pharmacology f

8/8/2019 Pharmacology F

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Metronidazole

Mechanism of antibacterial action is unclear, but needs

reductive metabolism of drug bactericidal

DOC for Entamoeba histolytica, Giardial species and T

vaginalis

DOC for anaerobes B fragilis, C. difficile and G. vaginalis,

and used in regimens for H. pylori associated GI ulcers


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Metronidazole

Adverse effects: metalic taste, brown-black urine,

glossils, stomatitis, urethral burning, dysuria,

neurotoxicity (vertigo, peripheral neuropathy). Disulfram-

like interactions with ethanol

Antibiotics for H. pylori GI Ulcers

Amoxicillin, clarithromycin, tetracyclines and

metronidazole: used with H2 blockers, proton pump

inhibitors and antacids


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Antitubercular Drugs

Combinations: Decrease resistance; additive effects

Primary drugs: isoniazid, rifampin, ethambutol, and

pyrazinamide

Regimens usually 2 to 4 of these drugs, but in the case

of highly resistahnt organisms, other agents may also be

required


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Antitubercular Drugs

Prophylaxis usually INH, but rifampin if intolerant, in

suspected multi-drug resistance, both drugs may be

used in combination

Back-up drugs for TB, aminoglycosides (streptomycin,

amikacin, FQs, capreomycin (hearing loss) and

cycloserine (neurotoxic)


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Isoniazid (INH)

Inhibits mycolic acid synthesis. High level resistance

detection in cat K gene (codes for catalase); low level

(changed inhA gene)

Adverse: hepatis (age-dependent), peripheral results (use

B5), hemolysis in G5PD, deficiency, SLE in slow

acetylations (rare)


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Rifampin

Inhibits DNA-dependent RNA polymerase; resistance

(changed enzyme) emerges rapidly if used alone

Adverse: proteinuria, hepatitis ,flu-like syndrome,

induction of P450, throbocytopenia, red-orange metabolites


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Ethambutol

Inhibits synthesis of arabinogalactan (cell wall

component)

Dose- dependent retrobulbar neuritis, causing to

reduce visual acuity


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Pyrazinamide

Mechanism unknown, but metabolically activated bacterial

strains lacking bioactivating enzymes are resistant no cross

resistance

Adverse: polyathralgia, myalgia, hepatitis, rash,

hyperuricemia, phototoxicity, increasing porphyrin synthesis


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M. avium intracellulare (MAC)

Prophylaxis azithromycin (1 x week) or clarithromycin

(daily)

Treatment: clarithromycin + ethambutol +/- rifabutin


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Antifungal Agents

Drug groups: Polyenes ( amphotericin B, nystatin)

Antimetabolite (Flucytosine)

Azoles (ketoconazole, fluconazole,

itraconazole)

Antidermatophytics (griseofulvin,

terbinafine)


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Polyene Antifungals

Amphotericin B and Nystatin

Interact with ergosterol retention, leading to increase

disrupt memebrane permeability

Resistant fungi have low ergosterol content in cell

membranes

Amp B Rx uses: DOC (or co DOC) for infections due to

Aspergillus, Candida, Cryptococcus, Histoplasma,

Mucor and Sporotrichosus


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Amphotericin B Characteristics

Given by slow IV infusion minimal CNS penetretion;

slow clearance ( halflife > 2 weeks), via metabolism and

renal elimination

Adverse effects: IV infusion related- fever, chills, muscle

rigor, hypotension (histamine release ) - by pre-treatment

with NSAIDs, antihistamines and adrenal steroids


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Amphotericin B Characteristics

Dose dependent nephrotoxicity includes decrease GFR,

tubular acidosis, decrease K and Mg and anemia through

decrease erythropoietin protect by Na loading use of

liposomal amp B, or drug combinations (eg. + flucytosine)


