Host Defense

Question 1

H1 Receptors

Answer 1

H1 receptors work through the phospholipase C pathway, hydrolyzing phosphoinosotol. It generates PIP3 and DAG. This pathway causes bronchial constriction, and these receptors are often found in the bronchial tree (more often/dense than H2). Calcium is often found in contraction. This is why we worry about airways in inflammatory responses, and is why we use antihistamines to target the H1 response. H1 is not a vasoconstrictor due to the fact that H1 receptors are not located on the smooth muscle, but on vascular endothelial cells. This activates machinery in endothelial cells that makes NO and arachadonic acid derivatives (especially PGI2, prostacyclin) via the increase in calcium. The endothelial cells also have some contractile elements, and the calcium causes constriction on a cell by cell basis. This leads to the leakiness associated with histamine, which is used to allow leukocytes to exit vasculature. Histamine is algesic, especially with H1 responses. Histamine is also useful for wakefulness in the CNS, which comes back as a side-effect of antihistamines, sedation. Retains amino group.

Question 2

Histamine

Answer 2

involved in the inflammatory response and released following chemical, mechanical stimuli. It is found in mast cells, basophils, et c.

When released, it targets specific receptors, such as H1 and H2 (there are multiple other H receptors, but these are the most important.

Out of the two, H1 is most important)

The drugs of Host Defense are primarily H1 antagonists. H2 blockers are used more for GI effects.

Question 3

H2 Receptors

Answer 3

H2 works through adenylate cyclase, generating cAMP, which can signal through a variety of pathways.

This response is more straightforward. The receptor is on the smooth muscle itself, and the adenylate cyclase causes muscle relaxation directly. Prominantly in the gut. In a big inflammatory response, we worry about excessive acid release in the gut leading to ulcer formation.

Retains imidazole ring.

Question 4

Diphenhydramine

Answer 4

First generation H1 antagonist

Ethanolamine

High sedation, anti-muscarinic actions

Question 5

Dimenhydrinate

Answer 5

First generation H1 antagonist

Ethanolamine

High sedation, anti-muscarinic actions

Question 6

Clemastine

Answer 6

First generation H1 antagonist

Ethanolamine

High sedation, anti-muscarinic actions

Question 7

Carbinoxamine

Answer 7

First generation H1 antagonist

Ethanolamine

High sedation, anti-muscarinic actions

Question 8

Pyrilamine

Answer 8

First generation H1 antagonist

Ethylenediamines

Medium sedation, GI side effects

Question 9

Tripelennamine

Answer 9

First generation H1 antagonist

Ethylenediamines

Medium sedation, GI side effects

Question 10

Chlorpheniramine

Answer 10

First generation H1 antagonist

Alkylamines

Potent as H1 blockers, mild sedation

Question 11

Brompheniramine

Answer 11

First generation H1 antagonist

Alkylamines

Potent as H1 blockers, mild sedation

Question 12

Hydroxyzine

Answer 12

First generation H1 antagonist

Piperazines

Mainly used for treating vertigo, motion sickness; sedation, anti-muscarinic

Question 13

Meclizine

Answer 13

First generation H1 antagonist

Piperazines

Mainly used for treating vertigo, motion sickness; sedation, anti-muscarinic

Question 14

Cyclizine

Answer 14

First generation H1 antagonist

Piperazines

Mainly used for treating vertigo, motion sickness; sedation, anti-muscarinic

Question 15

Promethazine

Answer 15

First generation H1 antagonist

phenothiazines

sedation, anti-cholinergic, used as anti-emetic; multiple CNS effects—dopaminergic and adrenergic receptors

Question 16

Cyproheptadine

Answer 16

First generation H1 antagonist

Piperidines

used in temperature sensitive people, which leads to mast cell degranulation.

It may have something to do with the serotonin response, but its not well known.

Question 17

Loratadine

Answer 17

A second generation H1 antagonist

The first of the second generation antihistamines were pro-drugs. They required metabolism by cytochrome p450. This made them more polar, which prevented them from crossing the blood brain barrier.

