PCOL312LEC.pdf

R.A. Cuarteros PCOL312LEC┃1  Family History aof Cardiovascular Diseases Legends: Manifestations of End Organ Damage Topi...

R.A. Cuarteros PCOL312LEC┃1  Family History aof Cardiovascular Diseases Legends: Manifestations of End Organ Damage Topic Age Sub topic Obesity Sub Sub Topic Stress High Dietary Intake of Saturated Fats and so Part 1 Sedentary Lifestyle Hypertension ➔ Secondary hypertension ➔ It is the blood pressure elevated enough to perfuse tissues ◆ Resulting from an identifiable cause such as renal and organs disease or adrenal hyperfunction ➔ A systolic reading greater than or 130 mmHg and a ◆ This type usually develops between the ages of 30 diastolic reading equal to or greater than 90 mmHg and 50 Hypertension - most common cardiovascular disease Secondary Hypertension - may disease na nagccause ng QUESTION: Can Hypertension cause organ damage? pagtaas ng BP ○ ANSWER: Yes. In the Kidney, Heart, Brain, and ○ Diseases such as: Eyes 1. Pheochromocytoma - tumor in adrenal glands (Adrenal Hyperfunction) Types of Hypertension Iniincrease nya yung secretion ng NE (NT (Based on Blood Pressure) of SNS) → Increased level of NE may ➔ Normal Blood Pressure: 126mg/dl= (+) DM ➔ 2) Glycosylated Hemoglobin ◆ Glycosilated Hgb (>6.5%) ◆ Perform at least 2 determinations ◆ Measures the three-month average plasma glucose concentration ➔ GLUCOSE TRANSPORTERS ➔ 3) Oral glucose tolerance (OGGT) ◆ Give 75g anhydrous glucose ◆ 2 hour postprandial glucose (>200mg/dl=+ DM) ◆ It measures the body's ability to use a type of sugar, called glucose, that is the body's main source of energy. ➔ 4) Random blood glucose/ Plasma glucose ◆ RPG (> 200mg/dl or 11.1 mmol/L= (+) DM) ◆ It is performed from non-fasting patients. NON-PHARMACOLOGIC INTERVENTION ➔ 1. MEAL PLANNING ➔ Used in patients who present initially with very high blood ◆ Carbohydrates should be included at all meals if glucose levels, especially with weight loss. taking medications with the potential to cause ➔ Used in patients who have failed to respond oral therapy. hypoglycemia. Types: ◆ Consistency in meal and medication schedules will 1) Based on source help to ensure more even glucose levels. ➔ ANIMAL SOURCE ➔ 2. WEIGHT LOSS ◆ Bovine and Porcine Insulin ◆ A modest amount of weight loss can have a More immunogenic (it can cause hypersensitivity significant effect on blood glucose levels, especially reactions)= it is already obsolete early in the course of the disease when the primary ➔ RECOMBINANT INSULIN cause of hyperglycemia is insulin resistance. ◆ Recombinant DNA is a technology scientists ➔ 3. PHYSICAL ACTIVITY developed that made it possible to insert a human ◆ Adults with diabetes= 150 minutes per week of gene into the genetic material of a common moderate-intensity aerobic physical activity. bacterium. INSULIN ◆ This “recombinant” micro-organism could now ➔ One of the hormone produce in the pancreas (consists of produce the protein encoded by the human gene. approximately 1 million islets of Langerhans) ◆ It is less immunogenic ➔ PRECURSOR: PRO INSULIN ◆ Examples: ◆ (1) Stimulates GLUCOKINASE-àglycolysis (1) Native insulin (Human Insulin, NPH/ Isophane ◆ (2) Causes translocation of glucose transporters insulin, Insulin Zn suspension) (facilitates the entry of glucose into the cell) (2) Modified insulin R.A. Cuarteros PCOL312LEC┃18  Insulin-Lispro, Aspart, Gluisine Protamine- ◆ 4) Insulin Determir- with peak Lispro, Aspart Insulin- Glargine, Detemir ◆ TIMING: given once a day 2) Based on the use ◆ Zinc is known to play a major role in the stabilization ➔ 1) Basal insulin- given to provide glucose control over 24 of insulin hexamers and in the pancreatic storage of hours (Intermediate-long acting) insulin because it can enhance insulin binding to ➔ 2) Demand insulin- given to prevent postprandial hepatocyte membranes hyperglycemia (short acting) INSULIN DELIVERY SYSTEMS ➔ Postprandial or reactive hyperglycemia occurs after eating ➔ (1) using conventional disposable needles and syringes. (postprandial means "after eating") ➔ (2) Continuous Subcutaneous Insulin Infusion 3) Based on duration of action ◆ Devices (Csii, Insulin Pumps) ➔ A. SHORT ACTING W/ RAPID ONSET ◆ user-programmable pump ◆ Regular insulin ◆ Approved for use: Velosulin, Insulin aspart short-acting soluble crystalline zinc insulin ➔ (3) Inhaled Insulin finely powdered and aerosolized insulin Only insulin administered IV ➔ (4) Insulin Pen Used in the management of diabetic INITIATION OF INSULIN THERAPY ketoacidosis and when the insulin requirement is ➔ Type I DM patients received an average total dose of changing rapidly, such as after surgery or during about 40 units insulin a day. acute infections. ➔ Because type II DM patients are insulin resistant, they require more insulin. onset peak duration ➔ Those who are severely hyperglycemic and obese may be Regular 30 mins 2-3 hrs 5-8 hrs started on about 40 units insulin a day. insulin UNDESIRABLE EFFECTS OF INSULIN THERAPY ➔ Hypoglycemia insulin lispro 5-15 mins 1 hr 3-5 hrs ➔ “TIRED” (Humalog) ➔ Tremors, Tachycardia ➔ Irritability insulin aspart 10-20 mins 1 hr 3-5 hrs ➔ Restless (Novolog) ➔ Excessive hunger ➔ Diaphoresis, Depression decreases the risk of late post-meal ➔ Redness hypoglycemia. ➔ Swelling at the injection ➔ B. INTERMEDIATE ACTING ➔ site ◆ 1) Lente (Monotard)- 70% ultralente & 30% ➔ Lipodystrophy semilente ➔ Urticaria ◆ 2) NPH (Humulin N, Insulatard)- contains insulin and ➔ Weight gain protamine (no excess of Protamine) O.H.A. OF INSULIN THERAPY ◆ 3) Protamine Lispro ➔ Drug treatment should be added only when diet, physical ◆ 4) Protamine Aspart activity and education have not achieved individual ◆ Duration: 10-16 HRS treatment targets. ◆ TIMING: 2x/day ➔ (1) Insulin releasers/Secretagogues ◆ This helps control nocturnal hepatic glucose ◆ SULFONYLUREAS and MEGLITINIDES production. Starting the day with lower morning ➔ (2) Insulin sensitizers- glucose levels will improve glucose tolerance ◆ decrease insulin resistance (BIGUANIDES, throughout the day. THIAZOLIDINEDIONES) ➔ C. LONG ACTING WITH SLOW ONSET ◆ 1) Ultralente = extended insulin zn suspension ◆ 2) PZI (Protamine Zinc Insulin) ◆ 3) Insulin Glargine (Lantus)- “peak less insulin” Classification of O.H.A. Insulin releasers/ A. SULFONYLUREAS Secretagogues ○ 1st line drug treatment in type 2 DM patients who are not very obese. Mechanism of Action: Stimulates insulin release from the pancreatic beta cells ○ Two additional mechanisms: R.A. Cuarteros PCOL312LEC┃19  1) a reduction of serum glucagon levels 2) closure of potassium channels in extra pancreatic tissues. ○ Drugs: A. FIRST GENERATION: Less potent and more A/Es 1. Chlorpropamide (Diabinese)= the longest duration of action (60 HRS) half life: 32 hrs 2. Acetohexamide (Dymelor) = with diuretic and uricosuric activity 3. Tolbutamide (Orinase) = shortest duration of action, safe among elderly 4. Tolazamide B. SECOND GENERATION: More potent and less A/Es 1. Glibenclamide (Euglucon) 2. Gliclazide (Diamicron) 3. Glimepiride (Solosa)= has the longest T ½ Once a day dosing is applicable. 