosiglitazone (Avandia®) Basically good drugs but since 2010, both drugs have been implicated in serious adverse medical events After November 2011, Avandia and all avandia products are restricted in distribution to the FDA REMS program www.fda.gov/Drugs/DrugSafety/ucm255005 15 Novel New Drugs dipeptidyl peptidase- 4 inhibitors Blocks an enzyme in the kidney called dipeptidyl peptidase- 4 Blockade of this enzyme allows a hormone called glucagon like peptide I or GLP1 to last longer GLP1 helps augment insulin release in response to a sugar rich meal Onglyza ®(saxagliptin) Januvia ® (sitagliptin) Incretin Mimetics (GLP like) Exenatide (Byetta®) Liraglutide (Victoza®) Injectable hormones GLP-1 agonists 16 Thyroid Disease Thyroid gland is responsible for secreting thyroid hormone, T4. T4 basically controls metabolic functions in the body More T4 equals a higher basal metabolic rate Less T4 equals a lower basal metabolic rate Hypothyroidism is a condition where thyroid gland does not secrete adequate T4 Condition products slow BMR, slow heart rate, electrolyte abnormalities, lipid disorders Tx: Levothyroxine (synthroid ®, Levoxyl ®) Hyperthyroidism is a condition of to much T4 Can produce a dangerous heart condition called Atrial Fibrillation Tx: Methimazole (Tapazole®), Propylthiouracil (PTU) SSKI (super saturated potassium iodide) used in the emergency tx of “thyroid storm” 17 Corticosteroids Adrenal gland naturally produces cortisol and other “corticosteroids” These hormones are very important in priming the body to deal with stress. They control artery’s and heart’s sensivity to norepinephrine, blood pressure, water clearance by the kidney and many others A loss of cortisol secretion by the adrenal gland produces “adrenal crisis” which is a medical emergency Generic Brand Prednisone Deltasone Methylprednisolone Medrol (oral) Solu Medrol (IV) Dexamethasone Decadron Hydrocortisone Hytone (topical) Solucortef (IV) Severe side effects: immune suppression, osteoporosis, elevated blood glucose, cataracts, growth suppression in children With Inhalation products like Advair® tell patients to rinse mouth after the dose 18 CHAPTER THIRTY ONE 19 The Nervous System Divided into central nervous system (CNS) and peripheral nervous system (PNS) Central nervous system Includes brain and spinal cord Controls all nervous system functions Control may be direct or indirect Peripheral nervous system Includes all other nerves and sensory organs Controlled by central nervous system Divided into somatic and autonomic nervous systems 20 Functions of the Nervous System Sensory (afferent) Sends impulses from other parts of body toward the CNS Senses external changes or conditions in the environment, such as cold or heat Senses internal changes in the body, such as decrease in potassium or calcium Integrative Processes perceived information about the sensory changes Interprets or explains changes in external/internal environments 21 Functions of the Nervous System (cont.) Motor (efferent) Sends impulses away from the CNS to other parts of the body Allows and controls body movement Causes glands to secrete hormones or other chemicals into the bloodstream 22 Sympathetic Nervous System Governed by the neurotransmitter norepinephrine Prepares body for energetic tasks, stressful situations, and the “fight or flight” response Stimulates heart, lungs, and blood vessels Decreases activity of gastrointestinal and genitourinary functions 23 Parasympathetic Nervous System Governed by the neurotransmitter acetylcholine Activates body for sleep in nonstressful periods Effects the “rest and relaxation” response Decreases activity of heart, lungs, and blood vessels Increases activity of gastrointestinal and genitourinary functions 24 Neuron Smallest unit of the nervous system Brain is composed of approximately 100 billion neurons Highly differentiated from other cells 25 Neuron (cont.) Has specialized projections called dendrites and axons that communicate with the rest of the body: Dendrites bring information to the cell body from the central nervous system Axons take information away from the cell body to the central nervous system 26 Nervous System Communication Neurons communicate with each other through an electrochemical process Can be compared to a computer sending electrical signals over its wires Brain sends electrical signals through neurons instead of wires Neurons produce electrochemical hormones called neurotransmitters Neurotransmitters are stored in the ends of the nerve cells 27 Neurotransmitters Released at the end of the neuron Synapse is the space between two different neurons Neurons transfer information by crossing synapses Neurotransmitters travel across the synapse to reach a receiving neuron Attach to special structures called receptors Communicate with and control glands, organs, and muscles 28 Anxiety Uncomfortable emotional state characterized by