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Azole Antifungals

Fungicidal reduces synthesis of ergosterol by inhibiting

P-450- dependent demethylation of precursos molecule,

lanosterol

Resistance via decrease intracellular accumulation

Ketoconazole

Co-DOC for Paracoccidodes and back-up for

Blastoyces and Histoplasma. Rx: mucocutaneous

candidasis or dermatophytoses


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Azole Antifungals

Ketoconazole

Effective orally, but antacids reduce absorption

Adverse effects: reduce synthesis of cortisol and

androgens, rash, fluid retention, leading to increase BP,

hepatoxicity (rare)


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Azole Antifungals

Fluconazole

DOC for esophagal and invasive candidiasis and

coccidomycoses, prophylaxis and suppression incryptococcal meningitis, vaginal candidiasis (single dose)

Oral absorption, penetrates CSF and saliva; renal

elimination

Adverse effects: similar to ketoconazole but less

intense


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Azole Antifungals

Itraconazole

DOC in blastomycoses and sporotrichoses back up

other mycoses and in candidiasis (eg. Fluconazole

resistance)

Oral absorption increased by food; hepatic metabolism

Adverse effects: similar to ketoconazole but less P-450

inhibition


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Flucytosine

Activated by fungal cytosine deaminase to 5 FU, decrease

RNA , thymidine synthase. Rapid resistance

Rx use: with amp B in candidial and cryptococcalinfections enters CSF. Toxic to bone marrow


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Griseofulvin

Anti-dermatophytic (oral) disrupting microtubulestructure

Adverse effects: headace, thrush, peripheral neuritis,

phototoxicity, avoid with history of porphyria

Terbinafine

Anti-dermatophytic-inhibits squalene epoxidase, decrease

ergosterol

Adverse effects: GI distress, rash, headache, increase

LFTs


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Sites of Antiviral Drug Actions

Viral

adsorption

HOST

CELL

Enfurvitide Amantadine

penetrationuncoating

Nucleic Acid

Synthesis

Protein synthesis

and processing

Viral

assembly

Viral

release

Neuraminidaseinhibitors

Protease

Inhibitors

Polymerase

Inhibitors

Reverse

Transcriptase

Inhibitors


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Acyclovir

Monophosphorylated by viral thymidine kinase (TK), then

further bioactivated by host cell kinases to the triphosphate

Acyclovir TP is both at substrate for, and inhibitor of viral

DNA polymerase incorporated into the DNA it acts as a chainterminator, since it lacks the 3 hydroxyl group


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Acyclovir Characteristics

Rx uses: HSV, VZV and Vanicella : decrease viral

shedding in general herpes and decrease acute neuritis

in shingles no effect on postherpetic neuralgia

Prophylaxis; immunocompromised patients

Topical, oral and IV forms short halflife

Adverse Effects: crystaluris (maintain full hydration)

and neurotoxicity (agitation, headache, confusion seizures in OD), NOT hematotoxic


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Acyclovir Characteristics

Famciclovir and Valacyclovir

Approved for HSV infection similar

mechanism to acyclovirActive vs strains resistant to acyclovir; but not

TK


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Gancyclovir

Mechanism similar to acyclovir, 1st phosphorylation

viral-specific via a phosphotransferase, Gancyclovir-TP

inhibits viral DNA polymerase, but does not cause chain

termination

Resistance mechanisms similar to acyclovir

Rx uses: HSV, VZV and CMV. Mainly prophylaxis and

treatment of CMV including retinitis, oral, IV and retinal

implant forms


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Gancyclovir

Adverse Effects: dose-limiting hematotoxicity, mucositis,

fever, rash and crystaluria (maintain hydration); seizures

in OD


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Foscarnet

Not an antimetabolite, inhibits viral DNA and RNA

polymerases

Rx uses identical to ganciclovir, plus activity versus

acyclovir resistant strains of HSV

Adverse effects: dose-limiting nephrotoxicity with

tubular necrosis, electrolyte imbalance with hypocalcemia,

and then tremors and seizures. Avoid pentamidine (IV)


