Opioid receptorsOpioid receptors• All opioid receptors are GGii-protein coupled-protein coupledreceptors (receptors (↓ cAMP)↓ cAMP)• Opioid receptor activation leads to:– Opening of K+channels → neuronal membranehyperpolarization– Closing of voltage-gated Ca2+channels on presynapticterminals → reduce NT release (glutamate, substanceP)
The majority of currently available opioidanalgesics are μ receptor agonists• Full agonistsFull agonists::• MorphineMorphine• MethadoneMethadone• FentanylFentanyl• HeroinHeroin• Metabolism: CYP3A4oxidation followed byglucoronide conjugationwww2.addictioncme.com/PageReq?id=1145:15053...
Organ system effects of full agonistsOrgan system effects of full agonists• CNS effects:• Analgesia (they reduce both the pain and its emotionalcomponent; continuous dull pain is relieved moreeffectively than sharp pain)• Euphoria (dopamine pathways involved)• Sedation• Respiratory depression (occurs even with therapeuticdoses; dose-related; a problem during management ofsevere pain)• Cough suppression• Constriction of the pupils – valuable in the diagnosis ofopioid overdose• Nausea and vomiting
Organ system effects of full agonistsOrgan system effects of full agonists• Peripheral effects:• Orthostatic hypotension (peripheral vascular dilation)• Decreased GI tract motility (constipation)• Contraction of biliary smooth muscle (can result in biliarycolic)• Stimulation of ADH and prolactin release• Histamine release from mast cells causes itching, flushingof the skin, urticaria + bronchoconstriction
www2.addictioncme.com/PageReq?id=1145:15053...• When a partialagonist is given to apatient also receivinga full agonist, there isa risk of diminishinganalgesia or eveninducing withdrawalsymptoms• Partial and fullagonists shouldn’t becombined
• Effective when given orally• Weak analgesic on its own, but metabolized by CYP2D6to morphine– Genetic polymorphism in CYP2D6 makes codeine ineffective asan analgesic for 10% of the Caucasian population• Combined in formulations with caffeine andacetaminophen• Effective antitussive action at doses lower than requiredfor analgesiaCodeineCodeine
• Partial μ receptor agonist + κ receptor antagonist• Long duration of action• Maintenance of opioid dependenceBuprenorphineBuprenorphine
OpioidOpioidantagonistsantagonists• Used in treatment ofacute opioid overdose• Short duration of actionof naloxone (1-2 hours);repeated administrationnecessary when treatingopioid overdose• Administration of anopioid antagonist to anopioid-dependent personwould precipitate severewithdrawal symptoms
Cocaine• Stimulant and local anesthetic• Leaves of the Erythroxylon coca plant have 0.5 to 1%cocaine• Potent vasoconstrictor properties• Administered orally, intranasally, IV, inhalationthrough smoking• Cocaine increases synaptic conc. of dopamine,norepinephrine, and serotonin– Binds to transporter proteins in presynaptic neurons andblocks reuptake(negative feedback)
Cocaine• Brief, dose-related stimulation and enhancement ofmood• Tolerance develops• Affects almost every organ system• Increases heart rate, blood pressure, bodytemperature• Pyrexia or hypertension could be lethal• Also respiratory depression, cardiac arrhythmias,seizures, hepatic cirrhosis
PCP• Diagnosis of overdose is difficult because thesymptoms resemble a psychotic episode• PCP remains in urine 1 to 5 days followinghigh-dose intake• Overdose requires life-support measures,including treating respiratory depression• Psychiatric emergency – risk for suicide orextreme violence
Acetaminophen• Toxicity– Ethanol is an inducer of CYP2E1, which is the main P450enyme that converts acetaminophen to the toxicmetabolite– Treat with N-acetylcysteine to increase glutathionesynthesis– Also thought that Kupffer cells play an important role intoxicity– A different toxic metabolite can bind to cellular proteins inthe kidney medulla and cause damage– Nephrotoxicity is characterized by proximal tubularnecrosis
Ethylene Glycol• Toxicity– Clinical presentation• Initial asymptomatic phase (EG is metabolized)• A period of inebriation – duration and degree depends on dose• Cardiopulmonary phase – 12-24 h after exposure – tachycardia andtachypnea – may progress to cardiac failure and pulmonary edema• Renal toxicity phase – 24-72 h after exposure• Increasing severity of metabolic acidosis during last two stages– Metabolism – ethylene glycol to glycolaldehyde (by alcoholdehydrogenase) and on to glycolic acid• Ethanol is given as an antidote because it effectively competes with EG foralcohol dehydrogenase– Rapid metabolism, so no bioaccumulation upon repeated exposure
Dextromethorphan• http://teens.drugabuse.gov/peerx/pdf/PEERx_Too• USED IN COUGH SYRUP
Cancer Terminology• Benign vs. Malignant– Malignant: a tumor that can result in deathand is capable of metastasis = breaking theboundaries of the initial organ to colonize inother organs.• Naming of tumor is cell of origin, plus“carcinoma”, if epithelial in origin; or“sarcoma”, if originating from connectivetissue.• Ex: colorectal carcinoma, pancreaticcarcinoma; leiomyosarcoma,chondrosarcoma,
Principles of Oncology• Fig. 55-1. The log-kill hypothesis.– Relationship oftumor cell number totime of diagnosis,symptoms,treatment, andsurvival. Threealternativeapproaches to drugtreatment are shownfor comparison withthe course of tumorgrowth when notreatment is given(dashed line). Surgery +5 trtmts withshort recoveryNo surgery,14 trtmts withshort recoveryNo surgery +trtmts withlong recovery
Choice of Cancer Treatment• Tumors are heterogenous cellmasses.– Initial cell is mutated = initiation– cell growth of the mutated cell ispromoted = promotion– cell becomesimmortalized/transformed (loss ofcontrol of the cell cycle) =conversion or transformation– progeny cells continue toaccumulate mutations =progression– cells spread out of local boundariesinto surrounding tissues = localinvasion– cells break off, circulate andcolonize in other tissues to formnew tumors = metastasis.http://en.wikipedia.org/wiki/Cancerapoptosisclonalevolution
Cancer Chemotherapy• Chemo is not usually the first treatment choice.– Can be first choice for some cancer types– Can be used in combination with other therapies.• Systemic treatment for systemic cancers.– Leukemias– Inoperable tumors– Advanced cancer – multiple metastases• Adjuvant therapy– Systemic treatment to prevent micrometastases after localtreatment (surgery, radiation)• Palliative treatment– Shrinking of tumors that cause blockage or constriction– Relief of bone pain
Alkylating Agents• General Mechanism of action (two modes):– Alkylation of DNA• primarily at N7 position of guanine, resulting intransfer of a group that blocks the replicationmachinery, preventing tumor growth and, ideally,promoting apoptosis (programmed cell death).• also, guanine O6• also alkylate other bases, including adenine N1 andN3, cytosine N3– Alkylation of cellular proteins• react with cellular nucleophiles, such as sulfhydryl,amino, hydroxyl, carboxyl and phosphate groups ofvarious cellular proteins.– Most are bifunctional = 2 reactive groups 1agent molecule can alkylate 2 different targetmolecules.
Alkylating Agents• Most major, clinically useful alkylatingagents are of three structural subclasses:– Bis(chloro-ethyl)amines• Cyclophosphamide, mechlorethamine (nitrogenmustard), melphalan, chlorambucil, bendamustine– Nitrosoureas• Carmustine (BCNU), lomustine (CCNU), semustine(methyl-CCNU), streptozocin– Ethyleneimines or Aziridines• Thiotepa (ovarian cancer), triethylenemelamine,altretamine• BCNU = bis-chloroethylnitrosourea; CCNU = bis-chloroethylcyclohexylnitrosourea
Alkylating Agents• Bis(chloro-ethyl)amines– Each chloro-ethylamine groupcan alkylate the N7 of 2adjacent purines, (intrastrand)resulting in cross-linked DNAstrands.– Cross-linked DNA is stable andcannot be replicated ordegraded by normal cellularmeans.bendamustine
Alkylating Agents• Platinum Analogs–Platinum-containing complexes–Mechanism of action:• Same manner as alkylating agents –forms interstrand and intrastrand DNAcross-links, inhibiting DNA synthesis andfunction.
Alkylating Agents• Platinum Analogs– Cisplatin – first-generation drug– Carboplatin – second generation• significantly less renal and GI toxicity• IV hydration is not required• has replaced cisplatin in combo therapies– Oxaliplatin – third generation• cisplatin- and carboplatin-resistant cancer cells arenot cross-resistant to oxaliplatin• Part of FOLFOX regimen = 5-fluoruracil + leucovorin+ oxaliplatin = most widely used regimen in first-line treatment of advanced colorectal cancer.
Antimetabolites• Methotrexate– = folic acid antagonist– Binds to active catalytic site of dihydrofolatereductase (DHFR), competing with binding ofDHF, inhibiting conversion to THF (active folicacid)– Interferes with production of DNA, RNA andkey cellular proteins.• Pemetrexed and Raltitrexed (Tomudex)– = TS antagonists– Target DHFR activities, but their main action isthrough inhibition of thymidylate synthase(TS), the methyltransferase that convertsdUMP to dTMP.5,10-methylenetetrahydrofolate + dUMP + TS -> dTMP + dihydrofolatedihydrofolate + DHFR -> tetrahydrofolate dTMP dTTP
Antimetabolites•Pyrimidine Antagonists–5-FU and capecitabine–5-FU = 5-fluorouracil•Metabolized to ribosyl and deoxyribosylmetabolites that produce cytotoxicity via combinedDNA- and RNA-mediated events.
Antimetabolites• Pyrimidine Antagonists– Capecitabine• Also leads to inhibition of DNA synthesis and “thymine-less death” because it is a prodrug that is metabolizedto 5-FU. Thus, cytotoxicity is identical to 5-FU.• Difference: capecitabine is converted to 5-FU bythymidine phosphorylase, which has significantlyhigher expression in solid tumor cells than in normalcells.• Result: main side effects of myelosuppression,mucositis, nausea and vomiting are less frequent andsevere with capecitabine, compared to 5-FU = selectivetoxicity.
Antimetabolites• Pyrimidine Antagonists– Cytarabine• Inhibits DNA polymerase α and β– (like purine antagonistsfludarabine & cladribine)– Gemcitabine• = deoxycytidine analog• Mimics cytidine, is incorporated intoDNA, preventing elongation• Inhibits ribonucleotide reductase,preventing production of dNTPsnecessary for DNA synthesis
Antimetabolites•Purine antagonists–6-thiopurines: 6-mercaptopurine (6-MP), 6-thioguanine (6-TG)•Both inhibit several enzymes inthe de novo purine nucleotidebiosynthetic pathway.•Decreases DNA and RNAsynthesis by way of reducingavailable functional purines.–Fludarabine and cladribine•Inhibit DNA polymerase α andβ–(like pyrimidine antagonist cytarabine)
Plant Alkaloids• Vinblastine and vincristine– Vinca (periwinkle) alkaloids– MOA: Inhibit tubulin polymerization, halting cell cycle,leading to cell death• Vinorelbine– Synthetic version of the vinca alkaloids• All have the same mechanism of action, butdifferent spectrum of clinical activity and toxicity.