4. Glipizide (Glucotrol)= has the shortest T ½ 5. Glyburide ○ CONTRAINDICATIONS: 1. Pregnant, lactating and children (it can be secreted in the milk) 2. Not for px with allergy to sulfa drugs 3. Not for stressful conditions such as infection, injury or surgery (use insulin) ○ SIDE EFFECTS: 1. Hypoglycemia 2. Disulfiram like reaction 3. Nausea and vomiting 4. GI discomfort 5. Agranulocytosis and anemia 6. Dilutional Hyponatremia (Chlorpropamide) 7. Cardiotoxicity B. MEGLITINIDES ○ Short duration of action ○ Used to prevent post prandial hyperglycemia ○ Drugs: 1) Repaglinide (Prandin, Novonorm) ­ 0.25mg-4mg before meals 2) Nateglinide (Starlix)- 60-120mg before meal INSULIN SENSITIZERS BIGUANIDES ○ AKA: Euglycemic agents ○ Enhances insulin sensitivity and glucose uptake in the liver and muscles ○ Reduces TG and LDL and increases HDL ○ Proven to reduce mortality ○ Taken before meals to reduce GI effects ○ Drugs: 1. Metformin (Glucophage 500mg & 750mg), 2. Buformin 3. Phenformin ○ CLINICAL USES: (1) 1st line in the management of Type 2 DM (only drug approved for the mgt of prediabetes) (2) Mgt. of polycystic ovarian syndrome (PCOS) (3) Useful as 1st line therapy in the obese, and are recommended as 1st line therapy in non-obese subjects in some country. ○ ADVERSE EFFECTS: Diarrhea (most common) Nausea and vomiting GI effects is resolved after chronic use and taken before meals R.A. Cuarteros PCOL312LEC┃20  Decrease absorption of Vit. B12 (long term use) ○ CONTRAINDICATIONS: 1) renal disease, alcoholism, hepatic disease, or conditions predisposing to tissue anoxia (eg: chronic cardiopulmonary dysfunction) 2) increased risk of lactic acidosis induced by biguanide THIAZOLIDINEDIONES ○ Mechanism of Action: Activate PPAR-y, a nuclear transcription factor for fat cell differentiation and fatty acid metabolism. Enhance insulin sensitivity in muscle, liver and fat tissues. ○ Drugs: 1. Rosiglitazone (Avandia)= 2-8mg once daily 2. Pioglitazone (Actos)= 15-45mg once daily 3. Troglitazone- banned due to hepatotoxicity ○ S/E: Hepatoxicity, fluid retention and weight gain ALPHA GLUCOSIDASE Drugs INHIBITORS ○ 1. Acarbose (Precose, Glucobay, Gluconase) ○ 2. Voglibose (Basen) ○ 3. Miglitol (Glyset) Retards absorption CHO by preventing the breakdown of sucrose and complex CHO in the intestines. Use to prevent postprandial hypergylcemia Take with first bite of meal A/E: Flatulence, Diarrhea, Abdominal pain INCRETINS ANALOG & GI hormones secreted in response to oral glucose load. INHIBITOR OF Effects: increase insulin secretion and decrease glucagon secretion METABOLISM Drugs: GLP-1 (Glucagon like polypeptide) ○ A) GLP-1 AGONISTS 1. Exenatide, 2 Liraglutide (SQ for Type 2 DM) ○ B) DPP IV inhibitors 1. Sitagliptin 2. Linagliptin 3. Vildagliptin AMYLIN ANALOG Drug: ○ 1. Pramlintide (SQ) Given as an add on to patients on insulin § For type 1 DM § It suppress Glucagon release A/E: increase risk of hypoglycemia GLUCAGON Glucagon is synthesized in the α cell of the pancreatic islets of Langerhans Cardiac Effects ○ Glucagon has a potent inotropic and chronotropic effect on the heart, mediated by the cAMP mechanism. Effects on Smooth Muscle ○ produce profound relaxation of the intestine. Blood sugar ○ Increase blood sugar level. Bind to specific receptors on liver cells → increase in adenylyl cyclase activity and the production of CAMP → facilitates catabolism of stored glycogen and increases gluconeogenesis and ketogenesis. R.A. Cuarteros PCOL312LEC┃21  CLINICAL USES: ○ 1. Emergency tx of severe hypoglycemic reactions in patients with type 1 diabetes ○ 2. Used in overdosage of beta blockers ○ 3. Used as an aid to x-ray visualization of the bowel because of its ability to relax the intestine. R.A. Cuarteros PCOL312LEC┃22  ◆ (c) Hormonal: stimulation received from other Legends: hormones Topic Sub topic HYPOTHALAMUS Sub Sub Topic ○ It is the master endocrine organ ○ It secretes releasing/inhibiting hormones ENDOCRINE SYSTEM PITUITARY GLAND ➔ System of ductless glands that secrete hormones ○ Consists of an anterior lobe (tropic hormone) and ◆ Hormones are “messenger molecules” a posterior lobe (doesn’t produce hormone —> ◆ Circulate in the blood used only for storage of hormones like ◆ Act on distant target cells vasopressin and oxytocin) ◆ Target cells respond to the hormones for which they ○ Connected to hypothalamus by a stalk of have receptors neurosecretory fibers and blood vessels, including ◆ The effects are dependent on the programmed a portal venous system that drains the response of the target cells hypothalamus and perfuses the anterior pituitary. ◆ Hormones are just molecular triggers ○ The posterior lobe hormones are synthesized in the hypothalamus and transported via the Hormones are classified into two neurosecretory fibers in the stalk of the pituitary ○ Based on chemical structure to the posterior lobe, from which they are Amino Acid Base released into the circulation. Steroids ○ Sits in hypophyseal fossa: depression in sella ○ Based on location (either synthesize & stored) turcica of sphenoid bone Pituitary secretes 9 Anterior hormones Posterior ○ Two divisions: Purely endocrine organs Anterior pituitary (adenohypophysis) ➔ Pituitary gland - secretes “stimulating hormones” TSH - Thyroid Stimulating Hormone ➔ Pineal gland ACRH -Adrenocorticotropic Hormone ➔ Thyroid gland FSH - Follicle Stimulating Hormone ➔ Parathyroid glands LH - Luteinizing Hormone ➔ Adrenal: 2 glands PRL - Prolactin ➔ Cortex MSH - Melanocyte Stimulating Hormone ➔ Medulla ***the first five are “tropic” hormones, they regulate the Endocrine cells in other organs function of other hormones ➔ Pancreas Posterior pituitary (neurohypophysis) ➔ Thymus - behind the breast bone ADH - Antidiuretic Hormone or ➔ Gonads Vasopressin ➔ Hypothalamus - master gland that secretes “releasing Oxytocin hormone” HORMONAL AGENTS HORMONES ➔ Drugs that mimic or block the effects of hypothalamic and ➔ The control of metabolism, growth, and reproduction is pituitary hormones have pharmacologic applications in mediated by three primary areas: ➔ a combination of neural and endocrine systems located in ◆ as replacement therapy for hormone deficiency the states (analogs) ➔ hypothalamus and pituitary gland. ◆ as antagonists for diseases caused by excess ➔ Mechanisms of hormone release production of pituitary hormones (inhibitors) ◆ (a) Humoral: in response to changing levels of ions ◆ as diagnostic tools for identifying several endocrine or nutrients in the blood abnormalities. ◆ (b) Neural: stimulation by nerves R.A. Cuarteros PCOL312LEC┃23  HCG - human chorionic gonadotropin Somatostatin others ○ hormone produce during pregnancy and (−) can be detected using pt kits [neuroendocrin e inhibitory] Thyroid Thyrotropin-rele Thyroid Thyroxine, Stimulating asing hormone triiodothyron hormone (TRH) (+) ine (TSH) Adrenocortic Corticotropin-rel Adrenal