| Pharmachology•Pathology |
■Pharmacology ☉Tachyphylaxis: ADH, nitrate ☉Adrenoceptors α1 constricts blood vessels, relaxes GI tract, BP↑, mydriasis, bladder sphinctor constriction α2 aggregates platelets, decreases NA release from nerve terminals, inhibit insulin secretion β1 increases rate and force of contraction of the heart, relaxes GI tract, lipolysis β2 increases NA release from nerve terminals, dilates bronchi, vasodilation, peripheral esistance↓, glycolysis, glucagon↑, uterine smooth muscle relaxation β3-adrenoceptors are found in abundance in brown adipose tissue (BAT) - the major site of thermogenesis -where they have an important role in lipolysisβ3-agonists are being developed as anti-obesity drugs… ☉Vaughan Williams Classification of Antiarrhythmic Drugs Class Action Drugs I Sodium Channel Blockade IA Prolong repolarization Quinidine, procainamide, disopyramide IB Shorten repolarization Lidocaine, mexiletine, tocainide, phenytoin（你就罵死那個偷糞桶的人） IC Little effect on repolarization Encainide, flecainide, propafenone, moricizine(?) II Beta-Adrenergic Blockade Propanolol, esmolol, acebutolol, l-sotalol III Prolong Repolarization (Potassium Channel Blockade; Other) Ibutilide, dofetilide, sotalol (d,l), amiodarone, bretylium （ABS煞車系統） IV Calcium Channel Blockade Verapamil, diltiazem, bepridil （數位DV） Miscellaneous Miscellaneous Actions Adenosine, digitalis, magnesium ☉Drugs for hyperlipidemia GI tract: 1. Decrease Cholesterol absortion →Sitosterol（類似膽固醇而與之競爭） 2. Bile acid binding resins →Cholestyramine 3. Decrease lipoprotein synthesis →Nicotinic acid(Niacin, Vit B3, NAD): VLDL secretion↓ Lipoprotein lipase↑ →Gemfibrozil 4.HMG-CoA reductase inhibitor →Active form: provastatin, fluvastatin →Inactive form: mevastatin, lovastain, simvastatin（梅干肉/滷肉/燻肉） ☉Diuretics 1.Thiazides: inhibit luminal Na/Cl cotransport(DCT)（PTH，Ca也在這裡吸收） →depletion phenomena (K, Na, Cl, Mg↓↓) →retension phenomena (UA, Ca ↑↑) 2.Loop diuretics: inhibit luminal Na/K/2Cl cotransport(Thick ascending) →Furosemide(Type II)（可能引起腎耳毒性，不可與aminoglycoside並用） →Hypokalemia 3.Carbon anhydrase inhibitors: & increases HCO3 secretion(PCT) →Acetazolamide →Metabolic acidosis★ 4.K sparing: (collecting tubule) →Aldosterone inhibitor: hyperkalemia, gynecomastia →Amiloride →Triamterene（與ACEI並用造成Hyperkalemia!!） 5.Osmotics: (PCT, descending loop, collecting tubule)（ADH也在這裡作用） ☉Drug affecting neurotransmitter release or uptake 1.Reserpine：抑制NE送進synaptic vesicle，造成NE分解 2.Guanethidine: 抑制NE從囊中的釋放作用 3.Coccaine: 唯一阻斷負責回收NE的Na-K activated ATPase →→Hemicholinium-3 (HCh-3) :potent and specific inhibitor of the high-affinity "choline" transport process (HAChT)抑制Ach運送！ →→Botulinum: 抑制Ach釋放 ☉α2 agonist: clonidine, methyldopa: antihypertensives α1 blocker: (selective)Prazocin: no reflex cardicardia ☉Anticholinergics 1.Antimuscarinic (1)Atropine (2)Scopolamine (3)Ipratropium (4)Pirenzepine: M1 blocker治療胃潰瘍 2.Antinicotinic: Ganglionic blocker (1)Nicotine (2)Trimethaphan: antihypertensives, as an adjunct to anesthesia, IV bolus. (3)Mecamylamine 3.Antinicotinic: Neuromuscular blocking agents (1)Nondepolarizaing(competitive): curare（先搶先贏） (2)Depolarizing: succinylcoline（站著毛坑不拉屎） ☉Cholinergics 1.Direct acting (1)Acetylcholine (2)Bethanechol: 不具Nicotinic effect (3)Carbachol (4)Pilocarpine: treat POAG（開啟trabeculae而使aqueous fluid外流） 2.Anticholinesterase (1)Reversible→Physo/Neo（MG治療藥）/Pyridostigmine, Edrophonium（就是診斷MG的Tensilon試驗） (2)Irreversible→Isoflurophate（殺蟲劑類:Parathion） ←→Pralidoxime(PAM): reactivation of acetylcholinesterase ☉treatment of glaucoma 1.Cholinergic: pilocarpine 2.α adrenergic: phenylephedrine 3.