Plant Alkaloids• Taxanes– Paclitaxel, docetaxel– Alkaloid derivatives of Pacific and European yew• paclitaxel is natural; docetaxel is semisynthetic– MOA: Enhance abnormal microtubule assembly• Occurs in absence of regulatory proteins and GTP thatare necessary for cell division, thus inhibits cell division
Antitumor Antibiotics• Anthracyclines– Doxorubicin, daunorubicin, idarubicin, epirubicin– Exert their effects through 4 major mechanisms:• Inhibition of topoisomerase II• High-affinity binding to DNA through intercalation (=bindingin the groove of the double helix), blocking the replicationmachinery• Binding to cell membranes, altering fluidity and transport• Generation of semiquinone free radicals and oxygen freeradicals through an iron-dependent, enzyme-mediatedreductive process. (Estrogen can also mediate this reaction.)– This is the cause of cardiotoxicity from these drugs.
Antitumor Antibiotics• Anthracene– Mitoxantrone• Resembles anthracycline ring structure• Binds to DNA to produce strand breakage, inhibiting DNA andRNA synthesis• Dactinomycin– Intercalating agent, between adjacent guanine and cytosine basepairs, blocking replication machinery• Mitomycin– An alkylating agent that cross-links DNA• Bleomycin– A small peptide with a DNA-binding domain and an iron-bindingdomain at opposite ends of the molecule.– Binds to DNA at one end and produces hydroxyl radicals with theother end, in close proximity to the DNA, ensuring more DNAdamage.
Hormonal Agents• Gonadotropin-releasing hormone agonists &antagonists– MOA: bind to the GnRH receptors and preventgonadal release of estrogens and androgens.– Antagonists• “Relix” drugs = cetrorelix, ganirelix, abarelix, degarelix– Agonists:• Leuprolide, & “Relin” drugs” = buserelin, nafarelin, histrelin,deslorelin• Initial increase in gonadal hormone release followed byinhibition through negative feedback.
Miscellaneous Anticancer Drugs• Growth Factor Receptor Inhibitors– Bevacizumab (Avastin)• Vascular endothelial growth factor receptor (VEGF)inhibitors• Growth of tumors requires blood supply.• VEGF mediates adequate blood supply.• Blocking VEGF cuts off the blood supply to the tumor= antiangiogenic.
Miscellaneous Anticancer Drugs• Growth Factor Receptor Inhibitors– Cetuximab (Erbitux), trastuzamab (Herceptin),gefitinib (Iressa), erlotinib (Tarceva)• Epidermal growth factor receptor (EGFR) inhibitors– “-mabs” inhibit extracellular ligand binding domain– “-nibs” inhibit intracellular TK domain• EGFR family of receptors includes 4 subfamilies– Subfamilies dimerize to form complete functional receptor,esp. EGFR/HER2– EGFR = EGFR1, ErbB1, Her1– HER2 = EGFR2, ErbB2, Neu• EGFR is overexpressed in many tumors, implying thetumor’s need for these receptors for survival.– EGFR 1 & 2; differential tissue expression, thus differentialtumor sensitivity; choice of drug depends on typeexpressed.• Blocking these receptors blocks growth.
Miscellaneous Anticancer Drugs
Radiation Therapy• Ionizing radiation= the kind of radiation used in cancer treatment– Forms ions by dislodging electrons as it passesthrough cells.– Two major types:• Photons – gamma and x-rays; most widely used• Particle radiation – electrons, protons, neutrons, alphaparticles, and beta particles– Higher energy types penetrate tissue better, butalso cause more damage to normal cells.
Radiation Therapy• Common types of cancer radiation treatments:– High-energy photons• Come from radioactive sources such as cobalt, cesium, or amachine called a linear accelerator (or linac, for short.)• By far, the most common type of radiation treatment in usetoday.– Electron beams• Produced by a linear accelerator.• Less tissue penetration, so it is used for tumors close to abody surface.
Radiation Therapy• Common types of cancer radiation treatment:–Protons• A newer form of treatment.• Cause little damage to tissues they pass through, but are verygood at killing cells at the end of their path – may be able todeliver more radiation to the cancer while causing fewer sideeffects to normal tissues nearby.• Used routinely for certain types of cancer, but still need morestudy in treating others.• Some of the techniques used in proton treatment can alsoexpose the patient to neutrons (see below).• Proton beam radiation therapy requires highly specializedequipment and is currently only offered in certain medicalcenters.
Radiation Therapy• Common types of cancer radiationtreatment:– Neutrons• Used for some cancers of the head, neck, andprostate.• Can sometimes be helpful when other forms ofradiation therapy dont work.• Use has declined over the years because of severelong-term side effects.
Radiation Therapy• Radiation delivery methods:– External beam radiation• the most widely used type of radiation therapy.• Linear accelerator emits focused beam on the areaaffected by cancer.• The beam is aimed at the tumor, but also affects thenormal tissue it passes through on its way into and outof the body.• Allows large areas of the body to be treated and allowstreatment of more than one area such as the maintumor and nearby lymph nodes.• Usually given in daily treatments over several weeks.
Radiation Therapy• Internal radiation therapy– = brachytherapy, which means short-distance therapy.– Radioactive containers are placed into the tumor or into acavity close to the tumor.– Advantage: the ability to deliver a high dose of radiation to asmall area – useful in cases that need a high dose of radiationor a dose that would be more than the normal tissues couldstand if given externally.– The main types of internal radiation are:• interstitial radiation: the radiation source is placed directly into ornext to the tumor using small pellets, seeds, wires, tubes, orcontainers.• intracavitary radiation: a container of radioactive material is placed ina cavity of the body such as the chest, uterus, or vagina.– May be temporary or permanent
Radiation Therapy• Radiopharmaceuticals– Radiopharmaceuticals are drugs containingradioactive materials.– Systemic radiation therapy.– Can be given intravenously (IV), orally, or into abody cavity.– Depending on the drug and how it is given, thesematerials travel to various parts of the body totreat cancer.
Intravenous Anesthetics• Primarily used for the induction ofanesthesia• Reduce Stage II (excitatory phase) ofgeneral anesthesia• IV anesthetics:– Barbiturates (thiopental)– Propofol– Ketamine– Benzodiazepines (midazolam)
Inhaled Anesthetics• Used for maintenance of anesthesia after administrationof an intravenous agent• Volatile agents (halogenated hydrocarbons)– Halothane– Isoflurane– Sevoflurane– Enflurane– Desflurane• Anesthetic gases– Nitrous oxide (N2O)Halothane Enflurane
Organ System Effects• Respiratory system– All (except nitrous oxide) cause respiratory depression –reduce or eliminate ventilatory drive and reflexes thatmaintain airway patency – must assist breathing– Gag reflex lost– Stimulus to cough is blunted– Lower esophageal sphincter tone is reduced• Kidney– Decreased renal blood flow and GFR• Hepatotoxicity – halothane (toxic metabolites)
Organ System Effects• Postoperative Issues– N/V– Hypertension– Shivering– Airway obstruction – particularly of concern inpatients who snore or have sleep apnea• Potential for creation of negative pressure leading topulmonary edema– Pain – opioids can be problematic due to additiverespiratory depression
Mechanism of Action:Local anesthetics block voltage-gated Na+channels (need to accessthose channels from inside the cell)DOES NOT INCREASE GABA OR NMDA EFFECTSCharged (BH+) formbinds at the inside ofNa+channelsUnionized, lipid solubleform (B) enters the cell
Local Anesthetics• Drug of choice – depends on duration of action– Procaine (short-acting)– Lidocaine (intermediate-acting)– Tetracaine (long-acting)• Vasoconstrictor (epinephrine) needed with short- andintermediate-acting local anesthetics (procaine, lidocaine) toprolong their duration of action• Other local anesthetics – articaine, etidocaine, mepivacaine,prilocaine, ropivacaine, dibucaine, dyclonine hydrochloride,pramoxine hydrochloride, benzocaine
Why is it important that patientshave an empty stomach prior tosurgery?– Answer: General anesthetics act on the chemoreceptortrigger zone and the vomiting center of the brain stem.Because vomiting is a possibility while under generalanesthesia, it is important that the patient’s stomach beempty to minimize the vomiting. Also, when anesthesiais given, it is common for normal reflexes to relax. Thehorizontal position of the patient may allow for stomachcontents to travel from the gastrointestinal tract intothe esophagus, mouth, or even the windpipe and lungs.The foreign matter in the lungs may cause aspirationpneumonia.
Which over-the-counter anesthetics areavailable for dental issues? What are theirmechanisms of action and indications?• Benzocaine is the active ingredient used in themajority of dental issues. The mechanism ofaction is blocking the voltage gated Na+channels which causes a decrease in Na+permeability. As a result, the conduction ofnerve impulses is blocked. Alcohols are alsoused, which are inactive ingredients that havesome local anesthetic effect.
What is the main ingredient in the OTC urinaryanesthetics/analgesics available? What is themechanism of action and indications?• Ingredient - phenazopyridine• Mechanism of action – unknown – mostlylisted as an analgesic, but may also have localanesthetic properties; acts on the urinary tractas it is excreted
What anesthetics are available forsore throats?• Lozenges• Cepacol Sore Throat Sugar (Benzocaine 15mg;Pectin 5 mg)• Chloraseptic Sore Throat (Benzocaine 5mg;Menthol 10 mg)• Sucrets Classic Sore Throat (Dycloninehydrochloride 2 mg)
Miscellaneous• Lidocaine- used for surgery• Used in oral medications: lidocaine, dyclonine,tetracaine
Staining• Cell walls– Cytoplasmic membrane covered with peptidoglycancell wall (both gram neg and gram pos)– Amino acids from neighboring peptidoglycans willcross-link, stabilizing the structure• Enzyme that catalyzes crosslinks is a target for penicillin– Gram positive cell wall is thick with many complexcrosslinks– Gram negative cell wall is thin with few simplecrosslinks– Bacterial cytoplasmic membrane has no cholesterol orother sterols
Staining• Gram negative– Have inner cytoplasmic membrane, small space, thinpeptidoglycan cell wall (no teichoic acid), unique outermembrane that contains lipopolysaccharide (LPS)• Outer membrane is anchored to cell wall by murein lipoprotein• LPS contains three components, including lipid A, which is toxic tohumans (endotoxin)• When bacterial cells are lysed by a properly functioning immunesystem, fragments of membrane containing lipid A are releasedinto the circulation, causing fever, diarrhea, and possibly fatalseptic (endotoxic) shock– Outer LPS-containing layer blocks out molecules (Gramnegative), including antibiotics and lysozyme
Staining• Gram positive– Extensive crosslinking of cell wall outside cytoplasmicmembrane– Peptidoglycan, TEICHOIC ACID, polysaccharides,proteins– Inner surface of cell wall touches outer surface ofcytoplasmic membrane– Thickly meshed peptidoglycan layer does not blockthe passage of small molecules, so dyes can enter(Gram positive) – large enough to become trapped
Gram Positive• 6 main gram positive organisms that causedisease in humans – most of the other diseasecausing organisms are gram negative– Streptococcus sp.– chains of cocci– Staphylococcus sp. – clumps of cocci– Bacillus sp. – rods that form spores– Clostridium sp. – rods that form spores– Corynebacterium sp. – rods (no spores)– Listeria sp. – rods (no spores) – only gram positiveorganism that has endotoxin
Growth Requirements• Oxygen requirement– Obligate aerobes – require oxygen– Anaerobes – do not require oxygen• Aerotolerant anaerobes – can survive in the presenceof small amounts of oxygen, but thrive without oxygen– Facultative anaerobes – can grow under aerobicor anaerobic conditions• Temperature – most pathogenic bacteria growbest at body temperature (35-37° C)
Virulence• Enzyme-mediated tissue damage– Bacterial metabolites, degradative enzymes, cytolyticexotoxins• Adherence– Pili or adhesion molecules – allows for colonization• Toxin-induced localized and systemic effects– LPS (endotoxin) is in cell wall of gram negativebacteria – initiates complement and clotting cascade– can lead to shock• Resistance to antibiotics
Virulence• Invasion and growth in normally sterile sites –even normal flora can cause disease wheninvading sites such as CSF, blood, lung• Circulation via the blood or other means ofspreading from primary infection site– Tissue damage promotes the spread of bacteria• Evasion of host immune response by capsule,catalase production, intracellular growth andother mechanisms
Gram Positive Bacteria• Staphylococcus spp.– S. aureus, S. epidermidis, S. saprophyticus– Normal flora– S. aureus is most virulent• MRSA – Methicillin resistant staph aureus• Toxin-mediated diseases – food poisoning (salted or smokedmeats or creamy foods), toxic shock syndrome• Inflammatory diseases with pyogenic and necrotic functions –range from mild skin lesions to life-threatening systemic diseasesand bacteremia– S. epidermidis – can colonize prosthetic heart valves,stents, prosthetic joints– S. saprophyticus – frequent cause of UTIs in sexually activeyoung women
Gram Positive Bacteria• Streptococcus spp.– S. pyogenes, S. pneumoniae, and others (causes ofserious neonatal disease, endocarditis, dentalcaries)– S. pyogenes• Group A strep – causes strep throat, skin infections,postsurgical cellulitis,– Toxin-mediated diseases – also causes TSS, scarlet fever– Nonsuppurative autoimmune sequelae – acuteglomerulonephritis, rheumatic fever
Gram Positive Bacteria• Clostridium spp.– C. botulinum, C. difficile, C. perfringens, C. tetani– Gram positive (rods) anaerobes that form sporesand produce potent exotoxins– Produce serious diseases – gas gangrene, tetanus,food poisoning (botulism), necrotizingenterocolitis• Corynebacterium diphtheriae– Cause of respiratory and cutaneous diphtheria
Gram Negative Bacteria• Neisseria spp.– Neisseria meningitidis – causes meningitis, usuallyin children under 5 and among those living inclose quarters, such as college students andmilitary personnel– Neisseria gonorrhoeae – causes acute gonorrhea,pelvic inflammatory disease, infection of femalereproductive organs
Gram Negative Bacteria• Haemophilus influenzae– Type b (Hib) is the most virulent – can causemeningitis, epiglottis, arthritis, otitis, etc.• Pseudomonas aeruginosa– Causes opportunistic infections• UTI, burn wound infections, ear infections, skininfections, pulmonary infections (particularly in CF pts.)