Cortisol otropin easing hormone cortex (ACTH) (CRH) (+) Follicle Gonadotropin-r Gonads Estrogen, Stimulating eleasing [refers to progesteron hormone hormone the e, (FSH) (GnRH) (+) reproduct testosterone Luteinizing [regulate ive gland; ANTERIOR PITUITARY HORMONES hormone reproduction in which Anterior Hypothalamic Target Primary (LH) males and produces Pituitary Hormone Organ Target Organ females germ cells Hormone Hormone or either Mediator ovary or testes] Growth Growth Liver, Insulin-like hormone hormone bone, growth Prolactin Dopamine (−) Breast ------ (GH) releasing muscle, factor-I (PRL) hormone kidney, (IGF-I) (GHRH) (+) and Anterior Pituitary Hormone GROWTH Also known as SOMATOTROPIN HORMONES Its effects are primarily mediated by regulating the production in peripheral tissues of insulin-like growth factor 1 (IGF-1) Required during childhood and adolescence for: ○ Attainment of normal adult size. ○ Important effects throughout postnatal life. ○ Lipid and carbohydrate metabolism. ○ Lean body mass and bone density. Hormones that can increase glucose in the blood ○ Growth Hormone ○ Epinephrine ○ Glucagon ○ Cortisol Medicinal GH was isolated from the pituitaries of human cadavers. It is contaminated with prions that could cause Creutzfeldt-Jakob disease. ○ Somatropin (the recombinant form of GH) GH from cadaver ○ Somatrem (equivalent drug of GH) recombinant GH “LAB GROWN” used in GH deficiency DEFICIENCY R.A. Cuarteros PCOL312LEC┃24  ○ BEFORE PUBERTY: Dwarfism ○ AFTER PUBERTY: Obesity, increase risk of CV death CAUSES: ○ can have a genetic basis ○ can be acquired as a result of damage to the pituitary or hypothalamus. ○ Breech or traumatic delivery ○ Intracranial tumors & infection USES OF GROWTH HORMONES ○ 1) Prader-Willi syndrome - an autosomal dominant genetic disease associated with growth failure, obesity, and carbohydrate intolerance. ○ 2) Turner syndrome (45 X karyotype and variants) can cause female infertility ○ 3) Idiopathic short stature (ISS) ○ 4) Anti-aging remedy ○ 5) Use by athletes for a purported increase in muscle mass and athletic performance. TOXICITY OF GROWTH HORMONES ○ 1. Progression of scoliosis ○ 2. Edema ○ 3. Hyperglycemia ○ 4. Increased risk of otitis media Drugs GH Deficiency ○ IGF 1 - primary target organ hormone or mediator of GH DRUGS CLINICAL USE: ADVERSE EFFECTS: Mecasermin Treatment of severe IGF-I Hypoglycemia by consumption Mecasermin rinfabate deficiency that is not responsive of a snack or meal shortly to GH before mecasermin administration GH Excess ○ ACROMEGALY Excess of GH while the epiphyseal plates are close Unproportional features like hands and feet ○ GIGANTISM Excess of GH while the epiphyseal plates are open Proportional features like hands and feet ○ TREATMENT FOR EXCESSIVE GH: 1. Somatostatin analogs Inhibits the release of GH, glucagon(secretes in alpha cells), Insulin (secretes in beta cells) , Gastrin 2. Dopamine receptor agonists, which reduce the production of GH Bromocriptine 3. Pegvisomant - GH receptor antagonist DRUGS CLINICAL USE: ADVERSE EFFECTS: Somatostatin Inhibits the release of GH, TSH, Hyperglycemia glucagon, insulin, and gastrin. Octreotide Nausea, vomiting, abdominal Lanreotide cramps, flatulence, and steatorrhea Vitamin B12 ** most widely used deficiency somatostatin analog R.A. Cuarteros PCOL312LEC┃25  Pegvisomant GH receptor antagonist ** used to treat acromegaly GONADOTROPIN GONADOTROPINS ANALOG ○ These hormones serve complementary functions in the reproductive process. Follicle stimulating hormone (FSH) Luteinizing hormone (LH) HORMONE EFFECTS MEN WOMEN FSH ▪ Primary regulator of ▪ Ovarian follicle development spermatogenesis ▪ In the ovary- stimulates the ▪ Stimulates the conversion of conversion of androgens to testosterone to estrogen. estrogens LH ▪ Main stimulus for testosterone ▪ In the ovary - stimulates androgen synthesis production ▪ Estrogen and progesterone production * if pregnancy occurs, estrogen and progesterone production is under the control of human chorionic gonadotropin (hCG). Drugs: 1) MENOTROPINS ○ Human menopausal gonadotropins (hMG) ○ It is extracted from the urine of postmenopausal women ○ purified extract of FSH and LH 2) FSH ANALOG ○ Available forms of purified FSH: Urofollitropin - purified preparation of human FSH extracted from the urine of postmenopausal women ○ Recombinant forms of FSH Follitropin alfa Follitropin beta 3) LH ANALOG ○ Lutropin alfa - recombinant form of human LH ○ Lutropin has only been approved for use in combination with follitropin alfa for stimulation of follicular development in infertile women with profound LH deficiency 4) HUMAN CHORIONIC GONADOTROPIN ○ produced by the human placenta and excreted into the urine ○ Choriogonadotropin alfa recombinant form of hCG approved for the treatment of prepubertal cryptorchidism CLINICAL USES: ○ used in states of infertility: ○ Men- stimulate spermatogenesis ○ Women - induce ovulation TOXICITY: ○ Ovarian hyperstimulation syndrome ○ ovarian enlargement ○ Multiple pregnancies R.A. Cuarteros PCOL312LEC┃26  GnRH ANALOG secreted by neurons in the hypothalamus. Gonadorelin - acetate salt of synthetic human GnRH GnRH Agonist Synthetic analogs/GnRH agonists long acting: ○ goserelin ○ Histrelin ○ leuprolide ○ nafarelin ○ nafarelin CLINICAL USES: ○ 1. Female infertility ○ 2. Male infertility ○ 3. Prostate cancer ○ 4. Controlled ovarian hyperstimulation ○ 5. Endometriosis - syndrome of cyclical abdominal pain in premenopausal women that is due to the presence of estrogen sensitive endometrium-like tissue outside the uterus. TOXICITY OF GnRH ANALOG ○ 1. Women Symptoms of menopause: hot flushes, sweats, headaches. Ovarian cysts Reduced bone density and osteoporosis ○ 2. Men hot flushes and sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density GnRH Antagonist ○ inhibit the secretion of FSH and LH ○ Drugs Ganirelix Cetrorelix Degarelix ○ CLINICAL USES: 1. Suppression of Gonadotropin Production 2. Advanced prostate cancer SEX HORMONES Hormones that play an essential role in sexual development and reproduction. The main glands that produce sex hormones are the adrenal glands and the gonads, which include the ovaries in females and testes in males. TESTES: Testosterone OVARIES: Estrogen & Progesterone PROLACTIN ○ The principal hormone responsible for lactation ○ Dopamine (prolactin-inhibiting hormone) ○ Hyperprolactinemia - a syndrome of amenorrhea and galactorrhea in women, and loss of libido and infertility in men. Female Hormones A. ESTROGEN ○ Drugs: 1. Estrone This type of estrogen is present in the body after menopause. It is a weaker form of estrogen and one that the body can convert to other forms of estrogen, as necessary. 