β blocker: timolol 4.carbonic anhydrase inhibitor: ☉Activation of M1/M3 muscarinic responses. →M1-muscarinic receptors: acetylcholine→activation of a Gq coupling protein→alpha subunit of this G protein→phospholipase →release of IP3 (inositol 1,4,5-trisphosphate) and DAG (diacylglycerol) from phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5-P2)→ release of sequestered stores of calcium,→increased concentration of cytoplasmic Ca2+→activate Ca2+-dependent protein kinases →M2-muscarinic receptors cause action in the heart in the following manner: Heart SA node: decrease in heart rate. Heart AV node: decrease in conduction velocity Heart Atria: decrease in contractility →M3-Muscarinic receptors cause contraction of smooth muscle in the following organs: Eye: sphincter of the iris Eye: ciliary muscle Lungs: tracheal and bronchial muscle Stomach and Intestines: increase motility and parasympathetic tone Glands (lacrimal, salivary, bronchial, pancreatic, mucosal, and sweat(sympathetic), adrenal(sympathetic)): increase secretion Bladder: detrusor muscle Sex Organs, Male: M3-receptors cause release of nitric oxide in endothelial cells producing vasodilation (erection) →N1-nicotinic receptors cause depolarization of ganglia in the following manner: Autonomic Ganglia: firing of postsynaptic connection for both sympathetic and parasympathetic neurons. Adrenal medulla: secretion of epinephrine →N2-nicotinic receptors act in a similar fashion but are found at the neuromuscular junction of skeletal muscle. ☉Mechanisms of antibiotics 1.Wall synthesis inhibition: Penicillin, Cefa, Vanco, Monobactum, carbapenem 2.Outer membrane damage: b-lactams →membrane dusfunction: Polymixins★ 3.DNA/RNA synthesis modification: quinolone(Nalidixic acid)(DNA gyrase), rifampin(RNA polymerase) 4.Protein synthesis inhibition: →50S: Erythromycin, Chloramphenical, Clindamycin（紅「綠」對抗）（chloram-造成aplastic anemia, grey baby） →30S: Tetracycline, Aminoglycoside（四環三腺） 5.Metabolism(folic acid): Sulfonamide, Trimethoprim（下水道負責代謝）（前者先抑制dihydropteroate synthetase，後者與MTX後抑制dihydrofolate reductase） ☉Antifungal agent 1.Polyene Antifungal Drugs Amphotericin, nystatin, and pimaricin interact with sterols in the cell membrane (ergosterol in fungi, cholesterol in humans) to form channels through which small molecules leak from the inside of the fungal cell to the outside. 2.Azole Antifungal Drugs Fluconazole, itraconazole, and ketoconazole inhibit cytochrome P450-dependent enzymes (particularly C14-demethylase) involved in the biosynthesis of ergosterol, which is required for fungal cell membrane structure and function.阿祖不生 3.Allylamine and Morpholine Antifungal Drugs Allylamines (naftifine, terbinafine) inhibit ergosterol biosynthesis at the level of squalene epoxidase. The morpholine drug, amorolfine, inhibits the same pathway at a later step. 4.Antimetabolite Antifungal Drugs 5-Fluorocytosine acts as an inhibitor of both DNA and RNA synthesis via the intracytoplasmic conversion of 5-fluorocytosine to 5-fluorouracil. ☉Digitalis toxicity 1.Early: anoxia, nausea, lethargy 2.Cardiac: VT/VF(treat with Lidocaine/Phenytoin), AV block 3.Chronic: cachexia, gynecomastia, yellow vision, confusion 4.Precipitating factor: ↓↓K, O2, Mg, ↑↑Ca, Thy, 5.藥效長短：Digitoxin（肝代謝） > Ouabain > digoxin（腎代謝） ☉Cyanide antedote: Nitrite ☉Levodopa(dopamine前驅物可過BBB）常與carbidopa（decarboxylase inhibitor避免在levodopa在周邊代謝）合用，但不可與Vitamin B6合用，會增加周邊破壞率以及效果。 ☉嗎啡：Methadone戒毒，Naloxone解毒。 ☉Acetaminophen：只能解熱鎮痛，不能抗發炎 ☉Wilson dz Tx: Penicillamine, not BAL (for Hg, Au, As antidote) ☉Bleomycin: cause lung fibrosis ☉Redux (dexfenfluramine hydrochloride capsules) an anti-obesity drug, is a serotonin reuptake inhibitor and releasing agent. Redux is available for oral administration in white, opaque, hard-gelatin capsules. Cardiotoxicity. ☉Gabapentin (1-[aminomethyl] cyclohexaneacetic acid) an amino acid originally synthesized because of its structural similarity to the inhibitory neurotransmitter GABA. Unlike GABA, gabapentin passes freely through the blood-brain barrier. Despite its configurational similarity to GABA, gabapentin does not mimic this neurotransmitter. Gabapentin acts as an anticonvulsant; however, the precise mechanism of it's anticonvulsant