NRTIs andNNRTIsFusion inhibitors-stop entry into thecellProtease Inhibitors http://www.mcat45.com/images/HIV-replication-cycle.png
Viral Replication• DNA viruses– DNA enters host cell nucleus– Is transcribed to messenger RNA– mRNA is translated into viral proteins• RNA viruses– Host cell could use enzymes contained in viral particle tosynthesize mRNA– Or the viral RNA could serve as its own mRNA – the mRNA istranslated into viral proteins, such as RNA polymerase, and moremRNA and genomic RNA is made• Retroviruses– Contain reverse transcriptase enzyme that makes DNA from viralRNA and then the DNA inserts into the host genome
Clinical Course of Disease• Incubation period – site of disease and time neededfor damage to occur determines incubation period– Diseases that manifest at site of entry usually haveincubation periods less than 1 week – exception ispapillomaviruses (7-21 weeks)– Diseases that manifest in tissues distant from the site ofentry have incubation periods ranging from 1 week toseveral months– Diseases that result from damage to the immune systemor from slow accumulation of tissue damage may haveincubation periods ranging from several weeks (HBV, EBV)to years (HIV)
DNA Viruses• Noneveloped DNA viruses– Human papillomavirus• Infect and replicate in cutaneous and mucosalepithelial tissue• Leads to production of proteins that inactivate tumorsuppressor proteins Rb and p53, leading to hyperplasiaof host cells• Transmission occurs through direct contact with skinwarts or genital warts, or through mother/childtransmission during birth• HPV can lead to cervical cancer
DNA Viruses• Enveloped DNA viruses– Varicella zoster virus – still in Herpesviridae family– Double-stranded DNA virus– Human herpesvirus 3 – commonly called varicella zoster virus (VZV)and causes two common diseases• Chickenpox – called varicella• Shingles – called herpes zoster– Chickenpox is result of primary infection – one of the most commoncommunicable diseases worldwide• Highly contagious• Common in children, but can have serious consequences in adults andimmunocompromised patients– Shingles is result of VZV reactivation – not life-threatening, but causessevere pain and neuralgia
DNA Viruses• Enveloped DNA viruses– Epstein-Barr virus (EBV)• Herpes virus• Double-stranded DNA virus• Viral envelope is derived from cellular membranes of host cells throughbudding process – envelope is essential for infectivity• Infects B lymphocytes – establishes a latent infection with immortalization ofthe cell with restricted expression of viral proteins• Latent infection can be activated to lytic infection• Only B cells are infected• Transmission is through oral secretions – often through kissing• About 90% of adults have been exposed to EBV – two peaks of transmission(ages 1-6 and ages 14-20)• Diseases associated with EBV– Infectious mononucleosis, Burkitt’s lymphoma, nasopharyngeal carcinoma (NPC),Hodgkin’s disease, other lymphoid and epithelial tumors
RNA Viruses• Nonenveloped RNA viruses– Includes poliovirus, coxsackieviruses, hepatitis A virus,rhinoviruses (common cold), rotoviruses, Norwalk virus– Poliovirus binds to receptors on muscle cells and neurons• Different disease outcomes – paralytic, nonparalytic, may alsocause minor illness– Coxsackievirus A – hand-foot-and-mouth disease – self-limiting disease of young children with vesicular lesionsand mild fever– Rotovirus – infection of GI epithelial cells leading to waterydiarrhea and vomiting• Fecal-oral transmission• Most serious in infants (dehydration can be fatal)
RNA Viruses• Influenza– Large antigenic shifts occur every 10-40 years historicallyto cause pandemic influenza outbreak – because it is sodifferent from previous strains large segments ofpopulation is susceptible– Transmission – inhalation of respiratory droplets frominfected person– Vaccine is available – made based on strains prevalentduring the previous flu season– The major site of infectivity is ciliated columnar cells– No explanation for many of the symptoms, such asmyalgia
RNA Viruses• Respiratory syncytial virus (RSV)– Enveloped RNA virus with non-segmented, single-stranded, negative-sense genome– Leading viral agent causing death in children under 5years old (worldwide)– Common agent causing pneumonia and bronchiolitisin infants and trachobronchitis and upper RTIs inolder children and adults– RSV is highly contagious– Lower respiratory tract disease associated withprimary infection is almost entirely confined to thechild under 3 years of age
RNA Viruses• RSV– Transmission – requires contact with large particles of respiratorysecretions– Eyes and nose are major portals of entry– RSV will remain infectious on hands long enough to be transmitted toself or others – handwashing is essential to limit transmission– Healthcare workers may be important carriers of RSV, as they mayhave mild symptoms and continue to work– Early bronchiolitis – inflammation– Progresses to necrosis and sloughing of bronchiolar epithelia – deadcells will plug up small airways, blocking airflow
Nucleoside/Nucleotide Analogs• Similar mechanisms of action• Similar indications for clinical use• All are well tolerated – side effects uncommon• Analogs are incorporated into the viral nucleicacid, which is then nonfunctional– Insert themselves into DNA and makenonfunctional viral components• Converted by viral enzymes– For example, acyclovir is converted to acyclovirmonophosphate by a viral enzyme
Nucleoside/Nucleotide Analogs• Acyclovir (Valtrex)– Mechanism of Action• Viral thymidine kinase converts acyclovir to acyclovir-monophosphate• Further phophorylated to triphosphate• Competes with endogenous compounds for DNApolymerase and binds irreversibly to DNA template• Chain termination when incorporated into viral DNA– Clinical Uses• HSV-1, HSV-2, and VZV• Weaker activity against EBV, CMV, HHV-6
Nucleoside/Nucleotide Analogs• Acyclovir– ADME• Oral, IV, and topical formulations• Excreted in urine• Diffuses in most fluids and tissues, including CSF (levelsare 50% of serum levels)– Resistance• Occurs through mutation of viral thymidine kinase orDNA polymerase• Cross-resistance in other analogs that requirethymidine kinase activation
Nucleoside/Nucleotide Analogs• Other NS/NT analogs– Valacyclovir (HSV and VZV)– Famciclovir (HSV and VZV)– Penciclovir (topical) (HSV)– Trifluridine (HSV, vaccinia, and some adenoviruses)– Ganciclovir (HSV, VZV, EBV, HHV-6, CMV, and KSHV)• Oral, IV, or intraocular implant• Adverse effects – myelosuppression, retinal detachment
Preventing Viral Entry• Docosanol– Saturated 22-carbon aliphatic alcohol– Inhibits fusion between the plasma membraneand the HSV envelope, preventing viral entry intothe cells– Available without prescription (topical) fortreatment of herpes viral infection – Abrevahttp://www.abreva.com/
Antiretroviral Therapy• HAART – highly active anti-retroviral therapy– Multiple drug therapy – 3 or 4 drugs– Reduces viral replication to the lowest possiblelevel– Decreases likelihood of resistance
NRTIs andNNRTIsFusion inhibitorsProtease Inhibitors-block release of viralparticles (can still form,just don’t bud off)http://www.mcat45.com/images/HIV-replication-cycle.pngIntegrase StrandTransfer Inhibitors
NRTIs• Act by competitive inhibition of HIV-1 reversetranscriptase• Can be incorporated into the growing viralDNA chain to cause termination• Each requires intracytoplasmic activation viaphosphorylation by cellular enzymes to thetriphosphate form• Most have activity against HIV-2
NRTIs• Abacavir (Ziagen) – guanosine analog– Metabolism – glucuronidation and carboxylation– 50% protein-bound– Hypersensitivity syndrome• Didanosine (Videx)– adenosine analog– Degraded at low gastric pH – must be taken with antacid– Food decreases bioavailability– Renal secretion – little metabolism– Not extensively protein-bound– Main side effects – peripheral neuropathy and pancreatitis• Emtricitabine (Emtriva) – cytosine analog– Renal secretion – little metabolism– Not extensively protein-bound– Few adverse effects and no effect on mitochondrial DNA
Protease Inhibitors• Adverse Effects– Redistribution and accumulation of body fat(except atazanavir)– Increases in blood lipids levels– Glucose intolerance and insulin resistance– Causes of these adverse effects is unknown– Increased bleeding in pts. with Hemophilia A or B– May be inducers or inhibitors of P450 enzymes
Fusion Inhibitors• Enfuvirtide (Fuzeon)– First agent in this new class of antiretroviral drugs– Synthetic peptide– Blocks viral entry into the cell– Binds to the gp41 viral envelope glycoprotein– Prevents fusion of virus with plasma membrane– SC injection– Adverse effects - local reactions at the injection site
Anti-influenza Agents• Zanamivir (Relenza) and Oseltamivir (Tamiflu)– Neuraminidase inhibitors– Interfere with the release of progeny virus from infected cells to newhost cells– Effective against influenza A and B– Early administration is required– Zanamivir is administered via inhalation– Oseltamivir is administered orally– Avoid near vaccination times – noted exceptions– Look up adverse effects and warnings on Lexicomp
Categories• Superficial mycoses – surface of hair, nails, skin• Cutaneous mycoses – involve epidermis and deeper layers ofhair, skin, and nails• Subcutaneous mycoses – involves dermis, and subcutaneoustissues and muscles - cause chronic nodules or ulcers insubcutaneous tissues• Systemic mycoses – inhaled from the environment (soil, etc.)and produce lung infections that spread inimmunocompromised host• Candidiasis – caused by Candida albicans – opportunisticpathogen