2. Estradiol Both males and females produce estradiol, and it is the most common type of estrogen in females during their reproductive years. R.A. Cuarteros PCOL312LEC┃27  3. Estriol Levels of estriol rise during pregnancy, as it helps the uterus grow and prepares the body for delivery. Estriol levels peak just before birth. ○ FUNCTIONS: Ovary- stimulate growth of egg follicle Vagina- maintains thickness & promoteLubrication Uterus- maintains the mucous membrane that lines the uterus Breast- formation of breast tissue. ○ SYNTHETIC ESTROGEN Ethinyl estradiol, diethylstilbestrol Uses: 1. Oral contraceptive 2. Post menopausal syndrome 3. Acne 4. Prostate cancer 5. Off-label use: Increased female sex hormone (transgender) ○ ANTI-ESTROGEN ESTROGEN RECEPTOR BLOCKERS: Tamoxifen (Nolvadex) Clomiphene (Clomid) Use: adjuvant therapy for Breast CA. SERM (Selective Estrogen Receptor Modulator) Raloxifene (Evista) Use: reduce bone resorption in osteoporosis. AROMATASE INHIBITORS Anastrozole (Arimidex, Anazole) Letrozole (Femara) Used for BREAST CANCER B. PROGESTERONE ○ A female sex hormone that is produced mainly in the ovaries following ovulation each month. ○ FUNCTIONS: crucial part of the menstrual cycle maintenance of pregnancy (For endometrial growth for implantation) Breast development and breast feeding ○ Synthetic Progesterone Levonorgestrel, Norethindrone, Norethindrone Uses: 1. Contraceptive 2. Dysmenorrhea 3. Endometriosis ○ PROGESTIN ANTAGONISTS: Mifepristone (abortifacient) TYPES OF CONTRACEPTIVES ○ 1. POST COITAL CONTRACEPTIVES “Morning after pills” Ethinyl estradiol + Norgestrel Conjugated Estrogen, Estrone ○ 2. CHEMICAL CONTRACEPTIVES Gossypol- destroys seminiferous tubule ○ 3. COMBINATION CONTRACEPTIVES Monophasic, Biphasic or Triphasic Contains two hormones (estrogen and progestogen) Prevents the release of eggs from the ovaries (ovulation) ○ 4. PROGESTIN ONLY CONTRACEPTIVES: R.A. Cuarteros PCOL312LEC┃28  Minipill- Norethindrone + Norgestrel Implant- Norgestrel 216mg (Norplant) IM- Medroxyprogesterone (Depo-Provera) Intrauterine- Progestasert ○ Thickens cervical mucous to block sperm and eggs from meeting and prevent ovulation NATURAL METHOD OF CONTRACEPTION ○ TEMPERATURE METHOD Falling to rising temperature Abstinence 5 days after onset ofmenses until 3 days after transition of temperature ○ CERVICAL MUCUS METHOD Billing’s method Normal: Thick, creamy white Ovulation: clear and tenacious (eggwhite) Abstinence 3-4 days after peak change ○ CALENDAR METHOD Women tabulate menstrual period for at least 1 year. Male Hormones A. ANDROGENS ○ The male hormone (but it is also present in female in small amount) ○ Present in both males and females, the principle androgens are testosterone, dihydrotestosterone and androstenedione. ○ ROLES: 1. Inc. muscle mass (Abused by athletes), secondary characteristic in males 2. Play a role in male traits and reproductive activity. 3. Regulate sex drive (libido) 4. Regulate production of sperm cell ○ ANABOLIC STEROIDS synthetic, or human-made, variations of the male sex hormone testosterone Example: Nandrolone (19-Nortestosterone) Oxandrolone (Anavar) Stanozolol- derivative of dihydrotestosterone Trenbolone acetate- used in veterinary practice Uses: 1) Hypogonadism 2) Infertility 3) Impotence 4) Osteoporosis 5) Performing-enhancing drugs (abused by athletes) ○ ANTI-ANDROGENS ALPHA REDUCTASE INHIBITOR Finasteride (Propecia, Proscar, Altepros) for BPH and alopecia ANDROGEN RECEPTOR BLOCKER Flutamide, Bicalutamide, Nilutamide For prostate cancer ADRENAL Hormones produced in the adrenal gland. HORMONES Adrenal cortex ○ Secretes lipid-based steroid hormones, called “corticosteroids” ­ “cortico” as in “cortex” ○ MINERALOCORTICOIDS - Aldosterone is the main one 1. ALDOSTERONE the main mineralocorticoid R.A. Cuarteros PCOL312LEC┃29  Secreted by adrenal cortex in response to a decline in either blood volume or blood pressure (e.g. severe hemorrhage) ○ Is terminal hormone in renin-angiotensin mechanism (RAAS) Prompts distal and collecting tubules in kidney to reabsorb more sodium ○ Water passively follows ○ Blood volume thus increases ○ GLUCOCORTICOIDS - Cortisol (hydrocortisone) is the main one 1. CORTISOL the most important glucocorticoid Glucocorticoid receptors are found in the cells of most vertebrate tissues) It is essential for life Helps the body deal with stressful situations within minutes ○ Physical: trauma, surgery, exercise ○ Psychological: anxiety, depression, crowding ○ Physiological: fasting, hypoglycemia, fever, infection Regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions including water balance People with adrenal insufficiency: these stresses can cause hypotension, shock and death: must give glucocorticoids, eg for surgery or if have infection, etc. Keeps blood glucose levels high enough to support brain’s activity ○ Forces other body cells to switch to fats and amino acids as energy sources Catabolic: break down protein Redirects circulating lymphocytes to lymphoid and peripheral tissues where pathogens usually are In large quantities, depresses immune and inflammatory response ○ Used therapeutically ○ Responsible for some of its side effects Adrenal medulla ○ Secretes epinephrine and norepinephrine PROLACTIN The principal hormone responsible for lactation Dopamine (prolactin-inhibiting hormone) Hyperprolactinemia - a syndrome of amenorrhea and galactorrhea in women, and loss of libido and infertility in men. TREATMENT FOR HYPERPROLACTINEMIA Drugs ○ Ergot alkaloids: Bromocriptine Cabergoline Pergolide MOA: Dopamine agonists (suppress prolactin release) ADVERSE EFFECTS: nausea, headache, light- headedness, orthostatic hypotension, and fatigue ○ Non Ergot : Quinagolide (same lang din ang moa at ae sa ergot alkaloids) POSTERIOR PITUITARY HORMONES Oxytocin Milk ejection Uterine Hormone Effects contraction Vasopressin (ADH) Water reabsorption in kidney tubules OXYTOCIN During the second half of pregnancy, uterine smooth muscle shows an increase in the expression of oxytocin receptors and becomes increasingly sensitive to the stimulant action of endogenous oxytocin. CLINICAL USES: ○ induce labor R.A. Cuarteros PCOL312LEC┃30  ○ control of uterine hemorrhage after vaginal or cesarean delivery. ANTAGONISTS: ○ Atosiban - treatment for preterm labor (tocolytic) VASOPRESSIN Also known as anti-diuretic hormone. lay essential roles in the control of the body's osmotic balance, blood pressure regulation, sodium homeostasis, and kidney functioning. Receptor: V1- blood vessels (vasoconstriction) V2- kidney (water absorption) Deficiency results in diabetes insipidus ○ Central (Neurogenic DI)- DEC ADH (Tx: vasopressin, desmopressin) ○ Nephrogenic DI- normal/ elevated ADH. Destruction of V2 (Tx: Thiazide diuretics) Desmopressin acetate - synthetic analog of vasopressin. ○ CLINICAL USES: treatments of choice for pituitary diabetes insipidus TOXICITY: ○ 1) Headache, nausea, abdominal cramps, agitation, and allergic reactions ○ 2) hyponatremia and seizures ○ 3) Vasopressin (but not desmopressin) can cause vasoconstriction ANTAGONISTS: ○ Conivaptan and Tolvaptan - approved by the FDA for intravenous administration in hyponatremia R.A. Cuarteros PCOL312LEC┃31  thyroglobulin molecule are iodinated to form MIT and DIT Legends: —> Coupling - Two molecules of DIT combine to form T4. Topic One molecule of MIT (Monoiodotyrosine) and one Sub topic molecule of DIT combine to form T3 —> T4 and T3 are Sub Sub Topic released from thyroglobulin by exocytosis and proteolysis of thyroglobulin THYROID GLAND ➔ Anterior neck on trachea just inferior to larynx ➔ Two lateral lobes and an isthmus ➔ Produces two hormones ➔ Thyroid hormone: tyrosine based with 3 or 4 iodine molecules ◆ T4 (thyroxine) and T3 ➔ Calcitonin involved with calcium and phosphorus metabolism ➔ Thyroid is composed of spherical follicles ◆ Follicle cells: produce thyroglobulin, the precursor of thryoid hormone (thyroxin) Colloid lumen is of thyroglobulin ◆ Parafollicular “C” cells: produce calcitonin THYROID PHYSIOLOGY ➔ Thyroid hormones: ◆ 1. Triiodothyronine & Tetraiodothyronine normalize growth and development, body PROTEIN BINDING temperature, and energy levels. ➔ When in the circulation, thyroid hormone transported is ◆ 2. Calcitonin bound to several plasma proteins, a process that: important in the regulation of calcium ◆ Helps to protect the hormone from premature metabolism metabolism and excretion ➔ they seem to activate the mRNA transcription process and ◆ Prolongs its half-life in the circulation can promote protein synthesis or (in excessive amounts) T3 - 1 to 3 days protein catabolism. T4 - 7 to 10 days ➔ Thyroid hormones affect the following: ◆ Allows the thyroid hormone to reach its site of ◆ Growth and development action. ◆ Calorigenics by increasing the rate of basal ➔ Most thyroid hormone is transported by metabolism THYROXINE-BINDING GLOBULIN (TBG). ◆ CVS = by increasing the metabolic rate, which ➔ Prealbumin and albumin also serves as carriers. increases blood flow, cardiac output, and heart rate METABOLISM ◆ The CNS by increasing or diminishing cerebration ➔ SITES of Peripheral conversion of T3 and T4 cerebration of the brain/ the process of thinking ◆ pituitary gland BIOSYNTHESIS OF THYROID HORMONE ◆ Liver ➔ Synthesis & release is regulated by negative feedback ◆ kidneys mechanism ➔ accounts for about 80% of T3 generation. ➔ Iodide is transported into the thyroid gland by the ➔ DEIODINATION sodium/iodide symporter (NIS) —> Second I­ transport ◆ it is the primary pathway for the peripheral enzyme (pendrin) controls the flow of iodide across the metabolism of thyroxine. membrane. (if pendrin is absent it may cause pendred’s ➔ Deiodination of T4 may occur by monodeiodination of the syndrome) —> iodide is oxidized by thyroidal peroxidase to outer ring, producing 3,5,3’ triiodothyronine (T3), which is iodine —> Iodide organification - tyrosine residues of three to four times more potent than T4. R.A. Cuarteros PCOL312LEC┃32  ➔ Alternatively, deiodination may occur in the inner ring, Myxedema coma is an end state of untreated producing 3,3',5'-triiodothyronine (reverse T3, or rT3), hypothyroidism. which is metabolically inactive ○ It is associated with progressive weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, water intoxication, shock, and death. ➔ Hashimoto’s disorder ◆ autoimmune thyroid diseases (AITDs) and is characterized by the destruction of thyroid cells ➔ Goiter ◆ lodine deficiency is the main cause of goiters. When you don't have enough iodine, the thyroid works extra hard to make thyroid hormone, causing the gland to grow larger. ➔ Endemic and Sporadic goiter ◆ ENDEMIC GOITER results from inadequate intake of dietary iodine. This is common in regions with iodine-depleted HYPOTHYROIDISM soil and in areas of endemic malnutrition. ➔ inability of the thyroid gland to supply sufficient thyroid ◆ SPORADIC GOITER hormone. can follow ingestion of certain drugs or foods ➔ Causes: containing progoitrin, which is inactive and ◆ 1. Iodine deficiency converted by hydrolysis to goitrin. ◆ 2. After thyroidectomy ➔ TOXIC NODULAR (multinodular goiter) ◆ 3. Radioactive iodine therapy (destruction of iodine) ◆ This type of goiter forms one or more small nodules ◆ 4. Drug induced= amiodarone as it enlarges. ➔ PRIMARY: ◆ The nodules produce their own thyroid hormone, ◆ due to gland destruction or dysfunction caused by causing hyperthyroidism. It generally forms as an disease or medical therapies (e.g., radiation, surgical extension of a simple goiter. procedures) DIAGNOSIS OF THYROID PROBLEM ◆ due to failure of the gland to develop or congenital ➔ 1. THYROID BLOOD TEST- done by withdrawing blood incompetence (i.e., cretinism from a vein in your arm. These blood tests help to ➔ SECONDARY diagnose thyroid diseases. ◆ due to a pituitary disorder that inhibits TSH ➔ 2. THYROID SCAN & ULTRASOUND- show the size and secretion. condition of your goiter, overactivity of some parts or ◆ The thyroid gland is normal but lacks appropriate whole thyroid. stimulation by TSH ➔ 3. BIOPSY- A biopsy is a procedure that involves taking ➔ TERTIARY: small samples of thyroid nodules if present. The samples ◆ a condition in which the pituitary-thyroid axis is are sent to a laboratory for examination. intact, but the hypothalamus lacks the ability to secrete TRH to stimulate the pituitary. ◆ Thyrotropin-releasing hormone (TRH), Is a hypophysiotropic hormone, produced by neurons in the hypothalamus, that stimulates the release of thyroid-stimulating hormone (TSH) and prolactin from the anterior pituitary. CONDITIONS OF HYPOTHYROIDISM ➔ Cretinism & Myxedema ◆ Cretinism CONGENITAL HYPOTHYROIDISM Physical and mental retardation DIAGNOSIS: Newborn screening ◆ MYXEDEMA Hypothyroidism in adults R.A. Cuarteros PCOL312LEC┃33 DRUGS: LEVOTHYROXINE BN: (Eltroxin , Euthyrox, Levoxyl, Levothroid, Synthroid) synthetic T4 PHARMACOKINETICS: ○ Should be taken 30min before or 1 hour after meals ○ Once a day dosing (Long half-life) ADVANTAGES OF LEVOTHYROXINE: ○ 1) stability ○ 2) content uniformity ○ 3) low cost ○ 4) lack of allergenic foreign protein ○ 5) easy laboratory measurement of serum levels, and long half-life (7 days), which permits once-daily administration. LIOTHYRONINE synthetic T3 BRAND NAMES: Cytomel, Triostat PHARMACOKINETICS: ○ Short half-life ○ Not used alone for long term treatment ○ Increase risk for cardiac side effects LIOTRIX FIXED RATIO PREPARATION 4:1 ratio (T4:T3) the T3 component proved unnecessary (because T4 is metabolized to T3) T3 component is also disadvantageous because of T3-induced adverse effects. DESSICATED from animal source THYROID ratio of T3 and T4 Varies with the animal source. PREPARATIONS Porcine gland preparations have a higher T3 to T4 ratio than those from bovine sources. HYPERTHYROIDISM Conditions: ➔ Increase level of thyroid hormones. ➔ Exophthalmic goiter ➔ Thyrotoxicosis ➔ Grave’s disease ◆ tissue are exposed on high levels of thyrone ◆ autoimmune disorder ➔ Causes: ◆ that leads to overactivity of the thyroid gland ◆ Autoimmune disease = Grave’s disease (hyperthyroidism) ◆ Excessive ingestion of t3 and t4 (thyrotoxicosis ◆ lymphocytes secrete a TSH receptor-stimulating facticia) antibody (TSH-R Ab [stim]), also known as ◆ Drug