action is unknown. Gabapentin does not alter whole brain levels of GABA or have any significant effect on GABA transaminase activity, does not bind to GABA receptors and does not influence neural uptake of GABA at pharmacologically active doses. Gabapentin is believed to possess a unique, as yet undefined, mechanism of anticonvulsant action involving affinity for an unidentified receptor in brain tissue, primarily located on neurons but not detected in peripheral tissues. ☉Induction rate: desflurane > halothane > methoxyflurane ☉Methyflurane: MAC 最小（potency最大），induration time 最長 ☉Pain control 1. Substance P :When the opiate receptors on the pre-synaptic neuron are activated, a conformational change prevents to release of Substance P. opiate receptors are activated by endorphins released from a neighboring neuron. 2. Bradykinin: blocked by Aspirin ☉Sucralfate (Carafate) →a substituted sugar molecule with no nutritional value, does not inhibit gastric acid, but rather, reacts with existing stomach acid to form a thick coating that covers the surface of an ulcer, protecting the open area from further damage. A secondary effect is to act as an inhibitor of the digestive enzyme pepsin. Sucralfate does not bind to the normal stomach lining. The drug has been used for prevention of stress ulcers. →Sucralfate should not be used with aluminum containing antacids, because of the risk of increased aluminum absorption.而且不可與其他制酸劑共用，因為它必須在酸性下活化。 ☉cyproheptadine hydrochloride (Periactin) Periactin is an antihistamine that comes in syrup and pill form. Periactin also has sedative effects and calcium-channel blocking activity. Periactin is used to treat some hormonal disorders, including inhibited orgasm that may be a side effect of taking antidepressants. Periactin has also been shown to stimulate appetite and weight gain in children and adults. Periactin is sometimes used as an adjunct therapy in children who are taking human growth hormone. ■Pathology ☉Protooncogene products 1.Growth factors: PDGF, bFGF..... 2.Protein tyrosine kinase: →membrane receptors: C-erb B1(squamous LC), C-neu(breast, ovary, salivary ca...) →Cytoplasmic proteins: V-src 3.Signal-Transducing protein(ras proteins) GTPase activating protein(GAP) 4.Nuclear proteins: c-myc 5.Cyclin dependent kinase(CDK) ☉Activation of protooncogenes 1.point mutation: ras(pancreatic ca) 2.translocation & inversion: Burkitt's lymphoma-t(8,14)(★activate c-myc), Philadelphila chr.-t(9,22) 3.Gene amplication: HSR, double minute ☉Other tumor suppressor genes: 1.NF-2: acoustic neurofibroma, meningioma 2.VHL gene 3.PTEN 4.WT-1 ☉Genes regulating apoptosis antagonist: Bcl-2, bcl-xL agonist: bax, bad, bcl-xs ICE, c-myc, p53 ☉Genes regulating DNA repair HNPCC, Xeroderma pigmentosum, Bloom syndrome, Ataxia telangiectasis(AT gene mutation, p53 inactivated), Fanconi anemia, Telomeres ☉Karyotypic changes 1.Translocation: CML(Philadelphia), Burkitt's lymphoma 2.Chromosomal deletion: Retinoblastoma, Wilm's tumor 3.Gene amplification: HSR, DM(double minute), MDR 4.Whole chr lost/gain: ☉Multistep carcinogenesis 1.Gatekeeper genes: Rb, NF-1, VHL, APC (Oncosuppression) 2.Caretaker genes: BRCA-1,2 (DNA repair gene) ☉Metastasis: sarcoma by blood, carcinoma by lymph ☉General pathological changes →Liquefactive necrosis: liver abscess, CNS necrosis →Hyaline: Mallory body(alcoholic, cirrhotic), Russel body(plasma cell), Verocay body(Neurillemoma) →Coagulative necrosis: infarction →Amyloid: protein deposition, Throid medullary ca (C cell, secrete calcitonin, MEN II), ★Congo Red Stain(+) →★Bread-and-Butter: pericarditis, fibrinoid infection →Granulama: composed of epitheloid cells(Macrophage) →Nissle body: rough ER, basophilic →silvophilic: reticular fiber ☉Specific pathological changes →Wire loop: SLE (glomerular capillary walls) →★Onion skin: malignant arteriosclerosis/hypertension & fibrinoid necrosis, Ewing's tumor →Signet ring