Host Defense Flashcards
H1 Receptors
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.
Histamine
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.
H2 Receptors
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.
Diphenhydramine
First generation H1 antagonist
Ethanolamine
High sedation, anti-muscarinic actions
Dimenhydrinate
First generation H1 antagonist
Ethanolamine
High sedation, anti-muscarinic actions
Clemastine
First generation H1 antagonist
Ethanolamine
High sedation, anti-muscarinic actions
Carbinoxamine
First generation H1 antagonist
Ethanolamine
High sedation, anti-muscarinic actions
Pyrilamine
First generation H1 antagonist
Ethylenediamines
Medium sedation, GI side effects
Tripelennamine
First generation H1 antagonist
Ethylenediamines
Medium sedation, GI side effects
Chlorpheniramine
First generation H1 antagonist
Alkylamines
Potent as H1 blockers, mild sedation
Brompheniramine
First generation H1 antagonist
Alkylamines
Potent as H1 blockers, mild sedation
Hydroxyzine
First generation H1 antagonist
Piperazines
Mainly used for treating vertigo, motion sickness; sedation, anti-muscarinic
Meclizine
First generation H1 antagonist
Piperazines
Mainly used for treating vertigo, motion sickness; sedation, anti-muscarinic
Cyclizine
First generation H1 antagonist
Piperazines
Mainly used for treating vertigo, motion sickness; sedation, anti-muscarinic
Promethazine
First generation H1 antagonist
phenothiazines
sedation, anti-cholinergic, used as anti-emetic; multiple CNS effects—dopaminergic and adrenergic receptors
Cyproheptadine
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.
Loratadine
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.
Terfenadine
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
Astemizole
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
Fexofenadine
Second generation H1 antagonist
Don’t cross into CNS, therefore don’t cause drowsiness active metabolite of Terfenadine
Cetirizine
Second generation H1 antagonist
Don’t cross into CNS, therefore don’t cause drowsiness
Active metabolite of hyrdroxyzine
Desloratadine
Second generation H1 antagonist
Don’t cross into CNS, therefore don’t cause drowsiness
Active metabolite of loratadine
B1 and B2 receptors
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
Bradykinin
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
Aspirin
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.
SAIDS
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
Glucocorticoids
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
Sirolimus/Tacrolimus Pathway
Cyclosporine/ Tacrolimus
inhibits calcineurin phosphatase activity
decreases dephosphorylation of NFAT
T-cell selective
Adverse Effects: renal toxicity; hyperglycemia with tacrolimus
Sirolimus/ Everolimus
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).
Azathioprine/6-Mercaptopurine
Decreases purine biosynthesis
They are fraudulent nucleotides, inhibiting PRPP glutamyl transferase
allopurinol interaction
Mycophenolate Mofetil
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
Methotrexate
Anti-neoplastic used as an immunosuppressant
Inhibits DHFR
Cyclophosphamide
Anti-neoplastic used as an immunosuppressant
Alkylates DNA, leading to halting of cell proliferation
Effects rapidly proliferating cells (non-specific immunosuppressant)
Antithymocyte Globulin
Immunosuppressant
Mixture of cytotoxic antibodies to various CD molecules
Adverse effects: fever, chills, hypotension
Muromonab CD3
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
Daclizumab, Basiliximab
Monoclonal antibodies against IL-2 receptor
Blocks IL-2 mediated T-cell activation
Potential anaphylactic reactions
Alefacept
Binds to cell surface CD2 on T cells
Inhibits CD2/LFA-3 interactions
Inhibits T-cell activation
Main use: treatment of psoriasis
Rho(D) immune globulin
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
Etanercept
recombinant fusion protein consisting of
two soluble TNF receptor regions linked to
Fc portion of human IgG
Anti-inflammatory
Infliximab
chimeric monoclonal antibody with variable
murine region linked to constant human region
specific against human TNF
Similar to Etanercept, Adalimumab
Anti-inflammatory
Adalimumab
Recombinant human anti-TNF monoclonal antibody
Anti-inflammatory
Similar to Etanercept, Infliximab
All three drugs must be given by injection (broken down in gut)
Tocilizumab
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
Omalizumab
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
Levamisole
Immunostimulant
Synthesized as antihelminth agent
“Restores” depressed B- and T-cell function, moncytes,
macrophages
Use as adjunct in colon cancer therapy
Thalidomide
Potential anti-TNF alpha effect
May be anti-angiogenic
Increase NK cell activity
Associated with severe birth defects
Used in treatment of multiple myeloma
Penicillin G vs. Penicillin V
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
Vancomycin
Giant anti-biotic that binds to D-Ala-D-Ala subunit
This prevents trans-glycosylation reaction
Bacteriocidal
Erythromycin
Macrolide
Bacteriostatic agent that inhibits protein synthesis by binding reversibly to the 50S ribosomal subunits of sensitive organisms and inhibiting the translocation step.
Tetracyclines
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
Gentamycin
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
Miltefosine
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.
Sodium Stibogluconate
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.
Amphotericin B
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
Flucytosine
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
Griseofulvin
Inhibits microtubule formation and function in fungi
Used for most topical fungi
Taken orally
Nystatin
An alleleamine, like Amphotericin B
Given orally, but poorly absorbed. Can also be used as a topical agent
Trimethoprim-Sulfamethoxazole
Steps in folate metabolism blocked by sulfonamides and trimethoprim. This synergistic drug combination is used to treat *Pneumocystis jirovecii * in immunocompromised hosts.
Raltegravir
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
Maraviroc
Binds to CCR5, preventing HIV gp120 from binding, and inhibiting fusion of capsule with host cell
Only active against CCR5 tropic HIV
Enfuvirtide
Binds to HIV gp41
Inhibits HIV-host cell fusion
Trade name is fuseon
HIV Protease Inhibitors
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.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
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
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)
are effective against HIV-1 and HIV-2
Examples: Tenofovir disoproxil, abacavir, (everything ending in -vir)
HIV Plan of Attack
