Drugs-immmunity PDF

Preview

Summary

drugs of autoimmune disease ...

Description

Drugs Cyclophosohoamide

Mitoxantrone Doxorubicin

daunorubicin Methotrexate

MOA 1-Metabolized by the liver to phosphoramide 2- alkylate the DNA and inhabit cell division 3- act as immunosuppression at a lower dose.  leukopenia; decrease granulocytes, lymphocytes and monocytes NK cells inhibited 1-Intercalate into the DNA 2- inhibit topoisomerase 2 1- anthracycline antibiotics which intercalate with DNA 2- inhibits B-cell function more than T-cell and does not inhibit macrophage or NK function. 1- antibiotic 2-inhibits macrophage function 1- Inhibit dihydrofolate reductase which inhibit DNA synthesis 2- inhibits replication of B and T-cells 3- immunosuppression. Is at lower dose. 4- Anti-inflammatory effect: –MTX is poly-glutamated (long half-life)

Use - B-cells: No gastric ulceration

1- RA 2- Osteoartherties 3- Anti- inflammatory, analgesic, anti- pyretic.

1- increases risk for thrombosis

2- prevent heart attacks.

Paracetamol (Acetaminophen )

1- mediated by metabolite NAPQI which activates TRPA1 in the spinal cord producing antinociceptive response

1- No antiinflammatory activity. 2- Analgesic and antipyretic

Zileuton

inhibit LOX only

asthma

Meclofenamate

Inhibit both COX and LOX CysLT1 antagonist

asthma & COPD

1- Inhibit phospholipase A2 and COX and leads to reduce INF, IL1, IL2, PG, interferon and L. 2- decreases basophils, eosinophils and monocytes 3- increase in neutrophils 4- lymphocytes are also reduced; - T cells > B cells - CD4+ > CD8+

1- asthma 2 M. S. 3- RA 4- psoriasis 5- Crohn's disease

Special NSAID

Side effects 1- Gastro-ulceration 2- bleeding

2- myocardial infarction . overdose > hepatotoxicity

Leukotriene LOX inhibitor

LT receptors Zefirlukast and antagonist montleukast Steroids anti-inflammatory Synthetic Prednisolone, glucocorticoids declomethasone and hydrocortisone

asthma

. 1- hypertension, 2- osteoporosis 3- Cushing syndrome 4- infections 5- adverse effects on carbohydrate metabolism

IL2 targeting drugs Class Example Cyclosporine (CsA) (Tolypocladiu m inflatum fungs)

IL2 production Inhibitor

Tacrolimus fungus (Streptomyces tsukubaensis)

IL2 signaling inhibitor

- Rapamycin/ sirolimus )Streptomyces hygroscopicus (

- temsirolimus - everolimus –Zotarolimus –Biolimus –Deforolimus Anti-IL2 receptors anti bodies Recombinant hormone

Basiluximab and dalizumab

MOA 1- Attaches to intracellular receptor called Cyclophilin (immunophilins). 2- Once attached to Cyclophiline the complex will attaches to calceneurin and inhibit it. - Calceneurin is phosphatase that remove phosphate group from neuclear factor of activated T-cell (NF-AT - Activated NF-AT induce IL2 gene transcription 4- by inhibiting calcineurin -cyclosporine > inhibit IL2 synthesis - inhibit mixed lymphocyte reaction (MLR) but was not cytotoxic. - inhibits antibody production against T-celldependent antigens (sheep erythrocytes) but not T-cell independent antigens (LPS). 1- Attaches to intracellular receptor called FKBP (immunophilins). 2- Once attached to FKBP506 the complex will attaches to calceneurin and inhibit it. 3- same steps as CsA. - found to inhibit MLR. - more potent.

Uses prevent organ rejection

Side effects - nephrotoxicity due to endothelin release and inhibition of NOS

prevent organ rejection

- nephrotoxicity due to endothelin release and inhibition of NOS

1- Attaches to intracellular receptor called FKBP (immunophilins). 2- it does not inhibit calcineurin, instead it inhibits IL2 signaling. 3- Rapamycin-FKBP complex bind to mTOR ( phosphatidylinositol 3kinase) which is involved in IL2 signaling. 4- Leads to reduced expression of adhesion molecules including sphingosine-1-phoosphate receptor 5- Causes cell cycle arrest at G1.