cell: ca. →Aschoff body: rheumatic heart →Myxoma: LA →Reed-Sterberg cell: Hodgkin's lymphoma (lymphocytic predominance: good prognosis) →Asbestos（石綿）: mesothelioma →Tram-track: MPGN (hypocomplementemia) →Crescent: RPGN (Bowman capsule) →clear cell: RCC →Ground glass hepatocyte (GGH), piecemeal/bridge necrosis : chronic HBV infection and contains surface antigens in the endoplasmic reticulum (ER). →Struma ovarii: thyroid →Orphan Annie, Psammoma body: thyroid papillary ca. →Rossette: neuroblastoma, retinoblastoma →Kimmelstiel-Wilson nodules: DM nodular glomerulosclerosis (mesangial proliferation), hyalinosis →synechia: Focal segmental GS →Negri body: Rabies →perivascular cuffing: viral encephalitis( glial nodule, neurophagia) →Antonie A(Verocay body)/Antonie B: acoustic neuroma →Munro abscess: psoriasis ☉Myocardial Infarction: 0-30 minutes = none 1-4 hours = cell swelling, ★fiber waviness (normal cells are stretched when adjacent dead cells fail to contract) may be visible. CKMB rises by 4 hours. CKMB is extremely sensitive but not very specific. Also, it peaks at 24 hours and returns to normal within 72 hours so you can't test for it later. LDH1 rises by 18-36 hours. ★Troponins (cTn1 and cTnT) are extremely specific and rise in about four hours and stay elevated for 4-7 days. 4-12 hours = ★coagulation necrosis, edema 12-24 hours = intercellular edema and intense eosinophilia evident on histology, pyknosis of nuclei 24-72 hours = intense inflammatory response with lots of ★neutrophils visible between myocardial fibers 72 hours - 10 days = organization and lots of ★granulation tissue weeks = collagen deposition and loss of vascularity and contraction 2 months = dense collagenous ★scar without further modification (i.e., you cannot tell a 5 year old infarct from a 2 month old one) ☉Waterhouse-Friedrichsen syndrome →Adrenal insufficiency →Overwhelming sepsis caused by Meningococci!! →Common in children →Massive bilateral adrenal hemorrhage ☉Pseudomyxoma peritonei, mucinous material within the peritoneal cavity. It has a high protein content, encases the mesentery and organs and can calcify. It is very rare in children and when seen it is usually with ovarian tumours. Other described causes are desmoid tumours and cystadenocarcinoma of the pancreas. ☉Brenner tumor of ovary Brenner tumors are comprised of solid to partly cystic epithelial nests surrounded by stroma composed of bundles of tightly packed spindle-shaped cells. The epithelial cells are polygonal and of squamoid type, with pale, eosinophilic cytoplasm and oval nuclei with distinct nucleoli and longitudinal grooving, which is commonly described as "coffee-bean" in appearance. ☉Malacoplakia, bladder a benign process, manifesting in the formation of multiple yellow-grey plaques in the bladder mucosa. It is of unknown aetiology. It can be seen in patients with pulmonary tuberculosis, chronic osteomyelitis, chronic malignancies and coliform infections of the bladder. Histological evaluation reveals histiocytes, lymphocytes, plasma cells, and Michaelis Gutmann bodies, which are thought to represent phagocytosed bacteria(Foamy Macrophage). These plaques appear radiographically as rounded contour defects, primarily of the trigone, on cystography and CT. Differential diagnoses include cystitis cystica and occasionally a tumour. ☉Berger's disease (IgA nephropathy) : DM + Antibiotic + analgesic →glomerulopathy that is present in 50% of children with recurrent episodes of macroscopic haematuria. It also occurs in young adults. It is more common in males. →Episodes of haematuria are often simultaneous with periods of viral infection and flank pain. →Histology reveals a focal proliferative glomerulonephritis with IgA, and in some cases IgG, C3 and properdin deposits in the mesangium. ☉Focal Segmental Glomerulosclerosis →The primary pathophysiologic process in FSGS is an injury to podocytes, with proliferation