induced: amiodarone, levothyroxine and thyroid-stimulating immunoglobulin (TSI). liothyronine ◆ The three primary methods for controlling ➔ S/SX: hyperthyroidism are: ◆ Weight loss 1. Antithyroid drug therapy ◆ Increase appetite 2. surgical thyroidectomy ◆ Diaphoresis 3. destruction of the gland with radioactive ◆ Palpitation iodine. ◆ Frequent diarrhea ➔ Thyroid storm ➔ is the clinical syndrome that results when tissues are ◆ Thyrotoxic crisis exposed to high levels of thyroid hormone ◆ An acute, life-threatening state induced by excessive release of thyroid hormones R.A. Cuarteros PCOL312LEC┃34  ◆ During thyroid storm, an individual's heart rate, ➔ Inorganic anions blood pressure, and body temperature can soar to ➔ lodides dangerously high levels. Without prompt, aggressive ➔ Radiocontrast dye treatment, thyroid storm is often fatal ➔ B-blockers and glucocorticoids Anti-thyroid Drugs ➔ Radioactive iodine ➔.Thioamides DRUGS: Thioamides Drugs: ○ Propylthiouracil ○ Methimazole (Tapazole, Tapadin) ○ Carbimazole MOA: ○ Inhibit The Enzyme Thyroid Peroxidase(Inhibit organification and coupling) ○ Blocks peripheral conversion of T4 to T3 (PTU) ○ Since The Synthesis Rather Than The Release Of hormones is affected, the onset of these agents is slow, often requiring 3­4 weeks before stores of T4 are depleted. PHARMACOKINETICS: ○ Almost completely absorbed in the GIT ○ Can cross placental barrier (lesser with PTU) q Methimazole 10x more potent than PTU ○ PTU more protein-bound USES: ○ 1. Used for treatment of mild thyrotoxicosis and in preparation of surgery. ○ 2. Propylthiouracil is relatively safe and preferred in pregnancy. ADVERSE EFFECTS: ○ maculopapular rash ○ agranulocytosis ○ hepatitis (PTU) ; cholestatic jaundice (Methimazole) ○ vasculitis Inorganic anions Drugs: ○ K perchlorate ○ K thiocyanate MOA: ○ Block uptake of iodide by the gland by competitive inhibition can be overcome by large doses of iodides useful for iodide-induced hyperthyroidism (amiodarone-induced hyperthyroidism) rarely used due to its association with aplastic anemia Iodides Drugs: ○ Strong iodine solution ○ Iodone ○ KISS MOA: ○ acutely blocks release of thyroid hormone from the gland by inhibiting thyroglobulin proteolysis (> 6 mg daily), ○ inhibit iodide organification USES: ○ 1. useful in thyroid storms: 2-7 days ○ 2. Preoperatively- iodides decrease vascularity, size and fragility of hyperplastic gland CAUTION: ○ The gland will escape from inhibition after 2-8 weeks ○ Chronic use in pregnancy should be avoided ­ fetal goiter ADVERSE EFFECTS: ○ They include acneiform rash (similar to that of brominism) R.A. Cuarteros PCOL312LEC┃35  ○ swollen salivary glands, mucous membrane ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic taste, bleeding disorders and, rarely, anaphylactoid reactions. IODINATED Drugs: CONTRAST DYE ○ Ipodate (oral) (Oragrafin) ○ Iopanoic acid (oral) (Telepaque) ○ Diatrizoate (intravenous) (Hypaque) MOA: ○ inhibits conversion of T4 to T3 in the liver, kidney, brain and pituitary ○ inhibition of hormone release Useful in thyroid storms (adjunctive therapy) β-blockers and DRUGS: glucocorticoids ○ β-blockers - Propranolol, Metoprolol, Atenolol ○ Glucocorticoids ­ Prednisone MOA: ○ MSA: inhibits T4 to T3 ○ Ameliorate many disturbing s/sxs of hyperthyroidism Radioactive iodine PREPARATIONS: ○ (I 131) sodium iodide 131 * the only isotope used in treatment of thyrotoxicosis ○ MOA: Trapped within the gland and enter intracellularly and delivers strong beta radiations destroying follicular cells ○ NOTES: Penetration range: 400-2000μm Clinical uses: Grave’s, primary inoperable thyroid CA Contraindication: pregnancy Easy, effective, low cost and absence of pain are the advantages. ○ Six to 12 weeks following the administration of radioiodine, the gland will shrink in size and the patient will usually become euthyroid or hypothyroid. ○ Hypothyroidism occurs in about 80% of patients following radioiodine therapy. ADJUNCT THERAPY THYROIDECTOMY ➔ Diltiazem, 90­120 mg three or four times daily, can be ➔ A near-total thyroidectomy is the treatment of choice for used to control tachycardia in patients in whom -blockers patients with very large glands or multinodular goiters. are contraindicated, eg, those with asthma. ➔ Patients are treated with antithyroid drugs until euthyroid ➔ Adequate nutrition and vitamin supplements are essential. (about 6 weeks). ➔ Barbiturates accelerate T4 breakdown (by hepatic enzyme induction) and may be helpful both as sedatives and to lower T4 levels. R.A. Cuarteros PCOL312LEC┃36  achievable in the patient, thus limiting the spread of infection until the immune system attacks, Legends: immobilizes, and eliminates the pathogen. Topic Sub topic Sub Sub Topic HISTORY OF ANTIBIOTICS ➔ 1928 ◆ Alexander Fleming discovered the first antibiotic, penicillin. ➔ 1930 ◆ The first commercially available antibacterial was Prontosil, a sulfonamide developed by the German biochemist Gerhard Domagk ANTIMICROBIAL RESISTANCE ➔ 1938 ➔ DRUG RESISTANCE ◆ Florey and Chain isolated and introduced penicillins ◆ The susceptibility of pathogenic MOs to drugs in therapy becomes lower or even loses after contact with the ◆ Pasteur and Joubert discovered that anthrax culture drug many times. were killed by another living organism- antibiosis ➔ CROSS RESISTANCE ➔ 1940 ­ 1962: ◆ When the bacteria show resistance to one drug, they ◆ The golden era of antibiotics. Most of the antibiotic are also resistant to some other drugs. classes we use as medicines today were discovered and introduced to the market. ➔ 1942 ◆ Waksman introduced and gave the formal definition of the word “antibiotic” ANTIBIOTICS ➔ Substance produced by microorganisms which has the capacity to inhibit even destroy other microorganism ➔ Modern definition: ◆ ­ A product of metabolism ◆ ­ Synthetic product produced by living organism as structural analog of a naturally occurring antibiotic ◆ ­ Effective in low concentration ➔ A. According to spectrum of activity: ◆ The scope of a drug to kill or suppress the growth of microorganisms. ­ Broad Spectrum: The drugs that have a wide antimicrobial scope. ­ Narrow spectrum: The drugs that only act on one kind or one strain of bacteria. ➔ B. According to action: ◆ ­ Bactericidal: Drugs which kill bacteria at drug serum levels achievable in the patient. ◆ ­ Bacteriostatic: Drugs which arrest the growth and replication of bacteria at serum urine levels R.A. Cuarteros PCOL312LEC┃1  CELL WALL SYNTHESIS INHIBITORS BETA LACTAMS The active component Cyclic amide with four atoms in its ring When fused with 5-membered thiazolidine ring it produces PENICILLIN When fused with 6-membered dihydrothiazine ring it produces CEPHALOSPORIN MECHANISM: ○ PBPs ­ these are the beta-lactam receptors 1. PBP 1 ­ cell lysis (amoxicillin, cephalosporin) 2. PBP 2 ­ non-rigid, oval-shaped cells, no cell division (methicillin and cefotaxime) 3. PBP 3 ­ long, filamentous-shaped (mezlocillin and cefuroxime) 4. PBP 4 ­ 6 no