apprehension, worry, and fear Associated with the following risk factors: Genetics Brain chemistry Life events Personality • Treated with benzodiazepines, antidepressants • • • Xanax ® Alprazolam Restoril® Temazepam Valium ® Diazepam 29 Depression Symptoms include feelings of despair, lack of energy, inability to concentrate Related to decreases in concentration of the neurotransmitters Treated with drugs that: Block the reuptake of neurotransmitters TCA (tricyclic antidepressents) Nortripyline (Pamelor®), Amitripyline (Elavil®) Dangerous in overdose Doses over 1 gram can be fatal SSRI Fluoxetine (Prozac®) Paroxetine (Paxil®) Sertraline (Zoloft®) Citalopram (Lexapro) SNRI Duloxetine (Cymbalta®) Safer in overdose than TCA’s 30 Interfere with the breakdown of the monoamines within the synaptic cleft MAOI Used in the 50 and 60’s Very dangerous in overdose Many drug interactions especially with hypoglycemic drugs and antihypertensive drugs Drug food interactions with foods with high tyramine content like cheeses, wine, chocolates, etc Phenelzine (Nardil®) Tranylcypromine (Parnate®) Used now only a last ditch effort to treat SSRI resistant depression 31 Bipolar Disorder Characterized by severe emotional highs (mania) and lows (depression) Episodes, referred to as mood swings, can last hours, days, months, or years Treatment may include: Lithium—reduces hyperexcitability of the nerves Antidepressant drugs 32 Psychosis State in which a person is out of touch with reality One cause may be an increase in dopamine Treated with antipsychotic drugs that attach to the dopamine D2 receptor Treated with dopamine receptor antagonists Generic Brand Haloperidol Haldol ® Chlorpromazine Thorazine® Fluphenazine Prolixin® Thioridazine Mellaril ® Major side effects: Abnormal heart arrhthymias, hypotension, sedation, Extrapyramidal symptoms (Parkinson’s like) movement disorders 33 Mental Disorders The following mental disorders may be treated psychotherapeutically: Psychosis Depression Anxiety Obsessive-compulsive disorder Panic disorder • Although there is no cure for mental illness, drugs will help the patient to have a better experience in daily living and function more effectively 34 Mental Disorders (cont.) The National Institutes of Mental Health classifies the following four types of psychotherapeutic agents: Antianxiety Antidepressant Antimanic Antipsychotic 35 Parkinson’s Disease Degenerating neurons in the basal ganglia of the brain characterizes this disease These neurons are dopaminergic and secrete dopamine as a neurotransmitter These neurons coordinate with neurons in the motor cortex to help initiate movement Signs and symptoms Resting tremor: shaking limbs and hands at rest which goes away with movement (first sign noticed by family or patient) Gait imbalances: patient has problems initiating movement and may show signs of bradykinesia and muscle rigidity often called dystonia Weak and achy muscle in the face progresses to slurring speech Autonomic disregulation (low blood pressure) 36 Treatment of PD Dopaminergic drugs Used to “replace” dopamine in the brain Taken orally Sinemet® Carbidopa/Levodopa Levodopa is converted to dopamine in the brain Dramatically improves symptoms Often effective for several years before drug resistance sets in Dopaminergic type drugs Ergot alkaloid drugs that act at dopamine receptor Bromocriptine (Parlodel) Cabergoline (Dostinex®) Ropinirole (Requip®) 37 The Immune System Consists of two types Humoral Immunity Cell mediated Immunity Humoral Immunity Involves blood proteins Is recruited when physical barriers like the skin are breached Complement proteins are proteins in the blood that recognize bacterial cells and other microorganisms. They basically open holes in those cells and allow osmosis of water to lyze and kill them Antibodies These are proteins that are secreted by an activated B lymphocyte called a plasma cell. Antibodies are highly specific for the bacteria, fungi, protozoa that they target 38 Cell Mediated Immunity Immune reactions that are carried out by cells Macrophages are cells that engulf and “swallow” invader cell, bacteria and particles Neutrophils are cells that destroy invaders by engulfing these invaders and destroying them by reactive chemical contain oxygen radicals. Sometimes this process causes the rapture of the cell and causes inflammation B lymphocytes are cells that make antibodies to an given antigen (a marker on an invader) T lymphocytes are cells that orchestrate and guide the immune response CD4 or helper T cells help B cells make antibodies and are very important in the immune response. They are the targets for the HIV virus CD8 cells are cells that recognize viral infected cells are carry out an attack on these cells. They kill these cells to spare the host organism. NK Cells are cells that are similar to CD8 cells. These cells are important in cancer. 