Fungal Infections• Cutaneous mycoses– Caused by about 30 different fungi called dermatophytes– Includes ringworm, jock itch, athlete’s foot, scalp infection(common in children), nail infection– Also includes cutaneous candidiasis – oral thrush(neonates, diabetics, AIDS pts., pts. taking antibiotics orsteroids) and vulvovaginitis (antibiotic use, pH increase,diabetes) – in immunocompromised cancer and transplantpts will present as disseminated disease– Topical treatment
Fungal Infections• Subcutaneous mycoses– Often caused by organisms in the soil – may bemelanin-containing– Enter into breaks in the skin – may remain local ortravel through lymphatic system– Sporothrix schenckii – causes sporotrichosis ingardeners, from thorn prick
Fungal Infections• Systemic mycoses– Aspergillus spp. – appears as ‘fungus ball’ on X-ray –induces allergic reactions and becomes systemic inimmunocompromised patients– Pneumocystis jiroveci (sometimes classified as aprotozoan) – interstitial pneumonia in AIDS patients– Coccidioides immitis – endemic in desert areas ofsouthwestern US• San Joaquin Valley fever – acute, self-limiting flu-like illness
Fungal Infections• Systemic mycoses– Cryptococcus neoformans – found in pigeon droppings andnests• May appear as a single nodule resembling a tumor• Can spread to CSF – AIDS patients– Histoplasma capsulatum – endemic in Ohio andMississippi River valleys• Found in bird and bat droppings• Pulmonary granulomas visible on X-ray
Parasitic Infections• Blood and tissue protozoa– Leishmania spp.• Endemic to tropical and subtropical regions• Transmitted by sandfly• Infects macrophages leading to cutaneous, mucocutaneous, andvisceral disease– Plasmodium spp.• Endemic to tropical regions• Transmitted by female Anopheles mosquito• Causes malaria• Life cycle takes place in mosquito, human liver, and human redblood cells
Parasitic Infections• Blood and tissue protozoa– Toxoplasma gondii – acquired from cat litter, ingestion ofundercooked meat, or in utero• Mononucleosis-like syndrome in healthy individuals• Potentially fatal encephalitis in immunocompromised patients– Trypanosoma cruzi• Endemic to South America• Transmitted by reduviid bug• Causes Chagas’ disease – cardiomyopathy, megacolon,megaesophagus)
Parasitic Infections• Helminthic parasites– Roundworms• Trichinella spiralis– Transmitted by eating undercooked meat, especially pork– Encysted larvae in muscle – extreme muscle pain– Fever, diarrhea, eye edema, hemorrhages under nails
Parasitic Infections• Helminthic parasites– Flukes and flatworms• Schistosoma spp. – blood and bladder flukes– Transmitted through skin penetration by motile larvae – snails areintermediate hosts– Fibrosis of liver and ascites– Bladder granulomas and hematuria– Eggs are covered with spines – stool or urine• Taenia spp. – beef and pork tapeworms (up to 10 m)– Suckers and hooks on larvae– Abdominal pain, diarrhea, weight loss– Brain, eye, and muscle involvement (cysts and inflammation) due toingestion of eggs rather than larvae – rare in US
β-lactams inhibit peptidoglycancross-linking• Peptidoglycan:polymers of glycanunits, joined bypeptide cross-links(transpeptidation)mediated by atranspeptidaseenzyme AKA-PenicillinBinding Protein (PBP)• Cross linking give cellwall its structuralrigidity• Peptidoglycan is notfound in mammaliancellsNAG=N-acetyl glucosamineNAM=N-acetyl muramic aci
β-lactamsMechanism of Action- As structural analogs of terminal D-Ala—D-Ala onthe peptidoglycan strand, β-lactams bind to PBPsand competitively block its activity (competitiveinhibitor)- Prevent the formation of an intact cell wall,resulting in bacterial lysis (bactericidal)- For β-lactam antibiotics to work, bacteria must besynthesizing cell walls thus β-lactams should notbe combined with bacteriostatic drugs
Mechanisms of bacterial resistance toβ-lactams1. Production of β-lactamases (most common)2. Alteration of PBPs
Inactivation of β-lactams by β-lactamasesHundreds of bacterial β-lactamases identified–Differ between species and in selectivity• S. aureus, Haemophilus sp. and E. coli beta lactamases– Relatively narrow substrate specificity with preference forpenicillins• P. aeruginosa and Enterobacter sp. produce AmpCbeta-lactamase– Hydrolyzes both penicillins and cephalosporins• Several species produce Extended-Spectrum Beta-Lactamases (ESBL)– Both penecillin and cephalosporin selectivity
Penicillins1- Natural penicillins: Penicillin G , Penicillin VPharmacokinetics:Penicillin G: Acid labile; administered parenterallyProcaine and benzathine penicillin G: Waterinsoluble depot or repository formsadministered IMPenicillin V: Acid stable (oral)
Penicillins1- Natural penicillins: Penicillin G , Penicillin VMajor therapeutic use:PenG:Drug of choice for infections caused by streptococci (e.gpharyngitis), meningococci (e.g meningitis), and T.pallidum (syphilis)PenV:Indicated only in minor infections because of:– Poor oral bioavailability– qid dosing– Less active than Pen G
Penicillins1- Natural penicillins: Penicillin G , Penicillin VBacterial resistance:Mainly by production of penicillinases (a β-lactamasethat inactivates penicillins)
Penicillins2. Antistaphylococcal (penicillinase resistant) penicillinsMajor therapeutic use:• Used exclusively in treatment of Staphylococcal infections• Unfortunately, now there is Methicillin-ResistantStaphylococcus aureus (MRSA), Methicillin-ResistantStaphylococcus epidermidis (MRSE) as a source of serioushospital-acquired infections– Mechanism of resistance: PBP alteration (have lower affinityto β-lactams)– Treatment: MRSA and MRSE infections are treated withvancomycin
Penicillins2. Antistaphylococcal (penicillinase resistant) penicillinsPharmacokinetics:- Dicloxacillin, and oxacillin are acid stable (given orallyfor mild staph. infection)- Nafcillin is somewhat less stable in acidic media(given IV for serious systemic staph. infection)- Oxacillin can also be given IV for serious systemicstaph. infection
Penicillins3. Extended spectrum penicillinsMajor therapeutic uses:Amoxicillin, ampicillin:– Treatment of infections due to susceptible Gm- microbes(e.g RTI, UTI, Otitis, sinusitis )– Drug of choice for treating infections caused by enterococci– Treatment of mixed infections caused by susceptible Gm+and Gm- organisms– Treatment of penicillin-resistant pneumococci
Penicillins3. Extended spectrum penicillinsMajor therapeutic uses:PiperacillinTreatment of serious systemic infections caused byGram(-) bacteria• Hospital-acquired infections (Immunocompromised patients)• Sepsis• Pneumonias• Infected burns• Treatment of P. aeruginosa infections: usually in combinationwith an aminoglycoside
PenicillinsPharmacokinetics• Absorption of most oral penicillins (except foramoxicillin) is impaired by food; should beadministered 1-2 h before or after meal• Excretion of most penicillins (except forAntistaphylococcal penecillins) is by kidney;need to adjust dose in renal failure
CephalosporinsGrouped into 5 generations based on theirspectra of activity:– First generationDrug Administration EliminationCefadroxil p.o RenalCefazolin IV RenalCephalexin p.o Renal
CephalosporinsGrouped into 5 generations based on theirspectra of activity:– Second generationDrug Administration EliminationCefaclor p.o RenalCefprozil p.o RenalCefuroxime IV, IM RenalCefoxitin IV RenalCefotetan IV, IM RenalRed: Cephamycins
Cephalosporins– Third-generationDrug Administration EliminationCefixime p.o RenalCefdinir p.o RenalCefpodoxime p.o RenalCeftibuten p.o RenalCefotaxime IV RenalCeftazidime IV, IM RenalCeftizoxime IV RenalCeftriaxone IV, IM Biliary/renal
CephalosporinsGrouped into 5 generations based on theirspectra of activity:– Fourth-generation– Fifth generationDrug Administration EliminationCefepime IV, IM RenalDrug Administration EliminationCeftaroline IV Renal
CephalosporinsThird generation cephalosporinsSpectrum of activity:– Much less effective than 1stgeneration against Gm+– Compared with 2ndgeneration, these drugs have expandedGm- coverage– Resistant to some Gm- β-lactamases but susceptible toenterobacter β-lactamase (Amp C)– Ceftriaxone and cefotaxime: Anti-pneumococcal activity– Ceftazidime : Active against P. aeruginosa
CephalosporinsFourth generation cephalosporin (Cefepime)Spectrum of activity:- Extensive Gm- coverage plus better Gm+ coverage than 3rdgeneration- Better resistance to Gm- β-lactamases than 3rdgeneration(esp. of enterobacter and penicillin resistant streptococci)- Active against P. aeruginosaMajor therapeutic use:– Similar to 3rdgeneration– Useful in treatment of enterobacter infections– Used for severe infections (Pneumonia, sepsis, meningitis)
CephalosporinsFifth generation cephalosporin (Ceftaroline)Spectrum of activity:• Gm- coverage similar to 4rdgeneration• Gm+ coverage including methicillin-resistantStaphylococcus aureus (MRSA)Major therapeutic use:• Community-acquired pneumonia• Complicated skin and skin structure infection
CephalosporinsAdverse effects of cephalosporins– Select 2nd generation drugs (cephamycins) containN-MethylThioTetrazole side chain (MTT side chain)• Cephamycins (Cefoxitin, cefotetan)• These agents cause– Disulfiram-like reaction– Hypoprothrombinemia and bleeding(anti-vitamin K effect)N-Methylthiotetrazole
β-lactam antibioticsCarbapenems– Imipenem– Meropenem– Ertapenem– Poripenem General structure of carbapenems
β-lactam antibioticsCarbapenemsPharmacokinetics:– IV administration– IM: Ertapenem is formulated with 1% lidicaine– Renal excretion- Imipenem is inactivated by dehydropeptidases in the renaltubule; therefore administered with equal quantity of cilastatin- Cilastatin is a dehydropeptidase inhibitor and must be co-administered with imipenem to ensure its efficacy.