This class doesn’t have the drowsiness side effect, but also lacks the motion sickness treatment.

Question 18

Terfenadine

Answer 18

Second generation H1 antagonist

toxicity: polymorphic ventricular tachycardia when taken at high dose or with certain P450 inhibitors like erythromycin, ketoconazole; unmetabolized parent drug blocks delayed rectifier potassium channels;

prolongs QT interval, torsades de pointes

Question 19

Astemizole

Answer 19

Second generation H1 antagonist

toxicity: polymorphic ventricular tachycardia when taken at high dose or with certain P450 inhibitors like erythromycin, ketoconazole; unmetabolized parent drug blocks delayed rectifier potassium channels;

prolongs QT interval, torsades de pointes

Question 20

Fexofenadine

Answer 20

Second generation H1 antagonist

Don’t cross into CNS, therefore don’t cause drowsiness active metabolite of Terfenadine

Question 21

Cetirizine

Answer 21

Second generation H1 antagonist

Don’t cross into CNS, therefore don’t cause drowsiness

Active metabolite of hyrdroxyzine

Question 22

Desloratadine

Answer 22

Second generation H1 antagonist

Don’t cross into CNS, therefore don’t cause drowsiness

Active metabolite of loratadine

Question 23

B1 and B2 receptors

Answer 23

The receptors are named for bradykinin, B1 and B2 receptors.

They do very similar things to histamine. They constrict bronchial smooth muscle, dialate vascular smooth muscle, and have effects at nerve endings, especially as the source of pain during inflammation.

They are amplifiers of the inflammatory process

Question 24

Bradykinin

Answer 24

Important algesic in inflammation

Made from high molecular weight kininogen by kallikrein

Broken down by Kininase I and II One amino acid (more) different from Kallidin

Question 25

Aspirin

Answer 25

Irreversible inhibitor of the COXI and II. All other NSAIDs are competitive. It transfers an acetyl group in an active site. This is a big deal with platelets, which don’t have nuclei. It can’t make thrombaxane until new platelets are produced. This leads to a much longer lived effect. If you knock out platelets, you can cause an increase in bleeding, especially in patients that are already susceptible.

Question 26

SAIDS

Answer 26

SAIDS, steroidal anti-inflammatory drugs: These are glucocorticoids, or steroids (anything derived from cholesterol). Glucocorticoids are produced by the adrenal cortex and have effects on metabolism and glucose. They are very lipophilic, and can go through a membrane in absence of a cell surface receptor. They tend to work as dimers with receptors that serve as transcription factors. It will bind to a hormone response element and increase transcription (or decrease in negative regulation). Glucocorticoids work through gene-dependent actions

Question 27

Glucocorticoids

Answer 27

anti-inflammatory/immunosuppressive: decrease arachidonic acid metabolism, both PGs and LTs decrease COX-2 mRNA and protein decrease PLA2 activity decrease cytokine expression decrease cell-adhesion molecule expression decrease fibroblast DNA synthesis/proliferation

Question 28

Sirolimus/Tacrolimus Pathway

Answer 28

Question 29

Cyclosporine/ Tacrolimus

Answer 29

inhibits calcineurin phosphatase activity decreases dephosphorylation of NFAT **T-cell selective** Adverse Effects: renal toxicity; hyperglycemia with tacrolimus

Question 30

Sirolimus/ Everolimus

Answer 30

same family as tacrolimus/cyclosporine ** blocks T cell response to cytokines** inhibits a kinase involved in cell-cycle progression, (inhibit a CDK-2 protein), downstream of IL-2 receptor. This blocks the effects of IL-2 (proliferation).