39 Pathogens Bacteria are unicellular organisms that are know to be the simplest form of life. They grow and divide and require nutrition. Most bacteria are harmless but some are virulent pathogens to humans. Broadly speaking bacteria are divided into gram positive and gram negative depending a their cell wall chemistry Bacteria are aerobic and some are anaerobic Some are defined as fastidious and non fastidious (which means that some require a special growth medium) Brucella requires blood agar Some are intracellular parasites (they live inside the cell) Examples are chlamydia and Brucella and Rickettsia 40 Serious Bacterial Infections Bacterial Meningitis Caused by Neisseria Meningitidis, Streptococcus, Streptococcus species Mortality is high even with treatment Bubonic Plague Caused by Yersinia pestis, a gram negative intracellular bacterium Caused the black death in Europe during the 14th century that killed millions Today easily treated with fluoroquinolones Tuleremia Caused by Francisella Turensis (gram negative) Infects macrophages Carried to every organ in the body 10-20% mortality Fluoroquinolones, aminoglycosides, and tetracycline can be used 41 Flesh Eating Disease Called Necrotizing Fasciitis Commonly caused by a strain of bacteria called Group A Streptococcus or Streptococcus pyogenes Other bacterial species can cause as well Since the late 1990’s MRSA is the second leading cause Infection begins in the skin (subcutaneous tissue) Spread is very fast to the connective tissue called the fascia, which is the coating to muscle cells Infection is by contact with contaminated sewage and water contaminated with bacteria Streptococcal exotoxin activates T cells to produce massive damage to muscle and skin IV high dose antibiotics are required 42 Viral Infections Virus are non living things who primary reason for existence is to make more copies of themselves Infect various cells. Each virus may have its own preference called a virus’ trophism Can be a DNA or RNA virus Antibiotics can not be used to treat these infections Antiviral Drugs Acyclovir Gancyclovir Ribavirin These drugs usually acted on a viral DNA or RNA polymerase blocking its action 43 Serious viral infections Hepatitis B DNA virus Causes acute and chronic disease of the liver Even with therapy, infection is life long Results in cancer or cirrhosis of the liver Ebola Hemorrhagic Fever Caused by the marburgviridae family of viruses Originally found near a region near the Ebola river in the congo in 1970’s New species of virus Infects primates and bats (most likely vector) Can be spread by airborne droplets and infect body fluids Characterized by coagulalopathy which massive bleed and shock 44 HIV infection Target of HIV is the CD4 lymphocyte HIV also shows trophism to the macrophage and a cell in the CNS called a microglial cell RNA virus that replicates inside of CD4 cell CD4 cells die as virus is released and starts a new round of infection. Infection can not be cured; the virus spread to macrophages which can live for years provides a life long viral reservoir. 45 Natural History of HIV infection Exposure to blood or bodily fluids through sexual contact and/or use of needles Prodromal stage Initial stage of infection: about 4 weeks patient develops signs of flu like symptoms Before this period no antibodies against HIV can be deteched After this febrile flu like state passes, patient is said to be seroconverted (i.e. will show detectable antibodies) Clinical latency The immune system temporarily subdue infection Can last between 2-10 years As virus replicates in CD4 cells, these cells die by rupture, apoptosis or attack by the CD8 cell As CD4 levels decline, opportunistic infection sets in 46 Acquired Immunodeficiency Syndrome Final Stage Occurs when CD4 levels have fallen to less than 200 cells/microliter And patient has one of the following Pneumocystic Pneumonia caused by a protozoan, Pneumocytis Jirovecci Esophageal candidiasis MAC infection Kaposi Sarcoma Burkitt’s Lymphoma Patient will usually die from one of these cancers or infections 47 Drugs used in HIV infections Reverse transcriptase inhibitors Block RNA reverse transriptase (NRTI) AZT, Zidovudine (Retrovir®) Abacavir (Ziagen®) Lamivudine (Epivir®) Approved for both HIV and HBV Emtricitabine (Emtriva®) also called FTC Tenofovir (Viread®) approved for both HIV and HBV These drugs also come in various combinations Combivir (AZT and Lamivudine) NNRTI Efavirenz (Sustiva®) Etravirine (Intelence®) 48 Protease Inhibitors Kaletra ® (lopinavir/Retrovir) Reyataz ®(atazanavir) Aptivus® (Tipranavir) Prezista ® (Darunavir) Lexiva ® (fosamprenavir) Inhibits viral enzyme HIV protease which assists in viral assembly 49 Fusion Inhibitors Prevent HIV from attaching to CD4 cells Pharmacology is very complex Prevents “fusion” of virus with the cell Drugs include: Enfurvirtide (Fuzeon®) a drug given by subcutaneous injection Maraviroc (Selzentry®) oral drug 50