Term 1 Pharm - Respiratory Drugs Flashcards
(30 cards)
LABA-Salmeterol: Mech. of Action
Salmeterol has a much larger side chain than albuterol and binds to an exosite (Catecholamine binds to active site)
Together binding of both = DUAL BINDING SITES = less likely for drug to let go of receptor = longer duration of action (only need to take 2x a day) but should be prescribed with a steroid
BUT NOT USED FOR RELIEF… LATE ONSET (onset 30min, peak 1-3hrs)
LABAs are also NOT advised for monotherapy as they can mask symptoms until they became severe and they do not treat the underlying pathophysiology (airway inflammation) which can result in increases asthma associated mortality
βeta2 Agonists in Asthma/COPD
Adverse Effects/Toxicity
CVS:
Tachycardia, palpitations, flushing
Exacerbation of angina/arrhythmias
Vasodilates Pulm Art V/Q mismatch
CNS: Tremor/Anxiety Headache Insomnia Metabolic: Hypokalemia, Hyperglycemia
βeta2 Agonists for Asthma/COPD
Additional PD Properties Other than the Primary mechanism of action
- Enhance mucociliary clearance
- Decrease microvascular permeability
- Suppress mediator release from inflammatory cells
Cellular Actions of βeta2 Agonists on Smooth Muscle (for Asthma/COPD)
1) Agonist binds to the beta2-adrenergic receptor.
2) In the unstimulated state the G-protein is complexed with GDP.
3) The receptor promotes exchange of GTP for GDP and release of G”/GTP.
4) The G”/GTP complex activates adenylyl cyclase.
5) Intracellular cAMP increases and activates cAMP dependent protein kinase (PKA).
6) (a) PKA phosphorylates the Ca2+ channel reducing Ca2+ influx, [Ca2+]i decreases & inhibits contractile proteins.
(b) PKA phosphorylates the sarcoplasmic reticulum leading to an increase in Ca2+uptake
(c) PKA phosphorylates troponin changing its calcium binding kinetics.
SUMMARY: βeta2 agonist binds to beta2 receptor which via G protein stimulates adenylyl cyclase —> increases cAMP protein kinases -> reduces [Ca 2+]i —> relaxes smooth muscle
Asthma: TH1 and TH2 lymphocytes
TH1 response results in…
NO Asthma
Asthma: TH1 and TH2 lymphocytes
TH2 response results in…
ASTHMA (special effects from IL-5)
Most important part of metered dose inhalers
patients are educated on how to use it correctly
What are some anticholinergic drugs used for Asthma/COPD and how do they work?
Ipratropium Bromide and Tiotropium Bromide
Odds (M1,3,5) = stimulatory
- stimulates Gprotein coupled receptor, activates PLC, results in Ca release
Ipotropin blocks Ca release from (M1,3,5)
THEY RELAX SM, preventing contraction
Slower onset than βeta2 agonist
Adverse Effects of Cholinergic Antagonists in Asthma/COPD
1) Bitter taste - compliance (adherence) issues
2)ACh effects: rare and mainly at high doses
(Tiotropium – longer acting (~ 24h) dry powder (nebulizer)… & ACh effects seen in patients with renal impairment)
Inhaled Corticosteroid drug used to treat Asthma/COPD
Fluticasone
Compared to oral steroids, inhaled steroids, such as Fluticasone, cause few significant side effects and are considered to be safe and effective treatments. The possible common side effects include a hoarse voice and oral fungal infection (thrush). Mouth rinsing after using the inhaler device should prevent these.
Systemic Corticosteroid (oral) drugs used to treat Asthma/COPD
1) Hydrocortisone
2) Prednisone
3) Methylprednisolone
While the anti-inflammatory effects of prednisone are rapid and effective, oral corticostreroids are infamous for their side effects. In children the benefits of prednisone should be carefully weighed against the potential side effects particularly stunted growth and delayed puberty.
Uses of Corticosteroids in Asthma
Systemic Therapy
- Acute severe asthma
- Chronic maintenance therapy
Inhaled Therapy
- Prophylaxis in mild/moderate or refractory asthma
- Combined with systemic steroids in chronic asthm (reduces systemic dose)
Mechanism of action for corticosteroids
Summary of anti-inflammatory mechanisms of action
(Multi-Tissue Effects)
- Inhibits enzymes producing PGs, LTs and TX e.g. PLA2 via lipocortin, COX-2.
