Arachidonic-Cox 1 & Cox 2-immune response

Lipooxygenase--bronchoconstriction, vasoconstriction (Zileuton stops this)

Steroids can stop arachidonic acid

H1

Smooth muscle, vascular endothelium, brain

Causes bronchoconstriction=asthma

Erythema, itching, pain, edema

(antihistamines targets these best) 

H1 Antihistamines

1st Generation: Lipohilic, neutral at physiologic pH

Cross BBB=causing sedation

(diphenhydramine, Hydroxyzine, chlorpheniramine, promethazine, doxepin.) 

2nd Generation: Albumin binding, ionized at physiologic pH

(Loratidine, desloratidine-more active form, cetririzine, levocetirizine, fexofenadine) 

PK:Absorption: 2-3 hr.

Distribution: 1st gen=nutral pH, lipophilic, crosses BBB. 2nd gen=polarized, hydrophilic, protein bound, decrease SE.  

Metabolism: CP350

Elimination: Urine

SE: 1st gen: Cant pee, see, spit, shit, sedation

Efficacy of H1 Antihistamines

(Dephenhydramine, hydroxyzine, chlorpheniramine, promethazine, doxepin)

(Loratidine, desloratidine, cetriizine, levocetrizine, fexofenadine)

uses: Rhinitis, cojuctivitis, urticaria, pruritis

Motion Sickness, Chemo N/V, Insominia (doxylaminie)

AE: CNS=sedative effects, qt interval prolongation, dryness, pupillary dilation, urinary hesitancy

Sypathetic tone=bronchodilation by B2

Parasympathetic tone=Bronchoconstriction

• Mild Intermittent: less than 2 times a week. short acting (albuterol)
• Mild Persistent: more than 2 times a week. short acting (albuterol), low-dose steroid (beclomethasone), can use theophylline
• Moderate: Daily symptoms. (albuterol),medium-dose corticosteroid (beclomethasone), theophylline
• Severe: continual symptoms, (Albuterol), high-dose steroid. and LABA ( Salmeterol, Formoterol) 

Asthma Drugs (mild inter, mild persis, moderate, severe) 

Bronchodilators

MOA: B-agonists-variable receptor selectivity: 

Epi: B2,B1,A (rairly used)

Isoproterenol: B2,B1

Metaproterenol: B2,B1

Terbutaline, Albuterol, Pirbuterol, Bitolterol: B2

Levalbuterol (isolated steroisomer)-B2

Rapid onset of action, Fast peak effect, short duration of action. Used prophylactically before known trigger. 

Asthma Drugs (Severe) 

Long-Acting Beta-agonists (LABA)

Salmeterol, Formoterol

MOA: lipophilic sides that resist degredation. Lower onset so not for flairs. Last 12-24 hours. Good Prevention of bronchoconstriction. 

Do not use as monotherapy-Black Box Warning for asthma related deatyh & pediatric hospitalizaiton)

Use w/ corticosteroids

Watch cardiac for toxicity-because Agonism of Beta 1 can occur

Asthma Drugs

Anticholinergics

• Competive antagonist at ACE & M3 
• Used in asthma and COPD
• M3 smooth muscle relaxation and mucous secretion in airway. 
• Atropin: Not used for asthma, Highly absorbed accross respiratiory epithelium  AE: Tachycardia, N, Dry mouth, GI upset (anticholenergic)
• Ipratropium Bromide: (charged) ammonium salt dirivative of atropine. Not significantly absorbed. Deposition in the mouth and inadvertent oral absorption.
• Tiotropium: (charged) similar to ipratropium but longer lasting (slow dissociation from receptors.

Asthma Drugs (mild, moderate)

Methylxanthines

Theophyline, Aminophyline

Adenosin Receptor ANTAGONISM

Works in Conjunction with Beta Agonist

MOA: Nonselective, narrow therapeutic index, CYP450 & IA2 drug interactions.

Cigarett smoking increases CYP & IA2

Inhibition of PDE, Airway smooth muscle broncohdilation. also an antiinflammatory.

Adenosine receptor antagonism-secondary effects: increase ventilation, increase endurance, decrease mast cell release. 

AE: N/V/D, HA, irratibility, insomnia, seizures, hypokalemia, hypotension, arrhythimias, brain damage, death. So decrease use of drugs now! 

Pharmacokinetics: the more CAMP=PKA=Better Bronchodilation

Anti-inflammatory Agents/Asthma (mild persisten, moderate, severe) 

Corticosteroids

Inhaled: Beclomethasone, Trimecinolone, Fluticasone (combined with salmeterol), Budesonide (can be combined with formoterol), Flunisoilide, mometasone, ciclesonide. 

MOA: increase B2 & anti-inflammatory proteins

Reversal of many Asthma features

NOT A CURE-on supresses 

Admin:

Inhaled: 25% reaches airway so need higher dose than PO. If swalloed PO or Inhaled will undergo first pass. 