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Drugs Active Against HIV

HAART can reduce viral mRNA, reverse decline in

CD4 cells and decrease opportunistic infections

Non-nucleoside RTIs (NNRTIs), which do not require

bioactivation (eg. Nevirapine, efavirenz) are also used in

combination with NRTIs


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Zidovudine (AZT)

Prototype, orally actve, hepatic metabolism, increase

ZDV toxicity with acetaminophen, ASA, cimetidine,

probenecid and sulfonamides

Dose-limiting hematotoxicity (neuropenia, anemia,

granulocytopenia), headache, asthenia, myalgia,

myopathy and peripheral neuropathy


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Specific Features of Other NRTIs

Didanosine pancreatitis, peripheral neuropathy,

hyperuricemia, increasing LFTs

Zalcitabine peripheral neuropathy, GI distress,

pancreatitis, neutropenia

Stavudine peripheral neuropathy, myelosuppression

(< ZDV)

Lamivudine GI effects and neutropenia (minor);

active hepatitis B


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Mechanism of Action of Protease Inhibitors (PIs)

Aspartate protease (pol gene encodes) cleaves precursor

polypeptides in HIV buds proteins of mature virus core

PIs bind to a unique dipeptide structure inhibiting the

enzyme

Resistance via specific point mutation in the pol gene, such

that there is not complete cross-resistance between

different PIs

In HART regimens, indinavir and ritonavir have been

most commonly used (with 2 NRTIs)


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Adverse Effects of Protease Inhibitors

Indinavir: nephrolithiasis (maintain hydration), GI

distress, thrombocytopenia, inhibition of P-450

Ritonavir: GI distress, asthenia, paresthesias and

drug interactions induces CYP1A2 and inhibits majorP450 isoforms, increase effects of dronabiol,

erythromycin, ketoconazole and rifampin


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Adverse Effects of Protease Inhibitors

PI use is associated with disordered lipid and CHO

metabolism with central adiposity and insulin resistance

HAART regimen where PI is replaced by efavirenz ( a

NNRTI) are highly effective with deduce drug interactions


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HIV Prophylaxis

Needle stick

ZDV + 3TC, 1 month but in high risk (eg. High

HIV RNA copies) a combination of ZDV + 3TC +

indinavir is recommended


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HIV Prophylaxis

Pregnancy

ZDV, trimester 2 and 3,+ 6 weeks to neonate, reduces

vertical transmission by 80% - possible combinations if

high maternal viral RNA

ZDV restricted to intrapartum period, or nevirapine

(NRRTI) one dose at onset of delivery + one dose to

neonate and reduces transmission by 50% to 60%


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Amantadine

Blocks attachment and penetration and uncoating of

influenza A virus

Prophylaxis mainly, but may decrease duration of flu

symptoms by 1-2 days

Adverse: CNS effects include nervousness, insomnia and

seizures in OD. Causes atropin-likeperipheral effects and

livedo reticularis


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Zanamivir and Oseltamivir

Inhibit neuraminidases of influenza A and B, enzymes which

prevent clumping of virions, so that more particles are available of

infecting host cells. This inhibition decreases the likehood that the

virus will penetrate uninfected cells

Prophylaxis mainly, but may reduce duration of flu symptoms

by 2-3 days

Adverse: nausea and vomitting and zanamivir (via inhalation)causes nasal and throat irritation


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Ribavirin

Monophosphorylated form inhibits IMP dehydrogenase,

triphosphate form inhibits viral RNA polymerase and end-

capping of viral RNA

Rx uses: management of RSV, influenzae A and B, Lassa

fever

Hantavirus and as adjunct to alpha-interferons in hepatitis

C


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Ribavirin

Adverse: hematotoxic, upper airway irritation, tetratogenic


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Antiprotozoal Drugs of Choice