of mesangial, endothelial, and epithelial cells in the early stages followed by shrinkage and/or collapse of glomerular capillaries and, ultimately, sclerosis. →Proposed mechanisms include viral- or toxin-mediated damage or intrarenal hemodynamic changes such as hyperperfusion and high intraglomerular capillary pressure. →Patients present with proteinuria and microscopic hematuria. Hypertension is also common. ☉Carcinoid tumors →arise from neuroendocrine cells, particularly in the GI tract (90%), pancreas, and pulmonary bronchi (see also Chs. 34 and 81). →The most common GI sites are the stomach, ileum, and appendix(Most common!!), where they may cause pain, luminal bleeding, and obstruction. Although often benign or only locally invasive, carcinoid tumors of the ileum and bronchus are frequently malignant. →Carcinoid tumors may be endocrinologically inert or produce a variety of hormones. The most common endocrinologic syndrome is the "carcinoid syndrome". A syndrome of episodic cutaneous flushing, cyanosis, abdominal cramps, and diarrhea in a patient with valvular heart disease (and, less commonly, asthma and arthropathy), usually caused by metastatic intestinal carcinoid tumors that secrete excessive amounts of vasoactive substances, including serotonin, bradykinin, histamine, prostaglandins, and polypeptide hormones. ☉Desquamative Interstitial Pneumonia Chronic lung inflammation characterized by mononuclear cell infiltration of the airspaces.The most striking feature is the presence of numerous macrophages in most of the distal airspaces. Honeycombing may be present but is usually not as extensive or prominent as in UIP. ☉Lafora body disease an autosomal recessive stimulus-sensitive progressive myoclonic epilepsy with onset in the late childhood or adolescence. Unverricht (classic) type is associated with earlier onset and more severe symptoms. Lundborg type is associated with later onset and less severe symptoms. Clinical features include generalized seizures, myoclonus, visual deterioration, psychoses, and rapid intellectual decline with the development of dementia. Pathologically it is associated with neuronal inclusions (Lafora bodies) in the cerebral and cerebellar cortex and in brain stem nuclei. Inclusions are also seen in other organs including liver, muscle, and skin. Lafora body is an insoluble form of carbohydrate that contains 80-90% of glucose and are related to abnormal glycogenoses. ☉TB →Primary tuberculosis: seen as an initial infection, usually in children. The initial focus of infection is a small ★subpleural granuloma accompanied by granulomatous hilar lymph node infection. Together, these make up the ★Ghon complex. In nearly all cases, these granulomas resolve and there is no further spread of the infection. →Secondary tuberculosis: seen mostly in adults as a ★reactivation of previous infection (or reinfection), particularly when health status declines. The granulomatous inflammation is much more florid and widespread. Typically, the upper lung lobes are most affected, and cavitation can occur. →When resistance to infection is particularly poor, a★ "miliary" pattern of spread can occur in which there are a myriad of small millet seed (1-3 mm) sized granulomas, either in lung or in other organs. Spine TB is called Pott disease. ☉JC virus (JCV) →a human polyomavirus. Polyomaviruses are members of the Papovaviridae family, which are small, nonenveloped viruses with a closed, circular double DNA-stranded genome.1 Polyomaviruses are distinguished from papillomaviruses by a smaller virion size and a different genome size and organization. →JCV has been linked to the development of hemorrhagic cystitis, ureteral stenosis and allograft dysfunction in renal transplant recipients.1,2 JCV is believed to be the primary causative agent of both nephropathy after transplantation and progressive multifocal leukoencephalopathy (PML). |