1- allograft rejection 2-autoimmune diseases 3- inhibition of stent induced hyperplasia (SM proliferation) 4- Renal cell carcinoma (RCC) 5- Melanoma 6- Breast cancer

Monoclonal antibodies to IL2 reeptors

- preventing organ rejection - MS 1- Melanoma 2- renal cancer 3- breastcancer leukemia > T cell lymphoma.

Recombinant IL2 Denileukin Diftitox

1- Recombinant IL2 attached to diphtheria toxin. 2- bind to cells which express excess IL2 receptors.

- activate NFkB in fibroblasts leading to increased IL-6 production in kidney. - dyslipidemia - in-stent thrombosis

3- once receptor activated Denileukin Diftitox internalized and has toxin effect. Anti-TNF Drugs Class Example -Infliximab (Chimeric) Monocl onal antibod ies

MOA 1- bind to free TNF preventing its reaction with TNF receptor. 2- Chimeric A2 (cA2) IgG 1 monoclonal antibody 3- Binds to TNFa with high affinity and specificity 4- Half-life of 8-9.5 days 5- Can cross-link receptors*. 1- bind to Soluble and membrane-bound TNF (biologically active). 2- bind to and neutralize both (very potent) 3- High affinity and selectivity for TNF-a 4-Long half-life (14 days) Humized Fab fragment linked to two PEG molecules.

Uses 1- RA > with MTX. 2- given IV every 8 weeks. 3- Increase suitability to infection 4- RA 5- Crohn’s disease

1- Soluble TNF receptor fused to Fc portion of human IgG 1. 2- Binds soluble and membrane TNF-a and TNF-b (lymphotoxin) 3- Does not bind to receptor-bound TNF 4- Moderate- to high-binding affinity to TNF-a 5- Half-life of 4-5 days (shorter)

1- inject sc twice weekly With MTX or monotherapy

Thalidomide

1- Inhibit TNF production. 2-down-regulates b 2 and b3 integrins and inhibits TNFa production 3- effects phagocytes and not T-cells

Lenalidomi de

1-Derivative of thalidomide (same MOA). 2- Anti-angiogenic and antineoplastic 3- Alters cytokine expression; –Increases anti-inflammatory cytokines

1- morning sickness > sedative 2immunomodulator 3- leprosy and GvHD in children 4- HIV 5- mouth ulcers & wasting 1–Multiple myeloma 2–Myelodysplastic syndromes with 5q deletion.

Adalimumab - glimumab (human)

Solubl e Recept ors

Nonbiologic al antiTNF

Cetrolizumab (humanized Fv)) Etanercept

given subcutaneous (SC) fortnightly

Side effects 1- Immunological reaction to injection 2- infection –Viral –Pneumonia –TB  Diagnosis may be difficult because of lack of granuloma formation, atypical presentation - commonly extra-pulmonary Risk factors : concomitant corticosteroids and diabetes more with infliximab 3- Antibodies reduce efficacy of Moabs. Not a problem with etanercept. 4- Reflected in loss of efficacy 5- Requires dose escalation more with infliximab. 6- Infusion Reactions with Infliximab, Injection Site Reactions with Adalimumab and Etanercept 7- Malignancy 8-Neurologic 9 - Multiple Sclerosis, (seizures, inflammation of the ocular nerve) 10- Autoimmune – Antibody formation – SLE like illness 11- Worsening of Congestive Heart Failure 1- potent teratogen: - phocomelia; severe birth defects extreme shorting of limbs R isomer(occur at pH 7)

–Decreases pro-inflammatory cytokines 4- Inhibits cell growth No anti-TNF receptors agents because there are multiple receptors

IFN Example IFNβ-1a - Rebif® - Avonex and IFNβ1b Anti-IL1 drugs Monoclonal -Canakinomab -Gevokizumab antibodies Rilanocept Soluble Receptors IL1 receptors antagonist

Anakenra

MOA - high IL-17 response.

uses - MS

Monoclonal anti-IL1

RA

Fused IL-1RI and IL-1RAcP (IL1 receptors dimer) attached to Fc region of IgG to prolong its halflife Soluble IL1 receptor antagonist IL-1Ra

orphan diseases.

