The Endocrine System

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 • 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)

4. 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

5. Female hormones Drug Products • MOA: replaces estradiol in females • Indications: menopausal Sx, prevent osteoporosis,

6. Oral Contraceptives • Drugs that contain high doses of estradiol and/or progestins • MOA: high levels of hormones “tricks” the body to think its pregnant and ovulation don’t occurs • Indication: Birth control, vaginal bleeding control, endometriosis • Federal law mandates that the patient package insert be dispensed with Rx to patient in retail • 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 • Levonorgestrel is available as Plan B, or Next Step. • Take 1 tab as soon as possible after sex and 1 tablet 12 hours later

7. 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 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

8. Erectile Dysfunction Agents • Enzyme inhibitors of phosphodiesterase IV • Vasodilation of the penile blood vessels • Contraindicated in men taking nitrates for chest pain • Nitroglycerin • Isosorbide

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. Anti Obesity Drugs • Suppress hunger signals in the brain • Similar to amphetamines • Scheduled drugs except for orlistat

18. 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 • Drugs should not be stopped abruptly 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

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. 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

26. 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

27. Central Nervous System Drugs • Sedatives and Tranquiller: Drugs that cause depression of the reticular activating system in the brain. Differences in mechanisms of action. • Examples are • barbiturates: Phenobarbital (Luminal®) • Benziodiazepines: Chlordiazepoxide (Librium®), Diazepam (Valium®), Lorazepam (Ativan®), Alprazolam (Xanax®) • BDZ were developed in the 1960’s with the advent of librium®. BDZ are safer than barbiturates. Both dangerous with alcohol consumption. • Used in anxiety disorder, panic disorder, GAD, sleep disorders • Control Substance: CIV • Miscellanous agents in the class are zolpidem (Ambien®), zaleplon (Sonata®)

28. CNS Depressants • Benzodiazepines and Barbiturates • MOA: binds to GABA receptors in brain • Indications: sedation for anxiety and pre op use • Main Side Effect: drowiness, Dependence (CIV)

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. 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 Major side effects: Abnormal heart arrhthymias, hypotension, sedation, Extrapyramidal symptoms (Parkinson’s like) movement disorders

32. Second Generation Antipsychotics • The previous list of Antipsychotics had major side effects of hypotension, sedation, weight gain, erectile dysfunction, cardiac arrhythmias (Long QT) and EPS (Extra pyramidal Symptoms) • EPS is a movement disorder that is similar to Parkinson’s disease • Second generation drugs were developed to avoid EPS • A major side effects to these drugs are: risk of drug induced diabetes and weight gain. • Ziprasidone has the risk of cardiac arrhythmias (long QT) • Clozapine has the risk of fatal blood condition called agranulocytosis • (Very low white blood cell count) • FDA REMS requires registries set up to monitor this risk

33. 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)

34. 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®)

35. Antiepileptics • Indications: Drugs used to treat seizures. Off label use: Neuropathic pain • MOA: Many of the drugs block the sodium ion channel in nerves. • Main Side effects: Drugs in this group are known to cause birth defects • Levetiracetam is a known cause of SJS • Topiramate can cause kidney stones • For emergency tx: use diazepam or phenytoin IV

36. Phenytoin, Valproic acid, Levetiracetam and Diazepam are available as IV injections

37. Drugs used to treat Alzheimer Disease • Alzheimer disease is a degenerative neurological disease of primarily cholinergic neurons • Results in loss of memory, personality changes and complete loss of language skills

38. 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

39. 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 • 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.

40. 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

41. Serious Bacterial Infections • Bacterial Meningitis • Caused by Neisseria Meningitidis, Streptococcus, Streptococcus species • Mortality is high even with treatment • Flesh Eating Disease • Called Necrotizing Fasciitis • Commonly caused by a strain of bacteria called Group A Streptococcus or Streptococcus pyogenes • 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. Antibiotic mechanism of action • Penicillin and Cephalosporins: drugs inhibit the formation of the bacterial cell wall. Bacteria swell and die. Drugs are bactericidal • Macrolides: inhibits bacterial ribosomes and protein synthesis. Example includes erythromycin (E-Mycin®) and azithromycin (Zithromax®). Bactericidal or Bacteriostatic. • Tetracyclines: Bacteriostatic by inhibiting protein synthesis. • Fluroquinolones: Bactericidal. Binds to DNA gyrase • Aminoglycosides: (Gentamicin) Bactericidal by several mechanisms

43. Penicillins and Cephalosporins are classified as Beta Lactam antibiotics. • Very important antibiotics • Treats a wide variety of bacterial infections • Penicillins are several classes

44. Main Side Effects of penicllins/cephalosporins • Nausea/Vomiting • Diarrhea • Type I hypersensivity • Cephalosporins • Chemically similar to penicillins (Beta lactam) • Four generations • Excellent antibiotics • Similar side effects

45. Third and fourth generations are used to treat meningitis and hospital acquired infections and pneumonias

46. Fluoroquinolones • Must take oral forms of these drugs separate from antacids (Maalox) by 1-2 hours • Many drug interactions • Advised to limit the consumption of caffeine while on these drugs (ciprofloxacin more than others) • Used for URIs and UTI and GI tract infections • Fluoroquinolones are contraindicated in pregnant patients and patient younger than 18 years old • Cipro ® comes in IV, oral tablets, opthalmic and oral suspension

47. Tetracyclines • Broad spectrum antibiotic class • Effective for use in certain infections • Chlamydia and gonorrheal infections • Lyme Disease • Rocky Mountain Spotted Fever • Contraindicated in pregnant women and young children < 8 years old • CAUTION: never use expired tetracycline products. Toxin produces serious kidney damage • CAUTION: advise patient to wear protective clothing. Drugs are photosensitive chemicals

48. Macrolides and Ketolides • Commonly used to treat UTI like walking pneumonia and chronic bronchitis • Notorious for GI side effects • Contraindicated in patient with hepatic dysfunction and QTc prolongation (a EKG cardiac abnormality that can lead to VF and death) • Patient should take macrolides with food • CYP450 inhibitors- many drug interactions

49. Aminoglycosides • Used to treat severe life threatening infections • IV formulations of AG are toxic to the kidney and to cranial nerve VIII causing hearing loss (ototoxicity) • Requires monitoring of renal function and blood levels of these drugs

50. Miscellaneous Antibiotics