Systemic: only in severe cases becuse of AE. 

AE: osteopenia, osteoporosis, delayed growth in children, oropharyngeal candidais, hoarsness, hyperglycemia

Interactions: watch with other drugs that could cause a decrease in first pass because can result in AE worsening (cushings)

Anti-Inflammatory/Astma

Cromolyns

Cromylyn, Nedocromil

MOA: stabilize mast cells. Inhibit release of inflammatory agents. Prophylactic therapy. less systemic Absorbtion.

DO NOT RELIEVE AN ALLERGIC RESPONSE AFTER INITIATION. 

Anti-Inflammatory/Astma

Leukotriene Inhibitors

Zileuton, Monetelakast, Zefirukast

MOA: Breaks down arachidonic acid/ or inhibits binding. 

Easy to manage. Few AE & extrapulmonary effects. Can cause hepatotoxicity but very rare. Hepaticall metabolized. ORAL

Anti-Inflammatory/Astma

Anti-IgE Antibody

Omalizumab

Mouse to human monoclonal antibody binds to IgE. So decrease IgE. Prevents binding of IgE to mast cells. Down regulation of receptors. 

Sub-Q every 2-4 weeks.

AE: Rare triggering of an immune response 

• hyperuricemia >7 and Crystalizations in tisures and joints and inflammation. 
• MOA: happens by decrease in urinary excretion or an increase in metabolic synthesis
• Types: Primary-defect in purine metabolism and or uric acid excretion. Secondary: Cancer, CRF, Drugs(salicylates, antineoplastic agents, diuretics, ethambutol, nicotinic acid, cyclosporin, ethanol. 
• Goals of Gout Therapy: relief of pain anfd inflammation, termination of acute attacks, reduction in frequency and severity of attacks

Gout Medications

Colchine (Acute Gout)

inhibits microtubule assembly. Indicated for Acute Attacks. 

Uses: treatment of acute attacks (rarly used now) and prophylaxis in patients with chronic gout. 

MOA: Disruption of urate depostiton and subsequent inflammatory response. Specific treatment of gout. NO effects on uric acid levels.

AE: Abdominal pain, n/v/d 

DI: Can be Severe need to watch will all drugs. 

Results in high levels cyclosporine, tacrolimus, verapamil. because secreated in urine and bile. 

Gout Medications

Probenecid (Chronic)- increases secretion of uric acid. does not treat acute episode. 

Uses: prophylactic treatment. Prevention of disease progression, not useful in flair up (Acute attacks) 

AE: Hypersensitivity, GI Distress

MOA: decrease urate reabsorption on the proximal tubules (so stays in kidney and gets eleminated)

Can lead to a variety of drug interactions (penicillin=increase levels of probenecid)

Precautions: DO NOT initiate during acute attack because of kidney stones. can increase attacks during 6-12 months of therapy. Need to drink lots of fluid (>2L/day) to minimize stones. Also can give bicarb

Gout Medications

Allopurinol (Chronic)-Inhibitor of xanthine oxidase 

MOA: inhibits uric acid production

prodrug converted bvy cxanthine oxidase

as plasma uric acid decreases, dissolution of deposits can occur leading to disruption in urate equilibrium and acute attacks. - CAN GIVE W/ Colchicine

DI: Allupurinol when giving with azathioprine cases high high levels of 6-meracaptoprine. So need way lower dose of azathioprine. 

1st response

Bacterial (granulocytes)

Parastic (eusinophils)

Antigen Presenting Cells. 

Adaptive Immune Response

Specific

Generated

Native vs. Foreign cell recognition

Humoral immunity

Celular immunity

Cytotoxic and T-helper cells

Eicosanoids

involved in inflammation and cellular signaling (prostaglandins, prostacylins, thromboxanes, leukotrienes)

Common precursor to eicosanoids is arachidonic acid. 

End Products of Arachidonic Acid: 

1. The prostaglandins (from cyclooxygenase metabolism) (PG) esp PGE2, PGF2alpha and PGD2 2. The Prostacyclines PGI2 

3.. Thromboxane Tx A2 
4.. The leukotrienes ( from lipoxygenase metabolism)

Drugs affecting this pathway: 

NSAIDS/ Non-selective COX 1 inhibitors: 

ASA, IBU, Naproxen, Etodoiac, Indomethacin

COX 2 Inhibitors: Celecoxib

Leukotrience Inhibitors: Montelukast, zafirlukast

Corticosteroids: Prednisone, methylprednisolone, dexamethsone

H1=Smooth muscle, vascular endothelium, brain

H2=pepcid-gastric parietal cells, cardiac muscle, mast cells, brain

H3=CNS, some peripheral nerves

H4=Hemopoetic cells, gastric mucosa

H1: 

Vascular Smooth Muscle: erthema, venule dilation

Endothelium:bronchoconstrction

Peripheral Nerves: sensation, itching, pain

Heart: increase contractility

Stomach: PUD

Not used for anaphylaxix