what are some of the pharmacological sites of immune suppression?

• GLUCOCORTICOIDS (inhibit gene expression)
• LEFLUNOMIDE/MTX (inhibit clonal expansion of lymphocytes)
• CYCLOSPORINE/TACROLIMUS (interrupt intracellular signals)
• ETANCERCEPT/ANAKINRA (cytokine blockers)
• ABATACEPT (inhibits costimulation of APCs)
• EFALUZIMAB (inhibit lymphocyte cell adhesion)
• COMPLEMENT INACTIVATION

what are some of the intervention points of glucocorticoids to accomplish their immunosuppresive/anti-inflammatory role?

• lymphocytes (to halt their cytokine secretion)
• endothelial cell adhesion molecules
• basophils (histamine/LT release)
• monocytes

act on PLA or PLC, which is responsible for converting essential fatty acids into arachidonic acid

• to achieve adequate short term control for conditions like arthritis
• reduces chronic inflammation but there is also reduced healing
• problems occur with long term use, so only used chronically when other measures fail

what are the hematological and immunological side effects of GC therapy?

• reduced number of cells (eosinophils, leukocytes, lymphocytes)
• altered inflammatory response

what are the GI and metabolic/musculoskeletal side effects of GC therapy?

GI:

• fatty liver
• peptic ulceration

Metabolic/musculoskeletal

• protein wasting
• hyperlipidemia
• obesity (increased abdominal fat, buffalo hump)
• avascular necrosis of femoral head
• osteoporosis
  

what are the ocular and CNS side effects of GC therapy?

ocular:

• cataracts
• increased intraocular pressure

CNS:

• depression
• nervousness

what are the fluid/electrolyte and endocrinologic side effects of GC therapy?

fluid/electrolyte

• Na+ retention
• hypertension

endocrinologic

• H-P suppression (hypothalamo-pituitary axis)-->decreased libido among others...

what are the skin and general side effects of GC therapy?

skin

• striae
• hirsutism
• thinning
  

general

• truncal obesity

among the various GCs, how do they differ?

• affinity to GC-Rec
• anti-inflammatory potency
• Na retention
• duration (oral/IV)

prednisone, hydrocortisone, prednisilone are all low receptor affinity GCs--> low anti-inflammatory potency

• asthma
• bee sting
• IBD
• arthritis
• cerebral edema (post op)
• dermatitis
• conjunctivitis

• asthma and other non-infectious URIs
• allergic and non-allergic rhinitis

goal: reduce vasodilation and fluid exudation

toxicity: minimal; candidiasis at worst; rarely adrenal insufficiency

what cytokines do CD4+ cells secrete and how do they operate in the pathway towards rheumatoid arthritis?

CD4+ cells secrete:

• IL 2
• IL 6
• IFN gamma

These cytokines stimulate:

• B cells --> plasma cells --> rheumatoid factor --> immune complex --> CARTILAGE & BONE DAMAGE
• Macrophages -->
  
  • IL-1
  • TNF a
  • IL 6
  • IL 8 -->
  • OSTEOCLASTS, FIBROBLASTS, AND ENDOTHELIAL CELLS --> CARTILAGE & BONE DAMAGE

what is methotrexate and what is its mechanism of action?

• MTX: DMARD of choice with low side effects
  • purine synthesis inhibitor via AICAR-T/thymidylate synthase inhibition
  • directly inhibits B CELL PROLIFERATION
  • end result: less pro-inflammatory and more anti-inflammatory cytokines

what are the common ADRs of MTX and what are its most important contraindications?

• ADRs:
  • mostly GI
  • require folic acid supp
• Contraindications:
  • pregnancy + breast feeding (anti-mitotic)
  • major organ disease (xcpt heart)
  • XS EtOH
  • immune disorders
  • blood dyscrasias
• Use:
  • moderate to severe RA

what is the mechanism of leflunomide and what is special about its administered form?

leflunomide is a pro-drug that must be activated by the liver

it is a pyridimine synthesis inhibitor (preventing cell division; cells arrest in G1 blocking T cell prolif)

also blocks TNF-dependent NK-kB activation

what are the ADRs and contraindications for leflunomide?

• ADRs:
  • diarrhea and other GI disturbances
• Contraindications:
  • pregnancy or perinatal use (2 years)
  • care with other drugs (long half life)
• Use:
  • RHEUMATOID ARTHRITIS

what is the mechanism and pharmanokinetic profile of hydrochloroquine as tx for RA?