Amebiasis: metronidazole or Diloxanide for noninvasive

intestinal amebiasis

Giardiasis: metronidazole for diarrhea from

contaminated water or food

Leishmaniasis : stibogluconate

Pneumocystosis: TMP-SMX for Atovaquone or

pentamidine IV are backups

Toxoplasmosis: pyrimethamine + sulfadiazine

Trypanosomiasis: nifurtimox, arsenicals


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Antiprotozoal Drugs of Choice

Prophylaxis Pymethamine + sulfadoxine

Mefloquine

Treatment Falciparum Chloroquine

Malariae Chloroquine

Vivax Chloroquine + primaquine

Ovale Chloroquine + prmaquine

Chloroquine-resistance

Prophylaxis mefloquine

Treatment quinine +/- pyrimethamine or clindamycine


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Drugs for Helminthic Infections

Most Intestinal Nematodes (Worms)

Mebendazole ( reduces glucose uptake and

microtubular structure) , or pyrantel pamoate (NM

blocker and spastic paralysis)

Most Cestodes (Tapeworms and Trematodes )

Praziquantel ( increase Ca influx, vacuolization)


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Vaccination Strategies

Mechanisms of Protection within the Immune System

Divided into innate or primitive and adaptive or

acquired, against variety of bacterial and viral agents.


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Activation of Innate Immunity: Sensing the Enemy

Innate defenses are primarily aimed at recognizing

foreign structures and eliminating them.

Since infectious pathogens have often evolved to subvert

these mechanisms, specialized cells of the innate immune

system are also capable of presenting digested antigen to

T cells in a context and environment appropriate for

optimal effector cell development.


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Activation of innate immunity to provide this context may

be conceptually divided into two stages :

(1) a phase of antigen sensing during which a combination of

surface receptors detects the presence of non-self

structures on invading microorganisms (detection phase)

(2) a phase of translating this sensory information into a

language understood by the cells of the adaptive immune

system, e. g., chemokines and cytokines (transmission

phase)

Activation of Innate Immunity: Sensing the Enemy


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Some key elements of the adaptive immune system

B lymphocytes, their precursors and progeny, and their

products 8 different classes of antibodyT lymphocytes with / receptors, their precursors and progeny,

their lymphokine products,

and specifically CD4+ regulatory (suppressor) Tcells; CD8+

cytotoxic and cytokine secretorycells; and CD1-specific CD4+ or double negative NK-1 Tcells

T lymphocytes with / receptors, their various subsets, and their

lymphokine products

Other atypical Tcells

Fc receptors of various types on monocytes, macrophages,immature dendritic cells, B cells,

polymorphonuclear leukocytes, NK cells, mast cells, and

platelets, as well as soluble Fc receptors


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Some key elements of the innate defense system

Cilia

Enzymes in mucous secretions, e. g., lysozyme

Repair mechanisms of damaged anatomical barriers, e. g.

the clotting cascade or growth factor

and chemokine releaseDefensins

The complement cascade

Non-immunoglobulin opsonins, e. g., collectins such as

mannose-binding protein or C-reactive

protein, lectins, fibronectin, etc.


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Some key elements of the innate defense system

Recognition receptors on dendritic cells, macrophages,

NK cells, and mast cells including Tolllike receptors,

scavenger receptors, or integrin

Phagocytosis by polymorphonuclear leukocytes, monocytes,

or macrophages

Cytokines, including interferons , , and tumor necrosis

factor


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Overall view of innate immunity shaping adaptive immune

responses. Cells of the innate immune system(DC = dendriticcells; MC = mast cells) detect the presenceof foreign structures,

such as pathogen-associated molecular patterns, by surface expressed

pattern-recognition receptors,and translate this sensory

input into a language (cytokines,chemokines) understood by cells

of the adaptive immune system,skewing the response to either T

helper 1 (Th1)/T cytolytic 1 (Tc1) or Th2/Tc2-type immunity


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Pathogen-associated Molecular Patterns

Required for differentiation of adaptive immune

responses when cells of the innate defense system interact

with pathogen-associated molecular patterns (PAMPs, i. e.,

highly conserved structures that are necessary for thesurvival of microorganisms)


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Pattern-recognition receptors primarily serve the purpose

of enhancing phagocytosis.