lethal effects ○ Selectively and irreversibly inhibits the enzymes processing the developing peptidoglycan layer. ○ Autolysins cleave the N-acetylmuramic acid-peptide bond to L-ala. Beta Lactam ring mimics the shape of the terminal D-Ala-D-Ala peptide sequence that serves as the substrate for cell wall transpeptidases that form covalent bonds between different peptidoglycan chains during periods of cell growth. BETA LACTAMS HYPERSENSITIVITY REACTION ○ Beta lactam ring produces an inactive penicilloic acid ○ ALLERGENICITY: Rash or itching, or delayed onset CV collapse or shock Due to penicilloic acid reacting with lysine-amino group forming Penicilloyl proteins. ○ Beta lactams are also acid sensitive, and degrade at low pH by a more complex mechanism. BETA LACTAMS INACTIVATION CAUSED BY BACTERIAL ENZYME ○ Beta lactams form allergenic haptens in vivo. ○ PENICILLINASES 1. B-lactamases are a group of enzymes specifically designed to degrade and inactivate beta lactam antibiotics by directly attacking the beta lactam bond which leads to ring opening and inactivating the antibiotic. 2. Acylases are also a variety enzymes that have been isolated from some bacteria, and these enzymes cleave the acylamino side chain of the antibiotic inactive BETA LACTAMS PROTEIN BINDING ○ due to lipophilic structures Nafcillin is the most protein bound (90%) Amoxicillin and Ampicillin ­ 25 ­ 30% ○ Acylamino side chain-responsible for protein binding BETA LACTAMS RESISTANCE OF BACTERIA ○ 1. production of beta lactamases ○ 2. mutation of PBP's to a form with lower affinity for the antibiotic ○ 3. decreased permeability of the cell wall to beta lactams ○ 4. Presence of efflux pump ○ 5. PORINS The opening in porins is too small to allow diffusion of large molecules, such as vancomycin (resulting in an inherent or intrinsic form of gram-negative resistance against glycopeptide antibiotics. Some gram-negative bacteria express porins having an altered pore structure that does not permeation of smaller drugs (such as beta-lactams or carbapenems). ○ 6. Peptidoglycan is absent Some bacteria (e.g. mycobacteria) lack a cell wall, and can multiply in the presence of β-lactam antibiotics, potentially resulting in serious infection (e.g. atypical pneumonia). PENICILLINS A. Natural Penicillins ○ Natural penicillin are Pen G (Benzyl Penicillin) and Pen V (Phenoxymethyl) which are highly active against gram (+) cocci ○ Unit of activity is based on the antibiotic activity of 0.5μg of USP Pen G RS 1 mg PEN G Na = 1,667 U R.A. Cuarteros PCOL312LEC┃2  1 mg of PEN G - 1,530 U 1 mg of PEN Procaine ­ 1,009 U ○ Degradation may be due to water, alkaline or acid solutions and enzymes In basic media → penicilloic acid → penilloic acid In acid media → penicillamine, penilloic acid and penilloaldehyde ○ These solutions should not be exposed to sources of metal ions (accelerate the chemical degradation process ○ Degradation reactions can be retarded clinically by buffering solution of penicillins between pH 6.0 and 6.8. ○ Refrigerate or use promptly ○ Use inert plastics for lid of containers B. Penicillinase-Resistant Penicillins ○ Antistaphylococcal Penicillins These are less potent against bacteria that do not produce beta lactamase, but are effective against those that do. They are sufficiently acid stable to be taken orally. ○ Examples: 1)Methicillin (Prototype) 2)Nafcillin (Most protein bound; can be given to px w/renal problems → excreted by biliary excretion) (Isoxazolyl Penicillins) 3)Oxacillin 4)Cloxacillin 5)Dicloxacillin ○ Use: Infection by β-lactamase producing staphylococci ○ Adverse Effects: 1. Methicillin may cause nephrotoxicity and interstitial nephritis. 2. Oxacillin may be hepatotoxic. 3. All inhibit platelet aggregation, which may result in bleeding. ○ Isoxazolyl penicillins are eliminated by both kidney and biliary excretion. * no dosage adjustment is required in renal failure C. Aminopenicillins ○ Broad spectrum penicillin ○ Antimicrobial activity include such gram (-) microorganisms such as H. influenzae, E. coli and P. mirabilis. ○ Includes: 1) Ampicillin 2) Amoxicillin 3) Cyclacillin 4) Bacampicillin ○ Ampicillin and amoxcillin are the most commonly associated with druginduced rash and diarrhea. ○ Ampicillin is equivalent in activity to Pen G, widely used for out-patients for uncomplicated community ­acquired UTI. ○ Amoxcillin ­ more acidic better oral absorption enhanced blood levels, less GI disturbance. Antimicrobial activity and spectrum similar to ampicillin. D. Anti-pseudomonal Penicillins ○ klebsiela sp. and other gram (-) microorganisms. ○ Includes: 1) Carbenicillin 2) Ticarcillin 3) Mezlocillin 4) Piperacillin ○ * effective against Klebsiella pneumoniae R.A. Cuarteros PCOL312LEC┃3  ○ Generally used in combination with an aminoglycoside for pseudomonal infections. BETA LACTAMASE INHIBITORS ○ Used to produced synergistic activity against resistant strains ○ Inhibits the enzymes that inactivates or hydrolyzes the lactam ring resulting to inactivation ○ Classified to: Class I Prolongs inactivation of enzymes Used with extended-spectrum spectrum and β-lactamase-sensitive penicillins Sulbactam, clavulanic acid and tazobactam 1. Clavulanic acid ○ naturally occurring, from S. clavuligeris ○ Has weak antibacterial activity ○ Combined with Amoxicillin for skin, respiratory, ear and UTI (BN: Co-Amox) ○ Combined with Ticarcillin for septicemia, lower RTI and UTI ○ Compounds that irreversibly inactive Beta Lactamase 2. Sulbactam ○ ­Has weak antibacterial activity but potentiates activity of ampicillin and carbenicillin against β-lactamase producing staphylococcus and enterobacteriaceae ○ Non-synergistic with Carbenicillin ○ Sulbactam + Ampicillin- Sultamicillin (Unasyn) 3. Tazobactam ○ More potent than sulbactam, slightly broader in spectrum than clavulanic acid, weak antibacterial activity ○ With piperacillin for appendicitis, postpartum endometriosis and pelvic inflammatory infections Class II possess potent antibacterial activity in addition to its ability to cause transient inhibition of some β-lactamases Carbapenem, Monobactams A. CARBAPENEMS ○ Imipenem, Meropenem, Ertapenem ○ 1. Imipenem penetrates bacterial porins well, and is stable to and inhibitory for many beta lactamases. It is not orally active with cilastin sodium, an inhibitor of renal dehydropeptidase 1, which attacks and inactivates imipenem. B. MONOBACTAMS ○ Sulfacezin, Aztreonam ○ A product of fermentation of unusual microorganisms Aztreonam is the only important example. It is a totally synthetic parenteral antibiotic which is active almost entirely against gram negative bacteria. Its mechanism is similar to the penicillins CEPHALOSPORINS Derivatives of 7- amino-cephalosporanic acid and are closely related in structure to penicillin. Isolated from Cephalosporium sp. ○ C. acremonium which inhibits the growth of a variety g(+) and g(-) R.A. Cuarteros PCOL312LEC┃4  ○ Cephalosporins is appended to a 6 rather than a 5 membered ring, the system