Question 31

Azathioprine/6-Mercaptopurine

Answer 31

Decreases purine biosynthesis They are fraudulent nucleotides, inhibiting PRPP glutamyl transferase allopurinol interaction

Question 32

Mycophenolate Mofetil

Answer 32

Mycophenolate Mofetil inhibits inosine monophosphate dehydrogenase decreases de novo purine biosynthesis T and B cell sensitive due to lack of salvage pathway related drug: mizoribine

Question 33

Methotrexate

Answer 33

Anti-neoplastic used as an immunosuppressant Inhibits DHFR

Question 34

Cyclophosphamide

Answer 34

Anti-neoplastic used as an immunosuppressant Alkylates DNA, leading to halting of cell proliferation Effects rapidly proliferating cells (non-specific immunosuppressant)

Question 35

Antithymocyte Globulin

Answer 35

Immunosuppressant Mixture of cytotoxic antibodies to various CD molecules Adverse effects: fever, chills, hypotension

Question 36

Muromonab CD3

Answer 36

Antibody blocks binding of APC to T-cell Blocks T-cell function Decreases T-cell number Initial stimulation of cytokine release syndrome. Leads to release of small amounts of IL-2 that simulate horrible flu symptoms

Question 37

Daclizumab, Basiliximab

Answer 37

Monoclonal antibodies against IL-2 receptor Blocks IL-2 mediated T-cell activation Potential anaphylactic reactions

Question 38

Alefacept

Answer 38

Binds to cell surface CD2 on T cells Inhibits CD2/LFA-3 interactions Inhibits T-cell activation Main use: treatment of psoriasis

Question 39

Rho(D) immune globulin

Answer 39

Human IgG with high titer of antibodies against Rho(D) antigen of red blood cells Given to prevent sensitization of Rh-negative mother to Rh-positive child Example of passive transfer of immunity

Question 40

Etanercept

Answer 40

recombinant fusion protein consisting of two soluble TNF receptor regions linked to Fc portion of human IgG Anti-inflammatory

Question 41

Infliximab

Answer 41

chimeric monoclonal antibody with variable murine region linked to constant human region specific against human TNF Similar to Etanercept, Adalimumab Anti-inflammatory

Question 42

Adalimumab

Answer 42

Recombinant human anti-TNF monoclonal antibody Anti-inflammatory Similar to Etanercept, Infliximab All three drugs must be given by injection (broken down in gut)

Question 43

Tocilizumab

Answer 43

Recombinant humanized IgG that binds to IL-6 receptors Inhibits Il-6 mediated signaling in lymphocytes thus suppressing inflammatory processes main use in treatment of rheumatoid arthritis

Question 44

Omalizumab

Answer 44

Anti-IgE recombinant humanized monoclonal antibody Blocks the binding of IgE to Fc receptor on basophils and mast cells, which **suppresses IgE-mediated release** of Type I hypersensitivity mediators such as histamine and leukotrienes. main use: allergic asthma in patients whose symptoms are refractory to inhaled corticosteroids

Question 45

Levamisole

Answer 45

Immunostimulant Synthesized as antihelminth agent “Restores” depressed B- and T-cell function, moncytes, macrophages Use as adjunct in colon cancer therapy

Question 46

Thalidomide

Answer 46

Potential anti-TNF alpha effect May be anti-angiogenic Increase NK cell activity Associated with severe birth defects Used in treatment of multiple myeloma

Question 47

Penicillin G vs. Penicillin V

Answer 47

Penicillin V is given orally, Penicillin G is given IV Penicillins are PBP inhibitors that prevent transpeptidation They can be broken down by B-lactamases

Question 48

Vancomycin

Answer 48

Giant anti-biotic that binds to D-Ala-D-Ala subunit This prevents trans-glycosylation reaction Bacteriocidal

Question 49

Erythromycin

Answer 49

Macrolide Bacteriostatic agent that inhibits protein synthesis by binding reversibly to the 50S ribosomal subunits of sensitive organisms and inhibiting the translocation step.