β-lactam antibioticsCarbapenemsMajor therapeutic use– Drug of choice for ESBL infections– Plays a role in empirical therapy– Treatment of choice of Enterobacter infections– With/out an aminoglycoside for P. aeruginosa infectionsAdverse effects (More common with imipenem)– Hypersensitivity– NVD– Local reactions– Seizures
β-lactam antibioticsMonobactamsAztreonam (given IV)Spectrum of activity:– Relatively resistant to β-lactamases– No significant cross-reactivity with penicillins– Narrow spectrum of activity (Active against Gm-aerobes including Pseudomonas ; inactive againstGm+ bacteria or anaerobes)
Non-β-lactam Cell Wall SynthesisInhibitorsFosfomycin (p.o)Mechanism of action:– Inhibits step 1 in cell wall synthesis– Structural analog of phosphoenol pyruvate (PEP)– Inhibit enol pyruvate transferase: block the formation of N-acetyl-muramic acidFosfomycin Phosphoenol pyrovate
Non-β-lactam Cell Wall SynthesisInhibitorsFosfomycin (p.o, IV)Spectrum of activity:– Broad spectrumExcretion:– RenalMajor therapeutic use– Uncomplicated lower UTI
Non-β-lactam Cell Wall SynthesisInhibitorsBacitracinMechanism of action:– Inhibits Step 3 in cell wall synthesis– Blocks dephosphorylation of isoprenyl pyrophosphate, a lipidwhich carries the building blocks of peptidoglycan outside theplasma membraneSpectrum of activity:– Gram +; Neisseria; T. pallidumMajor therapeutic use– Topical application ONLY (renal failure)– Localized skin infections– Prevention of wound infectionsBacitracin: a cyclic polypeptide
Non-β-lactam Cell Wall Synthesis InhibitorsVancomycinMechanism of action:– Bind with high affinity to the D-Ala—D-Ala terminus of pentapeptide– Block transglycosylase (elongation of peptidoglycan) and transpeptidation (crosslinking)Spectrum of activity:– Active only against Gram(+) bacteria, including MRSA, MRSE (bactericidal)– Enterococci (bacteriostatic)Major therapeutic use– Used in treatment of serious infections with β-lactam resistant Gram(+) bacteria or incases of allergy to β-lactams– Treatment of MRSA, MRSE infections (sepsis, endocarditis)
Non-β-lactam Cell Wall SynthesisInhibitorsVancomycinPharmacokinetics– Administered IV (Slow infusion)– Administered orally only for the treatment of pseudomembranouscolitis caused by Clostridium difficile (local effect in colon);metronidazole is preferred as initial therapy.Adverse effects:– Vancomycin: Red Man Syndrome: flushing, shock in severe cases(caused by vancomycin-induced histamine release due to rapidinfusion)– Phlebitis at the site of injection– Ototoxicity– Nephrotoxicity
Non-β-lactam Cell Wall SynthesisInhibitorsVancomycinBacterial resistance– Vancomycin Resistant Enterococci (VRE) synthesizepentapeptide with D-ala-D-lactate or D-ala-D-serineterminus, (reduced affinity for drug)– Vancomycin Resistant S. Aureus (VRSA) can overexpressD-ala-D-ala (competitor to bind up the drug)
SulfonamidesMechanism of action• Structural analogues of para-aminobenzoicacid (PABA)• Inhibit dihydropteroate synthase (whichproduces dihydrofolic acid); competitiveinhibitor• Bacteriostatic• High concentrations of PABA inhibit sulfaactivity
SulfonamidesSpectrum of activity• Broad Spectrum• Active against many Gm+ bacteria including MRSA,Streptococci, Nocardia, and Clostridium perfringens.• Active against Gm- organisms (E Coli, Klebsiella,Proteus, Salmonella, Shigella)• Active against some protozoa (Plasmodium,Toxoplasma gondii) and atypical bacteria (Chlamydiatrachomatis)
SulfonamidesMajor therapeutic use• Not typically used alone for common bacterialinfections• Treatment of malaria• Treatment of CNS toxoplasmosis
SulfonamidesAdverse effects• Hypersensitivity (cross reactivity with othersulfonamides, diuretics (thiazides,acetazolamide), and sulfonylurea antidiabeticagents– Steven’s Johnson syndrome (SJS)• GI distress• Crystalluria: drink plenty of fluids (sulfadiazine)• Bone marrow suppression• Hepatotoxicity and nephrotoxicity• Photosensitivity• Kernicterus in infants -competes for bilirubinbinding sites on albumin and increases levels ofunconjugated bilirubin- CNS toxicity
SulfonamidesMechanism of bacteria resistance:• Overproduction of PABA• Reduced enzyme affinity(dihydropteroate synthase)• Reduced cell permeability tosulfonamides
TrimethoprimMechanism of action• Acts sequentially with sulfonamindes in thesynthesis of purines• Inhibit dihyrofolate reductase (DHFR) (whichproduces tetrahydrofolic acid)• 50,000X more active against bacterial DHFRthan human DHFR
Trimethoprim-SulfamethoxazoleSpectrum of activity• Broad spectrum: Many Gm+ (including MRSA)and Gm- (including E, coli, H. influenza, Moraxellacatarrhalis, Klebsiella pneumonia)• Not active against Pseudomonal spp, anaerobes,or atypical bacteriaMajor therapeutic use• UTIs (decreased efficacy with increasing E.coliresistance rates)• Pneumocystis pneumonia• Sinusitis, otitis media
Trimethoprim-SulfamethoxazoleAdverse effects• Same as sulfa• Folinic acid supplement?Bacterial resistance to trimethoprim• Overproduction of DHFR• Reduced enzyme affinity (DHFR)• Reduced cell permeability to trimethoprim
Mechanism of action• Inhibit bacterial DNA synthesis (DNA replication)• Inhibit bacterial topoisomeraseII (DNA gyrase) andtopoisomeraseIV– TopoisomeraseII : responsible for DNA unwinding needed for initiation ofDNA replication– TopoisomeraseIV: responsible for separation of replicated chromosomalDNA into the respective daughter cells during cell division.• Bactericidal• Killing is concentration dependent, significant PAEFLUOROQUINOLONES
FluoroquinolonesDrug-drug interaction• Certain fluroquinolones inhibit CYP1A2enzyme: decrease metabolism of xanthinederivatives (theophylline) and warfarin(Cipro>levo>moxi)• Increased risk of torsade de points incombination with agents that increase the QTinterval (class IA or III antiarrhythmic agents)
Post Antibiotic Effect (PAE): Persistentsuppression of bacterial growth that resultsfrom drug exposure after the drug has beencompletely removed.
Combination Antimicrobial TherapySome mechanisms of antibiotic synergism:1. Each antibiotic affects a different step in a biochemicalpathway (trimethoprim + sulfamethoxazole)2. One drug may enhance the uptake of a second drug bythe microorganism (penicillin + aminoglycoside)3. One drug may prevent the enzymatic degradation ofanother drug (amoxicillin + clavulanic acid)
Protein syn (50s)• Erythromycin• Chloramphenicol• Clindamycin
Protein syn (30s)• Tetracycline• Spectinomycin• Streptomycin• Gentamicin, Lobramycin• Amixacin
Chloroquine• Synthetic 4-aminoquinoline• Drug of choice since the 1940s• Resistance is a common problem in P. falciparum, andincreasing in P. vivax• Drug of choice for treatment and prophylaxis of sensitivemalaria• Mechanism of action– Blood schizonticide (moderately effective gametocide against allspecies but falciparum)– Not active against liver stage parasites– May act by concentrating in the parasite food vacuoles andpreventing the polymerization of heme into hemozoin – toxic dueto buildup of free heme
Amodiaquine• Closely related to chloroquine• Most likely shares mechanism of action andresistance• Low cost, limited toxicity, in some areas effectiveagainst chloroquine-resistant malaria• Heme to hemozosin• Adverse effects– Agranulocytosis, aplastic anemia, hepatotoxicity– Not used prophylactically because of toxicity with long-term use
Quinine and Quinidine• First-line therapy for falciparum malaria, esp. insevere disease• Toxicity may affect therapy• Resistance is uncommon but increasing• Derived from bark of cinchona tree• Quinidine is the D stereoisomer of quinine• Mechanism of action– Blood schizonticide for all four species– Gametocide for P. vivax and P. ovale– Not active against liver stage parasites– Mechanism of action unknown
Primaquine• Clinical Uses– Given in conjunction with chloroquine for radical cure– Given after completion of travel in endemic area– Could be used prophylactically, but toxicity of concern, sonot used routinely– Used in the treatment of Pneumocystis jiroveci• Adverse Effects– Rare – hematological and cardiac dysfunction• Contraindications– Patients with hematological problems or receivingmyelosuppressive drugs
Other Antimalarial Agents• Atovaquone– Effective prophylaxis with proquanil (Malarone)– Mechanism unknown• Inhibitors of Folate Synthesis– Pyrimethamine and proquanil– Fansidar (combination of sulfadoxine and pyrimethamine)– Effective against RBC forms of all four species– Also used to treat toxoplasmosis and pneumocystosis– Well tolerated
Other Antimalarial Agents• Antibiotics– Folate antagonists– Sulfonamides– Tetracycline and doxycycline – RBC form– Clindamycin – RBC form – given to children• Artemisinin– Oral administration only– More soluble analogs (artesunate, artemether)– Widely available in other countries– Blood schizonticide– Not effective against hepatic stages
Amebiasis• Amebiasis– Infection with Entamoeba histolytica– Luminal or extraintestinal infection• Metronidazole and Tinidazole– Metronidazole – drug of choice for extraintestinalinfection• Eradicates intestinal and extraintestinal inf.• Also drug of choice for giardiasis and trichomoniasis– Tinidazole• Similar activity and less toxicity– Mechanism of action – reduction of nitro group to reactiveproduct
Amebiasis• Iodoquinol– Luminal amebicide – commonly used with metronidazole– Mechanism of action unknown– 90% of drug retained in intestine• Diloxanide furoate– Luminal amebicide– Mechanism of action unknown• Paromomycin sulfate– Luminal amebicide– Less toxicity than other agents
Antihelminthic Drugs• Albendazole– Drug of choice for hydatid disease andcysticercosis– Also used for pinworms, hookworms, ascariasis,trichuriasis, and strongyloidiasis– Undergoes first pass metabolism to the activemetabolite– Inhibits microtubule synthesis– Well tolerated
Bithionol• Drug of choice for fascioliasis (sheep liverfluke)• Also used for paragonimiasis• Up to 40% of patients experience mild sideeffects – GI effects, headache, dizziness
Ivermectin• Drug of choice for strongyloidiasis and onchocerciasis• Alternate drug for a number of other helminth infections• Paralyzes nematodes and arthropods by increasing GABAsignaling• Also effective against other parasites• Adverse effects– Strongyloidiasis treatment – infrequent• Fatique, dizziness, N/V, abdominal pain, rash– Onchocerciasis treatment• Mazotti reaction – due to killing of microfilariae• Fever, headache, rash, weakness, hypotension, peripheral edema
Piperazine• Alternative treatment for ascariasis• Not recommended for other helminthinfections• Blocks acetylcholine at the neuromuscularjunction – causes paralysis of worm• Contraindicated in pregnancy, patients withimpaired renal or liver function, and inpatients with a history of epilepsy or chronicneurological disease
Pyrantel Pamoate• Poorly absorbed from the GI tract, so mosteffective against luminal parasites• Neuromuscular blocking agent – paralyzesworm, followed by expulsion of worms• Available in the US without a prescription fortreatment of pinworm infection• Also used for ascariasis and hookworminfections• Adverse effects similar to other agents
First-Line Therapy• Combine the greatest level of efficacy with anacceptable degree of toxicity– Isoniazid– Rifampin (and related drugs)– Ethambutol– Pyrazinamide
Isoniazid• The primary drug for treatment of TB– Used if patient has isoniazid-sensitive strain and if patientcan tolerate the medication• Bacteriostatic for ‘resting’ bacilli• Bacteriocidal for rapidly dividing microorganisms• Highly selective for mycobacteria• Can penetrate macrophages, so effective againstintracellular and extracellular bacteria
Isoniazid• Adverse Reactions– Pyridoxine (vitamin B6) should be administeredwith isoniazid to minimize risk of peripheralneuropathy and CNS toxicity• Indicated for malnourished patients and thosepredisposed to neuropathy (elderly, pregnant women,HIV-infected patients, diabetics, alcoholics, patientswith anemia, and uremics – also slow acetylators)