Example, the macrophage mannose receptor

(recognizing terminal mannose and fucose residues on

microbial cell walls) or the macrophage scavenger receptor

(recognizing polyanionic ligands such as double stranded

RNA, lipopolysaccharide, and lipoteichoic acid) are mainlyinvolved in clearing pathogens from the site of invasion



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PAMPs have multiple effects on the signals generated by

cells of the innate immune system and may therefore be

useful as natural adjuvants in driving adaptive responses



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Recognition of pathogen structures via surface receptors

on innate immune cells

Pattern-recognition receptors Pathogen-associated molecular patterns on innateimmune cells or similar insults

TLR1/TLR2 Triacylated lipopeptides

TLR2 Lipoproteins, lipoteichoic acid,

glycolipids,modulin,arabinose-capped lipoarabinomannan,

GPI-anchored molecules from parasites

TLR2/TLR6 Diacylated lipopeptides, zymosan

TLR3 Double-stranded RNA

TLR4 LipopolysaccharidesTLR5 Flagellin

TLR7 and TLR8 Imidazoquinoline Derivatives

TLR9 Unmethylated CpG-motif oligonucleotides


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Recognition of pathogen structures via surface receptors

on innate immune cells

Pattern-recognition receptors Pathogen-associated molecular patterns

on innate immune cells or similar insults

Complement receptors Activated components of complement coating

microbial surface

Scavenger receptors Polyanionic compounds, e. g., lipoteichoic acid,double-stranded RNA, lipopolysaccharide

Mannosefucose receptor Terminal mannose and fucose on microbial

glycoproteins/glycolipids

CD14 Monomeric lipopolysaccharides

CD48 Fimbrial protein FimH on enterobacteriaCD91 Heat-shock proteins 70, 90, gp 96; calreticulin

IgE/FceR-crosslink Parasitic lectins

unknown Allergens


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Host Cellular Sensors

At the immunological level, innate defenses rely mostly on

granulocytes, mast cells (MC), macrophages, dendritic cells

(DC), natural killer (NK), NKT, and T cells - a bridge between

PAMPs and the antigen-specific cells of adaptive immunity,translating the sensory input of pattern-recognition receptors

into soluble mediators that communicate with T and B cells via

specific cytokine/chemokine receptors.


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Dendritic Cells

The most potent type of any antigen-presenting cell,which is

able both to sense a foreign insult and to orchestrate the cells

of the adaptive immune system

Continuously produced from hematopoietic stem cells within

the bone marrow


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Dendritic Cells

Maturing DCs lose the ability to take up and process antigen,

but they up-regulate surface expression of MHC class I and II, as

well as of costimulatory and adhesion molecules such as CD86,

CD80, CD40, and CD54.

Mature DCs express proinflamatory cytokines like IL-6, IL-12,

IL-18, IL-23, and IL-27 and are able to detect the expression of

cytokines by infected cells, thus integrating different signals ofdanger


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Mast Cells

Mast cells (MC) are derived from CD34+ stem cells

Initiate their differentiationin the bone marrow under the

influence of stem cell factor and interleukin-3


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Mast Cells

Activation is followed by de novo synthesis of numerous

cytokines (TNF-alpha, interleukins 1-10, IL-12, IL-13, IL-15, IL-

16, IL-18, IL-25, and GM-CSF) and chemokines (CCL25, CCL8,

CCL11, IL-8). Mast cells are long-lived and therefore able to

respond repeatedly to the same stimulus

In addition to their well-established central role in the

pathogenesis of allergic disorders, MCs are now also appreciatedas key effector cells in the induction of protectiveimmune

responses to bacteria

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