Side effects - Some patient will develop resistance

RA

Fc receptors example

MOA

uses

Monoclonal antibody

Omalizuma b

asthma

IgIV

Monomeric IgG

1- Monoclonal IgG directed against Fc poetion of IgE ( FcƐ RI & FcƐ RII > on mast cells ) 2- reducing level of free IgE and reduce its receptors (FcɛRI). 1-Increase the level of IgG leading to inhibit Fcɣ RIIa by preventing its dimerization. 2- ntravenous IgG (IVIG) > pooled IgG given to increase levels. 3- it can be enriched for certain antibody types (e.g. anti-S. aureus antibodies)

Intravenous IgG (IVIG)

–Immune thrombocytopenia –Kawasaki syndrome –Multifocal Motor Neuropathy –Chronic Inflammatory Demyelinating Polyneuropathy

Side effects

Drugs targeting co-stimulation Class Example MOA Targeting CD28 CTLA-4 - Abatacept 1- Soluble CTLA-4 Fused with human Fc of Fusion IgG to prolong the t1/2. protein Belatacept 2- bind to B7 and prevent its interaction with CD28.. - Abatacept > B7-1 - Belatacept > B7-2 3- inhibit T-cell activation. 4- Reduces TNFa, IFNg and IL-2 secretion. CTLAIpilimumab Monoclonal antibodies that blocks CTLA-4 antagonis and so enhance immunity.. t

CD28 agonist

CD2 CD2 soluble receptors

Integrin Monoclonal antibodies

Uses

Side effects

1- RA 2- organ transplantation > Belatacept

Melanoma treatment by increasing immune surveillance Not used

TGN1412

Monoclonal antibodies that has been shown to induce potent anti-inflammatory response in mice (increases type 2 helper cells and regulatory T cell ) but it induced systemic inflammatory response syndrome in human during its clinical trials.

1- SIRS 2- cytokine storm

Alefacept

1- LFA-3 fusion protein that binds to CD2. 2- inhibit T-memory cells formation and induce apoptosis of activated memory cells. 3- Triggers NK cell-mediated apoptosis of activated T-cells.

plaque psoriasis

Not avia;ablr because of adverse effects and efficacy.

Efalizumab

1- Monoclonal antibody to aL b 2 (LFA-1, CD11a) 2- Blocks T-cell binding to endothelial cells

Psoriasis

- induce Progressive Multifocal Leukocephalopathy > withdrawn from markets

Natalizuma b

1- Monoclonal antibodies bind to α2 (α4B7 & α4B1) integrin. 2- It blocks the binding of inflammatory cells to endothelium (in the stroma or choroid plexus epithelium) 3- could block the binding of integrin to CS1 site on fibronectin which associated wth cerebeovascular endothelium) 3- preventing infiltration of lymphocytes into brain.

MS - Introduction of a risk evaluation and mitigation strategy (REMS) / Risk Management Plan (RMP).

PML (progressive multifocal leukoencphalopathy).

Immune cell depletion Class Example Rituximab

Monoclonal antibodies

Alemtuzuma b

Fingolamod

Sphingosine -1Phosphate receptor partial agonist

Siponimod

Miscellanous agents

MOA 1- Monoclonal anti bodies against CD20, protein on B cells surface. 2- complement activation leads to B-cell destruction. 3- destruction could be mediated by three pathways: a) complement mediated cytotoxicity (MAC) b) direct lysis by NK cells. c) FcγR/CR- mediated opsonic phagocytosis or ADCC. 1- Monoclonal antibodies that is directed against CD52 an antigen on mature lymphocytes. 2- causes depletion of t-cells through complements system activation. 1- Fungal (Isaria sinclairii ) metabolites that is ligand to all S1P but S1P2. 2- It binds to the receptors and trigger their internalization. 3- therefore cannot respond ro S1P signal. 4- inhibit lymphocytes migration from nodes.