Isoniazid – Adverse Effects• Common– Drug-induced hepatitis –requires immediatediscontinuation of drug– Increase in liver enzymes – doesnot require discontinuation ofdrug– Peripheral neuropathy– Occasional– Clinical hepatitis with N/V,jaundice, and RUQ pain – canbe fatal• Risk increases with age, inalcoholics, and duringpregnancy• Fever• Skin rashes• Drug-induced SLE• Hematologic abnormalities• Tinnitus• GI discomfort• Reduces the metabolism ofphenytoin• CNS toxicity – memory loss,psychosis, seizures
Rifampin• ADME– Distributed throughout the body to most organs and tissues– May turn body fluids orange-red (sweat, urine, saliva, tears, etc.)– Following oral administration, peak levels are reached in 2 to 4 hours– Elimination is through bile, and then undergoes enterohepatic circulation– The drug is progressively deacetylated, and retains full pharmacologicalactivity– The deacetylated drug is not reabsorbed as easily, so excretion is facilitated bydeacetylation– Half-life 1.5-5 hrs– During the first 14 days of treatment – liver enzymes are induced, so half-lifeis reduced by about 40%– Half-life is increased in patients with hepatic insufficiency and patients thatare also taking isoniazid and are slow inactivators of isoniazid– Incidence of adverse effects is low
Ethambutol Adverse Effects• Most Significant– Retrobulbar neuritis – resultsin loss of visual acuity andred-green color blindness(rare at lower doses)– Contraindicated in childrentoo young for vision testing– Increased urate in the blooddue to decreased renalexcretion of uric acid –important to note in patientswith gout• Occasional– Hypersensitivity– Rash– Fever– Joint pain– GI upset– Headache– Mental confusion– Disorientation– Possible hallucinations
Streptomycin• Only features relevant to treating TB will be discussed here –streptomycin has broader uses• The oldest and least used of the first-line agents• Does not enter cells, so only effective against extracellularbacteria• Most strains of tubercle bacilli are sensitive• Mechanism of action - aminoglycoside– Inhibits protein synthesis• Adverse Effects (Review)– Ototoxic– Nephrotoxic– Vertigo and hearing loss are most common and may be permanent
Interferon-γ• Activates macrophages to kill M. tuberculosis• Aerosol delivery of IFN-γ to the lungs ofpatients with multi-drug resistant TB – resultsin enhanced local immune stimulation
Membrane-active agentsPolymyxinsSpectrum of activity• Selectively toxic for Gm- bacteria• Active against Pseudomonas aeruginosaand enterobacteriaceae sppAdverse effects• Neurotoxicity• Nephrotoxicity
Membrane-active agentsDaptomycinMechanism of action• Binds to cell membrane (in a Ca-dependentmanner) via insertion of its lipid tail.• Forms complexes (pores) in the cell membranecausing rapid loss of cellular K+ and membranedepolarization, which results in loss of membranepotential• This inhibits DNA, RNA, and protein synthesisresulting in cell death• Bactericidal
Membrane-active agentsDaptomycinSpectrum of activity• Active against Gm+ only• Activity similar to vancomycin plus activeagainst vancomycin –resistant spp (VRSA,VRE)Major therapeutic use• Skin and soft tissue infection• Alternative to vancomycin• Should not be used for the treatment ofpneumonia (pulmonary surfactantsantagonize its effect)
Membrane-active agentsDaptomycinAdverse effects• Rash• Local reactions at injection site• Musculoskeletal effects: can progress torhabdomyolysis (weekly CPK monitoringis recommended)• Nephrotoxicity• Hepatotoxicity
TetracyclinesSpectrum of activity– Broad spectrum– Generally more active against Gm+ than Gm-– Active against MRSA– Active against atypical bacteria: rickettsia, Chlamydia,Mycoplasma pneumoniae, Yersinia pestis, Vibriocholera, Borrelia– Inactive against proteus and pseudomonas spp.(express efflux pumps)Inhibitors of Bacterial Protein Synthesis
Inhibitors of Bacterial Protein SynthesisTetracyclinesPharmacokinetics• Distribution– Wide; accumulation in liver, spleen, bone marrow,and in newly formed bone, dentine, and enamelof unerupted teeth– Good penetration into CNS– Crosses the placenta
Inhibitors of Bacterial Protein SynthesisTetracyclinesAdverse effects– Gastrointestinal irritation (N/V/D) and superinfections(may include pseudomembranous colitis) – Controlled by• Drug administration with food• Carboxymethylcellulose• Reduce dose• Discontinue therapy– Photosensitivity– Hepatotoxicity– Renal toxicity– Permanent discoloration of teeth, decreased rate ofenamel growth, bone deformity, growth inhibition –fetaland childhood risks (should NOT be given to pregnantwomen or to children <8 years of age)– http://www.tmj.ro/article.php?art=4646654684124440tetracycline dyschromia
Inhibitors of Bacterial Protein SynthesisAminoglycosidesMechanism of action– Bind irreversibly to the 30S ribosomal subunit andinhibit protein synthesis at several levels:• Interferes with the initiation complex• Misreading of mRNA• Block translocation of ribosomes on mRNA– Bactericidal– Concentration-dependent killing with significant PAE
Inhibitors of Bacterial Protein SynthesisAminoglycosidesAntibacterial spectrum– Primarily aerobic Gm- including P. aeruginosa (tobramycin)– No activity against anaerobesMajor therapeutic use– Combination therapy with penicillin or vancomycin: actssynergistically on Staphylococcus aureus and S. epidermidis– Gentamycin (IV): Severe Gm- infections (sepsis, pneumonia)– Gentamycin (topical): infected burns– Tobramycin (inhalation): P. aeruginosa LRTI in cystic fibrosis– Amikacin: TB– Neomycin: Preoperative bowel preparation(p.o), skin infections(topical)
Inhibitors of Bacterial Protein SynthesisAminoglycosidesAdverse effects– Ototoxicity (irreversible)• Tinnitus and loss of hearing• Vestibular toxicity (e.g., dizziness, vertigo, loss of balance)• Ototoxicity in the fetus (avoid in pregnancy)– Renal toxicity (reversible): Gentamycin, tobramycin– Neuromuscular blockade (reversible) when used invery high doses (curare like effect)
Inhibitors of Bacterial Protein SynthesisSpectinomycin (IM) (aminocyclitol not anaminoglycoside)Mechanism of action– Binds reversibly to the 30S ribosomal subunit– Bacteriostatic• Spectrum of activity– Mostly Gm-Major therapeutic use– antibiotic resistant gonorrhea, or gonorrhea inpenicillin-allergic patientsAdverse effects– Nephrotoxiciy, anemia (rare)
Inhibitors of Bacterial Protein SynthesisMacrolide antibioticsMechanism of action– Bind reversibly to 50S subunit– Bacteriostatic– Blocks aminoacyl translocation (step 4)– The site of action of macrolides is very close tothat of clindamycin, and streptogramin type B
Inhibitors of Bacterial Protein SynthesisMacrolide antibioticsSpectrum of activity– Active against Gm+ including penicillin-resistantstreptococci– Clarithromycin and azithromycin are moreeffective than erythromycin against anaerobes– Azithromycin is highly active against chlamydia
Inhibitors of Bacterial Protein SynthesisMacrolide antibioticsAdverse effects– Gastrointestinal disturbances: Stimulate GI motilityleading to abdominal pain, cramping, NVD– Hypersensitivity– Local reaction at injection site (erythromycinlactobionate)– Cardiac effects: QT prolongation– Ototoxicity– Telithromycin (Ketek)• Hepatotoxicity (FDA bloded warning)• Worsen the symptoms of myasthenia gravis (Should not beused in patients with myasthenia gravis (FDA boxedwarning))
Inhibitors of Bacterial Protein SynthesisMacrolide antibioticsBacterial resistance– Efflux pump– Modification of the bacterial ribosome, rendering itunable to bind the antibiotic (MLSB resistance)– Enzymatic inactivation of the drugMany macrolide-resistant strains are susceptible totelithromycin– Poor substrate for efflux pump– Bind ribosomes with higher affinity than macrolides
Inhibitors of Bacterial Protein SynthesisLincosamides - ClindamycinMechanism of action (similar to macrolides)– Bind reversibly to 50S subunit– Bacteriostatic– Blocks aminoacyl translocation (step 4)Spectrum of activity– Most Gm+ are susceptible; anaerobes (esp. B. Fragilis)– No activity against aerobic Gm-
Inhibitors of Bacterial Protein SynthesisLincosamides – ClindamycinBacterial resistance– Modification of the bacterial ribosome, rendering itunable to bind the antibiotic (e.g MLSB resistance)– Enzymatic inactivation of the drug
Inhibitors of Bacterial Protein SynthesisStreptograminsQuinupristin/dalfopristin (30:70) (Synercid)Mechanism of action– Quinupristin binds the 50S ribosomal subunit, samesite as macrolides; dalfopristin binds nearby,synergistically enhances quinupristin bindingSpectrum of activity– Mostly Gm+ including VRSA, VRE– Individually: Bacteriostatic– Combined: Bactericidal (due to synergistic effect)
Inhibitors of Bacterial Protein SynthesisChloramphenicolAdverse effects–Toxicity for newborn infants (Gray baby syndrome)• Infants have inadequate levels of liver glucuronyltransferase=> can’t metabolize the drug• Vomiting, flaccidity, gray color, hypothermia, shock,and collapse (death of 40% of patients within 2 days)• Chloramphenicol should not be used in infants
Flucytosine• Clinical Use– Cryptococcus neoformans, some candida spp.,dematiaceous molds that causechromoblastomycosis– Not used as a single agent – resistance does occurif used as a single agent– Exhibits synergy with other antifungals• With Amp B for cryptococcus meningitis• With itraconazole for chromoblastomycosis
Flucytosine• Adverse Effects– Metabolized to toxic agent 5-fluorouracil (possiblyby intestinal flora) – antineoplastic• Leads to bone marrow toxicity – anemia, leukopenia,thrombocytopenia• Affects liver enzymes occasionally• Toxic enterocolitis– Narrow therapeutic window – increased risk oftoxicity with higher drug levels
Azoles• Mechanism of Action– Reduction of ergosterol synthesis by inhibition offungal P450 enzymes – specific for fungal P450s• Imidazoles are less specific – higher incidence of druginteractions and side effects– Resistance to azoles are increasing
Echinocandins• Newest class of antifungal agents– Caspofungin, micofungin, anidulafungin– Only available in IV form• Mechanism of Action– Inhibit synthesis of fungal cell wall component β(1-3) glucan
Mucocutaneous Infections• Griseofulvin– Fungistatic– Absorption is improved when given with fatty foods– Only use is dermatophytosis– Mechanism of action unknown• Binds to keratin to protect skin from new infection– Adverse effects – allergic syndrome similar to serumsickness, hepatitis, drug interactions with warfarin andphenobarb– Replaced by itraconazole and terbinafine
Topical Drugs• Nystatin– Structurally similar to Amp B– Too toxic for systemic administration, so used onlytopically– Available in creams, ointments, suppositories, etc.– Not absorbed through epithelium, so little toxicity– Active against most Candida species– Thrush, vaginal candidiasis
Topical Drugs• Topical Azoles– Clotrimazole and miconazole– Available over-the-counter– Often used for vulvovaginal candidiasis– Oral clotrimazole troches are available for oral thrush– Both are useful for tinea corporis, tinea pedis, tinea cruris– Adverse effects are rare– Also available are econazole, terconazole, butoconazole,tioconazole, oxiconazole, sulconazole, sertaconazole,ciclopirox olamine, haloprogin, tolnaftate, terbinafine,naftifine, and butenafine
www.sfu.ca/.../Physiology/HPA_model.html• Negative feedback regulation occurs at multiple levels of theHPA axis and is the major mechanism that maintains normalcirculating levels of glucocorticoids.• Stress (injury, hemorrhage, pain, cold, severe infection) canoverride the normal negative feedback control mechanismsleading to markedly increased plasma glucocorticoid levels.