• mechanism: unclear
• pharmacokinetics: SLOW ONSET, used as long term therapy
• metabolism: takes a while to excrete, esp with chronic use; concentrates in various organs
• ADRs: leukopenia, hazy vision due to corneal depositions, photophobia
• use: when other drugs fail for RA and SLE

how does auranofin (gold) work and in what cases is it indicated?

• mechanism: multiple suspected
• ADRs: high incidence (25-50% pts); dermatoses, mucous lesions, blood dyscrasias, hepatitis, encephalitis, nephritis
• contraindications:renal failure, elderly with poor toleration; MONITORING req'd
• use: oral only (auranofin is soluble drug), in active rapidly progressing cases of RA when nothing else is working; affects long remissions (and when they do occur tend to be less severe)

what are the 3 TNF-a  binding biological response modifiers?

• adalimumab
• infliximab
• etanercept

• mechanism: rH mAb that binds soluble TNFa --> downregulates macrophage and T cell function
• ADRs: opportunistic infections (ie: TB); increases ANA (antinuclear ab test...but no sign of lupus)
• use: sc q2w for RA with MTX

what are the inflammatory cytokines stimulated by macrophage-released TNF a?

• IL 1
• IL 6
• IL 8
• more TNF a

• chimeric mAb binds to soluble & membrane bound TNFa
• ADRs: URIs (flu like), latent TB may surface, + ANA
• Use: iv in RA q8w with MTX; also used for ulcerative colitis and other arthritides

• 2 rTNFRs that bind 2 soluble TNFa/b's
• ADRs: erythema, pain, itching, headaches, and opportunistic infections, + ANA (many sxs look like an allergic rxn)
• use: sc twice weekly in RA, AS, JA, often with MTX

• anakinra is IL 1Ra (antagonist) that blocks IL 1 binding to its receptor
• ADRs: injection site, opportunistic infections
• use: sc qd in moderate to severe RA alone or with MTX and others

relatively long t1/2 enables less frequent dosing

• lung --> asthma
• nasal epithelia --> sinus inflammation, hay fever
• skin (face) --> dermatitis, eczema, hives, allergic conjunctivitis

what are some of the actions of histamine on H1 receptors?

• bronchial, bronchiolar constriction
• ileal smooth muscle constriction
• increased vascular permeability
• vasodilation

• sedatives/hypnotics
• local anesthesia

what molecular structure do H1 histamine antagonists resemble?

H1 histamine antagonists resemble cholinergic agonists

NOT similar in structure to histamine

*H2 antagonists resemble histamine*

what are the major pharmacodynamic characteristics of H1 histamine RAs?

• first generation H1 RAs:
  • sedating (early>late)
  • anticholinergic (muscarinic)
  • anti-emetic/antimotion sickness
  • short half lives
• second generation:
  • generally lack CNS effects
  • longer half lives

what is the clinical utility of H1 antagonists?

• conjunctivitis
• hay fever
• mild sleep disorder
• motion sickness
• pruritis
• rhinitis
• urticaria (hives)

• once histamine already bound
• anaphylactic rxns
• chronic sinusitis
• asthma

• CNS depressant effects:
  • dizziness, fatigue, sedation
  • additive with other CNS depressans (EtOH)
• antimuscarinic effects:
  • dryness, blurred vision, constipation, urinary retention
  • tachycardia, CNS excitation-->convulsions

• effective in motion sickness (but sedating)
• anti-nauseant
• contraindications:
  • BPH (bc of urine retention)
  • glaucoma
  • operation of machinery
• duration: around 4 hrs

• dramamine

• anti motion sickness

• sedation

• antimuscarinic = diphenhydramine

• late first gen H1 antag
• antihistaminic
• slightly sedative (dose dept)
• slightly antimuscarinic

trade name: chlor-trimeton/dimetane

• no antimuscarinic
• little or no sedation
• BID
• 2nd gen

other similar drugs:

• loratidine (claritin)
• fexofenadine (allegra)

• INHIBITS 5-LIPOX PATHWAY
• ASTHMA TX
• CONTRAINDICATIONS:
  • breast feeding, pregnant, or soon to be
  • hepatic disease
  • other meds
  • EtOH
• Leukotriene inhibitor

• ZAFIRLUKAST/MONTELUKAST (ACCOLATE/SINGULAIR): LT ANTAGONISTS
• 2-FOLD INCREASE IN FEV1 IN ASTHMATICS (SIMILAR EFFECT AS BECLOMETHASONE)
• ADRS:
  • ABDOMINAL PAIN
  • DIZZINESS
  • HEADACHE
  • RHINITIS
  • SORE THROAT

• prophylactic rx for upper respiratory tract
• multiple mechanisms