Question 50

Tetracyclines

Answer 50

Inhibit bacterial protein synthesis by binding to the 30S subunit and blocking tRNA binding to the A site. The breakdown products of most tetracyclines are nephrotoxic, except for doxycycline because it is excreted unchanged in the urine or bile (feces). Can discolor teeth in children or prevent proper development in fetuses

Question 51

Gentamycin

Answer 51

Aminoglycoside binds to the 30S ribosomal subunit and interferes with initiation of protein synthesis by fixing the 30S-50S ribosomal complex at the start codon (AUG) of mRNA. Aminoglycoside binding to the 30S subunit also causes misreading of mRNA, leading to premature termination of translation with detachment of the ribosomal complex and incompletely synthesized protein or incorporation of incorrect amino acids (indicated by the X), resulting in the production of abnormal or nonfunctional proteins. These actions are bactericidal

Question 52

Miltefosine

Answer 52

very effective as an orally active agent against visceral and mucocutaneous leishmaniasis. MOA is elusive but may alter lipid metabolism or cell signaling. Vomiting, diarrhea, teratogenic (women put on birth control) are toxicities. Approved in India, Afghanistan, Pakistan, South America and in clinical trials for approval by FDA in USA.

Question 53

Sodium Stibogluconate

Answer 53

A pentavalent antimonial (Sb) compound used to treat leshmaniasis in the US until recently. MOA is related to the trypanothione redox sytem in the organism. Toxicities are chemical pancreatitis, bone marrow suppression, muscle and joint pain, nausea, weakness, headache, changes in electrocardiogram (T-wave flattening, prolonged QT interval). Replaced by liposomal amphotericin B and miltefosine.

Question 54

Amphotericin B

Answer 54

Anti-fungal that inhibits fungal membrane function by interacting with Ergosterol May form pores as well as generate ROSs Originally the gold standard of fungal antibiotics

Question 55

Flucytosine

Answer 55

A cytosine analog that is incorporated into fungal DNA, RNA, and inhibits thymidiylate synthase It is synergistic with Amphotericin B, and is rarely used as a monotherapy

Question 56

Griseofulvin

Answer 56

Inhibits microtubule formation and function in fungi Used for most topical fungi Taken orally

Question 57

Nystatin

Answer 57

An alleleamine, like Amphotericin B Given orally, but poorly absorbed. Can also be used as a topical agent

Question 58

Trimethoprim-Sulfamethoxazole

Answer 58

Steps in folate metabolism blocked by sulfonamides and trimethoprim. This synergistic drug combination is used to treat *Pneumocystis jirovecii * in immunocompromised hosts.

Question 59

Raltegravir

Answer 59

Binds to HIV integrase, inhibiting integration After the "reverse transcription" of RNA into DNA is complete, HIV's DNA must then be incorporated (integrated) into the CD4 cell's DNA. This drug prevents the formation of covalent bonds between host and viral DNA—a process known as strand transfer—presumably by interfering with essential divalent cations in the enzyme's catalytic core. Integrase inhibitors may offer a lot of hope for HIV-positive people, especially those who have developed HIV resistance to drugs that target HIV's two other major enzymes: reverse transcriptase and protease

Question 60

Maraviroc

Answer 60

Binds to CCR5, preventing HIV gp120 from binding, and inhibiting fusion of capsule with host cell Only active against CCR5 tropic HIV

Question 61

Enfuvirtide

Answer 61

Binds to HIV gp41 Inhibits HIV-host cell fusion Trade name is fuseon

Question 62

HIV Protease Inhibitors

Answer 62

Saquinavir Ritonavir Indinavir Nelfinavir Lopinavir Fosamprenavir Tipranavir Atazanavir Darunavir The protease inhibitors inhibit the HIV-encoded protease that cleaves the initial protein products of the virus (Gag and Gag-Pol) to form the mature proteins necessary for viral assembly.

Question 63

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Answer 63

noncompetitive inhibitors of HIV reverse transcriptase (RT). They bind at different sites on HIV RT than the nucleoside analogs (NRTIs) and are not effective against HIV-2 (West Africa mainly). Examples: Nevirapine, Delavirdine, Efavirenz, Etavirine

Question 64

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Answer 64

Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) are effective against HIV-1 and HIV-2 Examples: Tenofovir disoproxil, abacavir, (everything ending in -vir)

Question 65

HIV Plan of Attack

Answer 65