Adrenocorticotropic hormone (ACTH)• A 39-amino acid protein, synthesized from aprecursor protein = pro-opiomelanocortin(POMC)– The first 13 amino acids of ACTH may becleaved to form α-melanocyte-stimulatinghormone (α-MSH)• Secreted from the anterior pituitary inresponse to CRH, which is released by thehypothalamus– Diurnal rhythm of ACTH release• highest plasma levels early in the morning
Glucocorticoids (GCs)• All GCs aresynthesizedfromcholesterol andare highlylipophilic• Cortisol is themainglucocorticoidin humans• Circulatingcortisol is eitherbound tocorticosteroid-binding proteinCBG (~85%) orfree (<10%)- Cortisol plasma levelsare regulated by ACTHand negative feedback- Circadian rhythm
Mechanism of action of GCs• The mechanism of GCaction is the regulationof gene expression• GR (GC receptor) belongsto the nuclear receptorfamily of transcriptionfactors• Free GCs are lipophilic –diffuse across the cellmembrane and bind tocytosolic and nuclear GRs• GC-GR complex dimerizesand binds to theglucocorticoid responseelement (GRE)• This interaction initiatestranscription andtranslation of target genes.www.people.vcu.edu/~urdesai/estr.htm
Sudden withdrawal from glucocorticoidtherapy leads to adrenal suppression• Synthetic GCs suppressACTH secretionthrough a negativefeedback mechanism• Without ACTH adrenalglands are not able toproduce cortisol• Adrenal suppressionmay occur when GCsare administered forlonger than 2 weeksSynthetic GCsNatural
Synthetic mineralocorticoids• Fludrocortisone• Used in treatment of adrenocorticalinsufficiency (Addison’s disease)• Most adverse reactions are caused by thedrugs mineralocorticoid activity (retentionof sodium and water) and includehypertension, edema, potassium loss, andhypokalemic alkalosis
Mineralocorticoid antagonist• Spironolactone• Binds MR (but also Androgen Receptor, AR)• Used in treatment of hyperaldosteronismand as a potassium-sparing diuretic• Side effects: hyperkalemia andantiandrogen effects
Hypothalamic-Releasing Hormones• Include:– Corticotropin-releasinghormone (CRH)– Gonadotropin-releasinghormone (GnRH)– Growth-hormone-releasinghormone (GHRH)– Thyrotropin-releasinghormone (TRH)– Somatostatin• Travel from hypothalamus topituitary via portalhypophysial blood vessels.• Control the synthesis andrelease of tropic hormonesfrom the anterior pituitary
Hypothalamic Neurohormones• Oxytocin andvasopressin (ADH)• Travel to the pituitaryvia the hypothalamo-hypophysial tract(neural)– Synthesized in thesupraoptic andparaventricular nucleiof the hypothalamus– Travel along the axonsto the pituitary– Released from theposterior lobe intosystemic circulation
Oxytocin• Physiologic roles:– PG stimulation in uterine smooth muscle:• Uterine contractions in the last trimester of pregnancy– PG stimulation in mammary myoepithelial cells:• Milk ejection in lactating women• Clinical application (uterine):– Induction of labor (administered IV via an infusionpump with appropriate fetal and maternalmonitoring)– Postpartum hemorrhage (administered IM or IV)
Vasopressin & Desmopressin• Desmopressin– Synthetic analog of vasopressin• Contains a D-arginine at position 8 and 1staa is deaminated.• Relatively selective V2 agonist• Longer acting because less readily degraded than ADH• Vasopressin and desmopressin are treatments forcentral (neurogenic) diabetes insipidus– Vasopressin:• administered IM or IV; half-life 15 min• Nonselective for V1 and V2– Desmopressin:• administered IV, SC, intranasally or orally; half-life ~ 2 hours• More selective for V2 (less V1 side effects)• Side effects of vasopressin and desmopressin:– peripheral vasoconstriction, arrhythmias, GI cramps,headache, water intoxication (hyponatremia, seizures,death)
Prolactin• 198-amino-acid protein• It is the principal hormone responsible forlactation.• Milk production is stimulated by prolactinwhen appropriate circulating levels ofestrogen, progesterone, corticosteroids andinsulin are present.• Note: oxytocin also stimulates lactation bystimulating milk let-down, in preparation forrelease.
GH replacement• 2 types of recombinant human GH (rhGH):– Somatropin (191-amino acid protein)– Somatrem – Use in pituitary dwarfism [Note thedifference between drugs and endogenous hormone somatotropin.]• rhGH is administered SC 3-6 times per week• rhGH is used in:– Treatment of GH deficiency in children– Treatment of idiopathic short stature (controversial)– GH replacement therapy in GH-deficient adults– For its anabolic effects, used in conditions associatedwith severe catabolic state (AIDS)• Also used by athletes (although banned by the OlympicCommittee)
Hypersecretion of GH• Gigantism– Hypersecretion of GH in children and adolescents(before closure of the growth plates)– Long bone growth• Acromegaly- DON’T USE SOMATREM– Hypersecretion of GH during adulthood– Connective tissue, cartilage and periostal growth– Gradual coarsening of facial features; enlargementof hands, feet, and lower jaw– Enlarged heart, kidneys, liver and spleen– Type 2 diabetes
GH receptor antagonist:Pegvisomant• GH analogue that blocks GH receptors• Prevents GH receptor dimers fromforming, which is required for receptoractivation• Leads to reduced IGF-1 level• Given SC
Lecture Outline• Hormones secreted at different levels of thehypothalamic-pituitary-gonadal (HPG) axisand their derivatives– Hypothalamic hormones: GnRH– Pituitary hormones: LH, FSH– Ovarian hormones:• Estrogens and progestins– Testicular hormones:• Androgens– Gonadal pathophysiology– Synthetic gonadal hormones• Estrogens & Progestins: contraceptives & HRT, cancertreatments• Androgens: prostate cancer treatments, HRT, others
professionals.epilepsy.com/page/specpop_men.html• The HPG axis plays acritical role in thedevelopment andregulation of thereproductive system• Hypothalamus:gonadotropin releasinghormone (GnRH)• Anterior pituitary:luteinizing hormone (LH)and follicle stimulatinghormone (FSH)• Gonads: ovarian andtesticular hormones
Gonadotropin-releasing hormone(GnRH)• Secretion is pulsatile – required to stimulate LHand FSH production and secretion.– Males: secreted in pulses at a constant frequency– Females: the frequency of the pulses varies during themenstrual cycle and there is a large surge of GnRHjust before ovulation• Nonpulsatile, sustained administration of GnRHor its analogs inhibits the release of LH and FSH(stimulates negative feedback)• Clinical use: used for diagnostic tests (todistinguish hypogonadism of pituitary origin fromhypogonadism of hypothalamic origin)
GnRH analogs• Agonists: Leuprolide– U.S. Brand Names: Eligard®; Lupron Depot-Ped®; Lupron Depot®; LupronDepot®-3 Month; Lupron Depot®-4 Month; Lupron®– Also a 10-amino acid protein, but longer-acting thanGnRH– Nonpulsatile, sustained administration inhibits therelease of LH and FSH– suppression of gonadotropin (LH and FSH) release byactivating GnRH negative feedback receptors, whichsuppresses gonadal hormone production– Important in treating hormone-dependent cancers• Use - Labeled Indications: Palliative treatment of advancedprostate cancer; management of endometriosis; treatment ofanemia caused by uterine leiomyomata (fibroids); centralprecocious puberty• Use - Unlabeled/Investigational: Treatment of breast cancer;infertility; prostatic hyperplasia
Gonadotropin hormones: LH, FSH, hCG• All 3 hormones consist of two peptide chains:–α and β– α chain: identical in all 3 hormones– β chain: distinct; provides specificity forreceptor interactions• Receptors:– All are G-protein coupled receptors– FSH receptors bind FSH– LH receptor binds both LH and hCG
Mechanism of action of estrogens• Estrogens bind toestrogenreceptors• 2 estrogenreceptors:• ERα and ERβ• Both belong tothe nuclearreceptor familyof transcriptionfactors.http://www.people.vcu.edu/~urdesai/estr.h2.gif
Mechanism of action of testosteroneand DHT• Similar to themechanism of actionof estrogens andprogesterone• Testosterone and DHTbind to androgenreceptor (AR)– DHT binds AR withhigher affinity thantestosterone• Results in increasedprotein synthesishttp://www.people.vcu.edu/~urdesai/estr.h2.gif
Misc.• Progestin- doesn’t affect anticoagulation factors• Dexamethasone- affect negative feedback onnormal PITUITARY release• MSH- actually made in the middle lobe• V2- aquaporin• Estrogen- causes positive feedback on day 12-14• PTH- doesn’t help with intestinal absorption
Hormonal control of Ca2+• Three principal hormones regulate Ca++andthree organs that function in Ca++homeostasis.• Parathyroid hormone (PTH), 1,25-dihydroxyVitamin D3 (Vitamin D3), and Calcitonin,regulate Ca++resorption, reabsorption,absorption and excretion from the bone,kidney and intestine.
Pseudohypoparathyroidism• PTH-resistant hypoparathyroidism– Due to defect in PTH receptor-adenylate cyclasecomplex• Mutation in Gαs subunit• Patients are also resistant to TSH, glucagonand gonadotropins
Calcimimetics• Cinacalcet – activates the calcium sensingreceptor. Target organ is the parathoroidalthough many tissues express the receptor.– Don’t use for peroxisome proliferator receptor• Useful for the treatment of secondaryhyperparathyroidism and parathyroidcarcimomas that hypersecrete PTH
4. Secretion of T4. Secretion of T44 and Tand T33• Proteolysis releases T4 and T3 stored withinthyroglobulin (TG)• Endocytosis of TG/colloid from follicular lumen• Fusion with lysosomal granules containingproteolytic enzymes• Breakdown of TG and release of T4 and T3• MIT and DIT deiodinated; iodine reutilized• T4 and T3 reversibly bind to specific serum proteinsthyroxine binding globulin and transthyretin;protect against metabolism
Pituitary-HypothalamusPituitary-HypothalamusHypothalamusHypothalamusAnterior PituitaryAnterior PituitaryThyroidThyroidT4 and T3T4 and T3TRHTSHadenyl cyclase(-)(-)Eventually causes theformation of T3 and T4
ThyroidThyroid HypofunctionHypofunctionThyroid hormone deficiency(Gull’s Disease)Hypothyroidism: mildMyxedema: more severe symptomsDegeneration or atrophy thyroid gland may beassociated with goiterHashimoto’s Thyroiditis: autoimmune destructionof thyroid gland; most common in US
Diagnosis and Treatment ofDiagnosis and Treatment ofHypothyroidismHypothyroidismDiagnosis: decreased T4 production;presence of anti-thyroid antibody (autoimmune)Treatment:Replacement therapy with levothyroxine (T4);Stable, long half-life (7 d), converted to T3; used totreat hypothyroidism, myxedemia, coma, cretinism,simple goiter, nodular goiter
Sulfonylurea MOA (insulinsecretogogues)BIND TO SUR 1 AND BLOCKCHANNELS SO k CANT GET OUT
Sulfonylurea and Meglitinides Both drugs block the KATP channel and causemembrane depolarization leading to…. Opening of the Ca2+and influx of Ca2+ Important - Ca2+needed for the secretion ofmost cellular products….including insulin! Thus increased insulin secretion occurs inresponse to sulfonylurea or meglitinides
DPP-4 inhibitors• Also known generically as– Gliptins• Linapgliptin• Sitagliptin• Saxagliptin• WORKS WHEN BLOOD SUGAR INCREASES DURING AMEAL
DefinitionsEicosanoidsClassifications• Cyclooxygenase products: (prostaglandins (PGs), prostacyclin(PGI2), thromboxane (TX)) see next slide• Lipoxygenase products: ( leukotriens)
Therapeutic uses of PG analoguesDinoprostone : vaginal gel or vaginal insertIndication : for the initiation or continuation of cervical ripeningin patients at or near term in whom there is a medical orobstetrical indication for the induction of labor.MOA: mimics the action of PGE 2• PGE 2is released during natural labor and plays a role incervical ripening (softening, thinning, and dilation) whichallows the fetus to pass through the birth canal
Therapeutic uses of PG analoguesEpoprostenol, Iloprost, treprostenil: PGI2 (prostacyclin)analoguesIndicationTreatment of severe Pulmonary Arterial Hypertension (PAH)– Improves symptoms– Prolong survival– Delays or prevent the need for lung or lung-heart transplantationMOA: Epoprostenol (PGI2) causes direct vasodilation ofpulmonary and systemic arterial vascular beds and inhibitionof platelet aggregation.