Uses –B-cell lymphoma –RA resistant to anti-TNF therapy

Side effects - Rare adverse effects involve: 1- PML 2- SIRS 3- reaction of hepatitis 4- severe infusion reaction

oral MS treatment

- adverse effects involve effecting: 1- HR 2- conduction 3- macular edema. 4- Small number of skin cancer 5- one PML 6- increased infections ; 2 deaths from Herpes virus infection.

1- Analogous of fingolimod but only bind to S1P1 and S1P5.

Still in phase III trial for MS treatment

less cardiovascular adverse effects. > improves specificity.

-MS - T cells leukemia

Example Dimethyl Fumarate

Glatiramer

Sulfasalazine

MOA 1- Small molecule that act to shift immune response from Th1 to Th2. 2- reduce the level of pro-inflammatory cytokines. 3- it may involve the activation of nuclear factor Nrf2 and modulating the response of oxidative stress. 4- Effects of DMF: a) T-cell & B-cell: apoptosis, Th1 to Th2 shift. b) Dendertic cells: inhibition of differentiation. c) Glia: inhibition of pro-inflammantory cytokinase. d) Endothelial cells: downregulation of Th1 response, inhibition of TNF α, ICAM-1, Eselectin, VCAM-1. 1- High molecular weight polypeptide that induce Th2 response to produce antiinflammatory cytokines and neurotropic factors that help demyelination of nerves. 2- Induction of a specific Th2 population in periphery 3- Reactivated (T-cell) in CNS due to crossreactivity with myelin 4- Secrete anti-inflammatory cytokines, 5- Produce neurotrophic factors 6- remyelination and axonal protection. 1- Anti-inflammatory: Salicylic Acid Antibiotic: Sulfapyridine 2- Sulfasalazine consists of salicylic acid and sulfapyridine joined by an azo bond.

uses MS

MS

-RA - Crohn treatment

3- Metabolized by gut bacteria to 5aminosalicylic acid and sulfapyridine. 4- 5-aminosalicylic acid reduce the activity of tcells and neutrophil. - effects neutrophil activity, - reduced production of IL-1, - TNF from monocytes/macrophages, - inhibits T-cell proliferation etc. Hydroxycloroquin e

1- Anti-malaria drug with immunosuppressant effects. 2- penetrate cell walls because its highly lipophilic 3- stabilize lysosomal membranes by raising pH and inhibiting the action of lysosomal acidic protease. 4- Inhibit metabolism of deoxyribonucleotides 5- Interferes with cell’s ability to degrade and process proteins.

Side effects

inflammator y arthritis

1- Side effects primarily due to sulfapyridine: –skin reactions, –hepatitis, –pneumonitis, –agranulocytosis, –aplastic anemia –Males - oligospermia and infertility 2- Dose-related side effects include: –gastrointestinal upset –less severe hematologic toxicities. - Common S/E 1- Rash, nausea, diarrhea 2- Ocular – retinopathy/colour vision - rare but requires monitoring 3- Depigmentation 4- Myopathy

Immune stimulator Drug Imiquimod

Goat treatment Class Antiinflammatory

MOA 1- Enhances cytokine production and increases infiltration of the tumour by immune cells 2- Induces apoptosis

uses 1- genital warts 2- basal cell carcinoma

Side effects

Example Colchicine

MOA Binds to tubulin in the cells effecting cell division. Inhibits the functions of leukocytes, chemotactic factors IL production and release of histamine

Side effects .. Associated with GIT, hematological side effects, hair loss and Muscular weakness

Uric acid synthesis inhibitor

Allopurinol

Oral Xanthine oxidase inhibitor use for treatment of hyperuricemia

its complications include Chronic gout not the acute one

Uricosuric

Probenecid

Uricase

Rasburicase

Interferes with kidneys organic anion transporter (OAT)which reclaim uric acid from urea and returns it to plasma Highly effective, decreasing serum urate level by degrading urate to allantoin.