is less strained and hence less reactive. MOA: ○ It inhibit bacterial cell wall synthesis, reducing cell wall stability, thus causing membrane lysis. ○ The cephalosporins are considered broad-spectrum antibiotics ○ exhibit uniquely potent activity against most species of Klebsiella pneumoniae (causative agent of sepsis and pneumonia) CLASSES OF CEPHALOSPORINS 1st Generation 2X- Cefalexin, Cefadroxil 1 Z- Cefazolon 2 IN- Cefalothin, Cefaparin DINE- Cephradine 2nd Generation ceFURoxime, CeFOXitine, CeFORanide, ceFONicid, cefoTEtan, cefMandole, cefMetazole 3rd Generation Cefotaxime, ceftizoxime, ceftriaxone, ceftazidime, cefoperazone, cefixime, cefpodoxime, cefdinir, ceftibuten, ceftamet, Moxolactam 4th Generation CefePime, CefePirome 5th Generation Ceftobiprole, Ceftaroline Susceptible cephalosporins can be hydrolyzed by beta lactamases, and in fact some beta lactamases are more efficient at hydrolyzing cephalosporins than penicillin itself. ○ Cephalotin and cefoxitin are the most resistant to beta lactamase ○ Cephaloridine and cefazolin are the least resistant to beta lactamase It causes cross sensitivity with penicillin. Allergic reactions are not as common in this chemical class as in the penicillin class. Cephalosporins are taken orally. ○ Cephradine is the ONLY cephalosporin derivative that is available in oral and parenteral preparation INDICATION OF CEPHALOSPORINS 1st Gen ▪ G (+) and G (-) infections in px with mild allergy ▪ Serious Klebsiella infection ▪ Cefazolin- Surgical prophylaxis 2nd Gen ▪ UTI (E.coli) ▪ Cefaclor- Otitis media ▪ Cefuroxime- Community Acquired Pneumonia 3rd Gen ▪ Can penetrate the CSF ▪ Meningitis ▪ Sepsis (unknown cause) ▪ Empiric therapy for life threatening condition 4th Gen ▪ Pneumonia ▪ Skin infections ▪ Empiric therapy for neutropenic patients ▪ Most resistant to Beta lactamase ADVERSE EFFECTS OF CEPHALOSPORINS ○ Generally non-toxic, with high degree of selective toxicity. R.A. Cuarteros PCOL312LEC┃5  1. Allergy and hypersensitivity reactions are the most common 2. Hypoprothrombinemia 3. Intolerance to alcohol is due to NMTT (N-methyl-5-thiotetrazole) group. ○ All cephalosporins (except cefoperazone) are eliminated renally , crosssensitivity may occur. May develop hypersensitivity ○ Other adverse effects include nausea, vomiting, superinfections, nephrotoxicity, clostridium difficile induced colitis BACITRACIN Cyclic peptide mixture obtained from Tracey strain of Bacillus subtilis Active against gram positive microorganisms NOTES: ○ Topical used only ○ Highly nephrotoxic when administered systematically ○ Poorly absorbed ○ Combined with other antibiotics GLYCOPEPTIDES Glycopeptide antibiotics are a type of antibiotic that inhibits bacterial cell wall formation by inhibiting peptidoglycan synthesis. They are used for treating multi-resistant Staphylococcus aureus (MRSA) infections and enterococcal infections, which are resistant to beta-lactams and other antibiotics. EXAMPLES: ○ 1. Vancomycin Vancomycin is an antibiotic produced by Streptococcus orientalis. A glycopeptide antibiotic MECHANISM OF ACTION Binds to precursor units of bacterial cell walls, inhibiting cell wall synthesis Bactericidal Synergistic with gentamicin and streptomycin against enterococcus CLINICAL USES: Parenteral vancomycin ○ Sepsis or endocarditis caused by methicillin-resistant staphylococci ○ In combination with gentamicin (alternative for enterococcal endocarditis) Oral vancomycin ○ Antibiotic associated enterocolitis caused by Clostridium difficile ADVERSE EFFECTS OF VANCOMYCIN 1. Phlebitis (at the site of injection) 2. Nephrotoxicity and Ototoxicity (rare) 3. Red man or red neck syndrome flushing, pruritus, erythematous rash on face and upper torso related to RATE of intravenous infusion ○ 2. Teicloplanin (similar with vancomycin) Actinoplanes teichomyceticus Given IM and IV A mixture of five related fermentation products related to vancomycin More lipid soluble, highly protein bound Less irritating than vancomycin PROTEIN SYNTHESIS INHIBITORS A. 30s inhibitor ○ Aminoglycosides ○ Tetracycline B. 50s inhibitor ○ Chloramphenicol ○ Macrolides ○ Lincomycins R.A. Cuarteros PCOL312LEC┃6  C. tRNA inhibitor ○ Mupirocin A. 30s inhibitor AMINOGLYCOSIDES 1,3-diaminocyclohexane central ring consisting of either deoxystreptamine or streptadine Isolated from: ○ MYCIN- Streptomyces ○ MICIN- Micromonospora Broad spectrum - Primarily used against gram (-) enterobacteria and in suspected sepsis. They have little activity against anaerobic and facultative organisms. The only protein synthesis inhibitor that is BACTERICIDAL Properties: ○ Are freely water soluble, basic and form acid addition salts (sulfates) ○ Highly water soluble, tends to concentrate in the kidneys. MOA: ○ inhibiting bacteria protein synthesis by binding to and impeding the function of the 30s ribosomal subunit ­ (Bactericidal) AMINOGLYCOSIDES from Streptomyces sp. ○ 1. STREPTOMYCIN produced from Streptomyces griseus the first aminoglycoside antibiotic to be used in Chemotherapy active against both gram (+) and gram (-) Administered via IM Uses: used for the treatment of tularemia bacterial endocarditis and tuberculosis long term use may cause an overgrowth of C. albicans ○ 2. Kanamycin is isolated from S. kanamyceticus: available as IV but painful occasionally used in TB. ○ 3. Amikacin is made semisynthetically from kanamycin A: with enahnced spectrum used competitively with gentamicin against susceptible strains ○ 4. Tobramycin is produced from S. tenebrarius: available as IV useful as less-toxic substitute for gentamicin-resistant P.aeruginosa ○ 5. Spectinomycin is from S. spectabilis bacteriostatic in activity particularly useful patients with pen-allergy ○ 6. Neomycin is derived from S. fradiae sometimes used in the preoperative bowel sanitation treatment of (EPEC) enteropathogenic E. coli infections AMINOGLYCOSIDES from Micromonospora sp ○ 1. Netilmicin is from M. inyoensis with clinical properties similar to gentamicin and tobramycin R.A. Cuarteros PCOL312LEC┃7  ○ 2. Gentamicin is derived from M. purpurea the most important aminoglycosides still in use with enhanced antibacterial activity, useful against susceptible g(-) bacteria ADVERSE EFFECTS OF AMINOGLYCOSIDES ○ Hypersensitivity reactions Special attention should be paid to the anaphylactic shock caused by streptomycin ○ Nephrotoxicity Neomycin is the most nephrotoxic Streptomycin is the least one Due to their water solubility, it tends to concentrate in the kidneys ○ Ototoxicity Cranial nerve damage - cochlea and ear vestibule toxicity (irreversible) Neomycin, kanamycin, and amikacin are the most ototoxic drugs Streptomycin and gentamicin are the most vestibulotoxic. Netilmicin is the least ototoxic ○ Neuromuscular junction blockade take place at high doses or in combination with curareform drugs ANTIDOTES: Calcium gluconate Neostigmine TETRACYCLINE Consist of four annelated 6-membered ring (octahydronapthacene) Amphoteric, the basic function is the 4