Therapeutic uses of PG analogues• Latanoprost, bimatoprost, travoprost: PGF2α analoguesIndicationFor the reduction of elevated intraocular pressure in patients withopen-angle glaucoma and ocular hypertension
Therapeutic uses of PG analogues• Bimatoprost: PGF2α analoguesIndication#2Bimatoprost (Latisse™): Hypotrichosis treatment of the eyelashesMOA: Bimatoprost may increase the percent and duration of hairs in thegrowth phase, resulting in eyelash growth
Therapeutic uses of PG analoguesLatanoprost, bimatoprost, travoprost: PGF2α analoguesAdverse effects:Ocular– Blurred vision, burning, foreign body sensation– Redness, dryness of the eyes ,itching– Irreversible brown pigmentation of the iris
Nonsteroidal anti-inflammatory drugs (NSAIDs)Specific mechanism of action• Nonselective NSAIDS: Reversibly (except for aspirin)inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes,which results in decreased formation of prostaglandins• Aspirin: Irreversible inhibitor of COXs• COX-2 selective inhibitors: Selectively inhibitingcyclooxygenase-2 (COX-2), which results in decreasedformation of prostaglandins- LESS RISK OF STOMACHPROBLEMS, INCREASED RISK OF CV EVENT
Nonsteroidal anti-inflammatory drugs (NSAIDs)• TXA2 generated by COX-1increases platelet adhesion• This is balanced by PGI2generated by COX-2 inendothelium which decreasesplatelet adhesionCOX-1TXA2 in plateletsPlatelet aggregation
Nonsteroidal anti-inflammatory drugs (NSAIDs)Other issues– NSAIDs delay bone healing after fractures(PGE 2 stimulate bone resorption and formation)– Highly COX-1 selective NSAIDs increase the risk ofsurgical bleeding– Aspirin: exacerbation of asthma– NSAIDs have increased toxicity in the elderly
Nonsteroidal anti-inflammatory drugs (NSAIDs)Black Box Warnings• Cardiovascular events: NSAIDs are associated with anincreased risk of adverse cardiovascular thrombotic events,including MI and stroke. (celebrex AND naproxen)• Gastrointestinal events: NSAIDs may increase risk ofgastrointestinal irritation, ulceration, bleeding, andperforation.
Acetaminophen toxicity is the is the mostcommon cause of acute liver failure in the US• Toxic dose– Vary (10g, or 200mg/kg body wt)• Symptoms– Phase I (<24hrs): GI symptoms– Phase II (24-72 hrs): Signs of liver damage– Phase III (3-5 days): Massive hepatic necrosis,encephalopathy• Risk factors– Excessive chronic alcohol intake• Treatment– Activated charcoal (adsorbs APAP in the GI)– N-acetylcysteine (replenishing body stores ofglutathione)
GoutColchicineAdverse effects• Gastrointestinal: Gastrointestinal disorders includingabdominal pain, cramping, nausea, vomiting, diarrhea (canbe severe enough to warrant discontinuation of therapy)• Bone marrow toxicity• Hepatic necrosis• Renal failure
Gout• Uricosuric agentsProbenecid- can cause gouty attack because it reduces excretionat subtherapeutic levelsSulfinpyrazoneAdverse effects• Gastrointestinal irritation: Take with food or antacids or alkalineash foods (milk, nuts, beets)• Renal: Uric acid stones, nephrotic syndrome– To minimize the possibility of stone formation maintain adequatehydration, titrate dose upward slowly, maintain an alkaline urine• Bone marrow suppression (with sulfinpyrazone)
GoutDrug therapy• Xanthine Oxidaze inhibitors– Allopurinol– FebuxostatMechanism of action• Inhibits xanthine oxidase (the enzyme responsible for theconversion of hypoxanthine to xanthine to uric acid) therebydecreasing uric acid formation
Histamine antagonism• Histamine has no clinical application in the treatment of disease, butdrugs that inhibit the actions of histamine are useful Histamine can be antagonized by the followings:1. Functional or physiological antagoniste.g. Adrenaline, by acting on β2-ARs can oppose histamine-inducedbronchoconstriction (important clinically because injection ofadrenaline can be lifesaving in systemic anaphylaxis, where massiverelease of histamine occurs)- FALSE2. Release inhibitorsCromolyn and nedochromil reduce the degranulation of mast cells3. Histamine Receptors AntagonistsCompetitive antagonists at histamine receptors• H1-receptor antagonists• H2-receptor antagonists
H1 receptor antagonistsFirst Generation Antihistamines• Older H1-receptor blockers• Small, lipophilic molecules that can cross the BBB (Marked sedative activity)• Not highly selective to histamine receptor (Also blocks cholinergic, α-adrenergic, & 5-HT receptors)• Different chemical groups:– Ethylenediamines– Ethanolamines– Alkylamines– Piperazines– Tricyclics• Common structural features of classical (1stgeneration) antihistaminesX = N, C, COR1 = R2 = small alkyl groups
Other clinical uses of 1st generationH1-receptor antagonists… not primarily due to H1 receptor blockade Sedatione.g Diphenhydramine Prevention of motion sicknesse.g cyclizine, meclizine Treatment of nausea & vomitinge.g promethazine
Second Generation (non-sedative)Antihistamines• Modifications of the first generation antihistaminesto eliminate side effects resulted in the secondgeneration Antihistamines• Does not readily cross the BBB (Bulky groups, less lipophilicity)• More selective for H1 receptorsDrug Trade name AnticholinergicactivityCommentsLoratadine Claritin® - Long actingCetirizine Zyrtec® -
Adverse Effects• First generation antihistamines:– Common side effects: sedation, dizziness, tinnitus, blurred vision,euphoria, lack of coordination, anxiety, insomnia, tremor, nausea andvomiting, constipation, diarrhea, dry mouth, and dry cough• Second generation antihistamines:– Common side effects: drowsiness, fatigue, headache, nausea and drymouthSide effects are far less common in second generation drugs
Regulation of Smooth Muscle Tone• Relaxation – bronchodilation– β2 adrenergic activation• Activation of adenylyl cyclase → increase in cAMP• Hyperpolarize smooth muscle cells• Constriction – bronchoconstricion– Muscarinic activation• Activation of the parasympathetic nervous system leads toliberation of acetylcholine (ACh) from preganglionic neurons andcontraction of bronchial smooth muscle• Bronchial smooth muscle contain predominantly M3 muscarinicreceptors
Decongestants• Indications:– Temporary relief of nasal congestion due to common cold,allergic rhinitis, sinusitis• Contraindications– MAOI therapy, hypersensitivity or adverse reactions tosympathomimetic amines that results in insomnia, dizziness,weakness, tremor, or arrhythmias• Oral – severe hypertension or coronary artery disease; sustainedrelease forms in nursing mothers and children under 12 years old• Topical – less systemic effects but use with caution in same group aslisted for oral agents; excessive use increases risk of adverse effects– Many warnings: hypertensive patients, diabetic patients,cardiovascular or ischemic heart disease, prostatic hypertrophy,nursing mothers; risk of rebound congestion, nasal irritation,drug interactions
Expectorants and Mucolytics• Aids in removal of mucus from the respiratorytract• May reduce adherence, surface tension, andviscosity of respiratory secretions – may alsoreduce the urge to cough because airway hasbeen cleared- USED IN CF– Expectorants - Guaifenesin (Mucinex, Robitussin,many others)– Mucolytics – acetylcysteine, dornase alfa
Skin• Stratum Corneum– Outer layer of deadcells– Can absorb water– Barrier of water andkeratin prevent skindehydrationhttp://en.wikipedia.org/wiki/File:Normal_Epidermis_and_Dermis_with_Intradermal_Nevus_10x.JPG•Thickness- K type question just I and II•Between 10 and 40 μm -- thicker on palms of hands andsoles of feet; thinner on face and other “sensitive” areas.•Confers sensitivity because thinner stratum corneumallows nerves to be closer to surface.•Partially determines permeability to topical drugs.
Pharmacokinetic considerations• Major variables that determine pharmacologicresponse to topical drugs:– Regional variation in drug penetration• More permeable tissues (scrotum, face, axilla, scalp)require lower dose of drug than less permeable tissues(forearm).– Concentration gradient• Increasing the concentration gradient increases themass of drug transferred per unit time• Ex: tissues resistant to topical corticosteroids may havehigher response to higher doses.
Pharmacokinetic considerations• Major variables that determinepharmacologic response to topical drugs:– Dosing schedule• Skin acts as a reservoir, thus local (skin) half-life maybe significantly longer than systemic half-life.– Vehicles• Maximize the ability of the drug to penetrate skin.• May be adjunctive therapy – exs: hydration,dehydration– Occlusion• = application of plastic wrap to hold drug and vehicleclose to skin.• Extremely effective in maximizing efficacy.
Antibacterial agents• Retapamulin– Pleuromutilin antibiotic– Effective against superficial infections of Gram(+) cocci– MOA: protein synthesis inhibitor due tointeraction with unique site on 50S subunit ofthe bacterial ribosome that inhibits peptidyltransferase function (but different site thanamphenicols)– Used for impetigo; approved for MRSA, butreserved use– Safe for pediatric use – 9 months & up
Antibacterial agents• Neomycin & Gentamicin– Neomycin:• Is used more often in combination ointments (ex.NeosporinTM) due to gentamicin’s toxicity and attemptsto prevent development of gentamicin-resistantstrains• Most frequent cause of hypersensitivity reactions tocombination ointments.• Extremely nephrotoxic, so not used IV, but can beadministered orally for GI infections because it is notabsorbed from the GI tract.
Antibacterial agents• Topical antibiotics for acne vulgaris treatment– Several systemic antibiotics for severe cases.– Four topical antibiotics for mild to moderate cases:• Clindamycin• Erythromycin- topical for acne, oral for other things• Metronidazole• Sulfacetamide– Effectiveness of topical therapy is less than that ofsystemic administration, but also produces less toxicside effects.
Antifungal agents• Topical azole derivatives/imidazoles– Clotrimazole (Lotrimin, Mycelex)– Econazole (Spectazole)– Ketoconazole (Nizoral)– Miconazole (Monistat)– Oxiconazole (Oxistat)– Sulconazole (Exelderm)– Clotrimazole is often combined with a corticosteriod – ex.Lotrisone = clotrimazole + betamethasone– Most are available as creams and/or lotions; ketoconazoleis also available as a shampoo for seborrheic dermatitis– Ketoconazole is the only imidazole that is currently alsoused orally.