Antibiotics Cell wall inhibtors B- lactams Example Penicillin. e.g. penicillin G, V Anti-staphylococcal penicillins: methicillin, oxacillin Aminopenicillins ampicillin amoxicillin

Anti-pseudomonal penicillins. Ureidopenicillins Carbenicillin Cephalosporin Generations (1-5) E.g. cephazolin Carbapenems:meropene m Monobactams: azteonam Glycopeptides

Uses

Resistance

Side effects

MOA

Streptococci Meningococci Syphilis

1- B-lactamase hydrolysis B-lactam ring. inhabited by Blactamase inhibitor e.g Clavulante, Sulbactam, Tazobactum.

.1- hypersensitivity to �-lactams (anaphylaxis > binds to album protein and make it antigentic)

Bacteriostatic: Mimetic Ala-Ala the natural substrate of transpeptidase, irreversible inhibition transpeptidas

2- MecA gene: mutant transpeptidase (PBP 2a) > cross link the cell wall + low affinity for methicillin.

2- neurological Effects: - hgh dose - renal clearance is comprimaized - intrathecal (injection into the spine)

Bacteriocidial: Leackage of lipotechoic acid cause decreased level of liptechoic acid; this leads to activation of autolysin which lysis bacteria

3- mexB gene: multi-drug efflux pump

3- seizure induction > Pencilin G.

(-), H.influenza E coli Salmonella & shigella Pseudomonas aeruginosa: Gram-ive bacterium Check the note

polyinfections Aerobic, (-)

Vancomycin teicoplanin, oritavancin, dalbavancin.

MARS

Telavancin (lipoglycopeptide)> IV

-gastrointestinal Infections > oral - only (+) - MRSA UTI (+/-)

Fosfomycin

1- genes: - Van R/S>detection and make promerter. - Van H>pyrvute to lactate. - VanX> hydrolase Dala-D-ala - VanA/B: produce Dala_lactate 2- thicker cell wall

1- bind to Ala-Ala 2- prevent Transpeptidase binding. 3- cell wall synthesis and repair cannot occur.

inhibits the enzyme UDPNacetylglucosamine3enolpyruvyltransferas e which transfers a pyruvate to the glycol which acts as a linker for the peptide component.

Protien synthesis inhibtors. Aminoglycoside example

uses

MOA

Side effects

resistence

Streptomyces gentamicin, amikacin and neomycin.

- aerobic Gramive - Gram+ive organisms such as Staphylococci. - UTI > not metabolised by cytochrome P450

1- oxygen dependent transporter to cross the cell membrane. 2- binds to 30S irreversibly 3- effects on protien making. - mis-reads in translation > stoped if stop codon - proteins with mutations in them.

1- effect foetus. 2- nephrotoxicity 3- ototoxicity.

1- Decrease permeability 2- Xenobiotic Pump 3- aminoglycoside modifying enzymes (9+) > acetylate, adenylate etc the antibiotic.

respiratory infections.

1- bindis to the 50S subunit to inhibit protein synthesis.

1- ventricular tachycardia when given in conjunction with certain H1antagonists,

1- Xenobiotic Pump 2- target mutation

IV, IM or topically

Macrololides erythromycin, clarithromycin and azithromycin > orally

2- Quinupristin and dalfopristin bind to sites beside each other > synergistic effect.

lincosamides > orally (clindamycin and lincomycin) streptogramins >IV (quinupristin and dalfopristin)

2- Erythromycin can cause nausea.

Tetracycline Tetracycline tigecycline

Minocycline

doxycycline

- intracellular pathogens: 1- Chlamydia 2- Mycoplasma 3- Rickettsia. 4- anthrax 5- bubonic plague good penetration into the CNS. 1- against protozoa > malaria prophylaxis

1- bind to the 16S component of 30S subunit 2- blocks the tRNA binding. 3- also bind to the 40S subunit of eukaryotic ribosomes, > less effect because bacteria pumps tetracycline against the concentration gradient into the bacterial cells.

1- meningitis 2- bubonic plague 3- cholera 4- typ...