- Inhibits gene transcription of pro-inflammatory cytokines e.g. IL-1,TNF-alpha,GM-CSF, IL-3,4,5 & 6
- Directly counteracts the positive effects of several cytokines on transcription factors AP-1 and NF-KB
- Induces enzymes e.g. ACE and NEP which degrade bradykinin and tachykinin (which cause bronchoconstriction)
- Increases βeta2 receptor transcription & expression
- Reduces cell trafficking by inhibiting effects of TNF etc and reduces expression of cell adhesion molecules
- Induces apoptosis in eosinophils
- Inhibits plasma exudation from venules by synthesis of an antipermeability factor- vasocortin
SUMMARY:
Corticosteroids intracellularly binds to receptor = turns off genes that casue inflammation & turns on genes that are anti-inflammatory
Overall effect: reduce inflammation
Acute Side Effects of Systemic Corticosteroids
- CNS-insomnia/psychosis
- Metabolic
- Hyperglycemia
- Na and H20 retention - Suppress signs of infection (Latent Infection)
- Acute/Chronic –prox. myopathy
Chronic Side Effects of Systemic Corticosteroids
- HPA axis suppression (adrenal suppression)
- Cushingoid appearance
- Hypertension
- Opportunistic infection
- Peptic ulcer
- Osteoporosis
- Posterior cataracts
- Growth suppression (kids)
- Pancreatitis
- Aseptic necrosis; femoral head
Anti-inflammatory Drugs used to treat Asthma/COPD/Allergic rhinitis
Leukotriene antagonists: Montelukast
Cromokalim derivatives: Disodium cromoglycate;
Pharmacology of Histamine: Anti-histamines, Diphenhydramine, Fexofenadine
The most potent (leukotriene) bronchoconstrictors and what do they do?
LTC4 and LTD4
- Bronchoconstrict (1000x > potency cf. histamine & PGF2 alpha)
- Increase vascular permeability (edema)
- Increase mucus secretion (decrease mucociliary clearance)
- Stimulate phospholipase A2
- Release prostaglandins and thromboxanes
- Increase cellular infiltrate into the airways
What do Leukotriene B4 do in the Lung?
- Promote neutrophil-endothelial adhesion and chemotaxis,
- Stimulate aggregation, enzyme (protease) release & superoxide generation in neutrophils via degranulation
- Promote leukocyte recruitment and activation
- Increases vascular permeability (edema)
Montelukast: Mechanism of action
ORAL
- Competitive inhibitor at the Cys LT1 receptor (decreased binding to LTC4 and LTD4) = MAIN effect
- Right shift (2 log) dose response curve to inhaled LTD4
- Plasma concentrations ∞ LTD4 decreases in airway conductance
- Blocks PAF induced airway hyper-responsiveness
- Attenuates response to inhaled antigens & cold air
- Montelukast would take too long to have an effect in an emergency setting
Uses, Pharmacodynamics, & Pharmacokinetics of Montelukast
Use:
- Prophylactic and chronic maintenance therapy
- Often used in combination with other anti-asthma Rx
- NOT as good a bronchodilator as βeta2 agonists
- Useful for aspirin induced asthma
- Effective and safe in children
Pharmacodynamics:
- Bronchodilatation within 1-2 h
- Duration of receptor blockade 10-14 h
Pharmacokinetics:
- Good ORAL absorption-Tmax 3-4 h
- Food decreases bioavailability by 40%
- T1/2 = 3-6 hours (maybe 20 hours in elderly)
- Hepatic metabolism - CYP3A /2C9
Adverse effects (rare, widely used)
Second Line Anti-Asthma Drugs
- Anti-histamines (H1blockers) e.g. Fexofenadine
- Steroid sparing: Methotrexate, Azathioprine (6-MP)
- Monoclonal antibody: Omalizumab (Anti-IgE Monoclonal Antibody ) - for allergic asthmatics, selectively binds to human Fc portion of IgE
selectively binds to human Fc portion of IgE
Adverse Effects of Omalizumab
- Gastrointestinal upsets (N &V)
- Local injection site reactions (S/C every 2-4 weeks)
- Rashes/urticaria
EXPENSIVE ($10-12k/yr)
Has a black box warning for anaphylaxis - Common in many large protein/monoclonal antibody drugs
Despite the high price of Omalizumab ($500-$2000 per month based on body weight) Omalizumab is being used more in adults and children over 5. It is indicated for moderate persistent or severe persistent asthma, especially when an inhaled steroid or an inhaled steroid plus a LABA are not giving a good response. Patients with occupational asthma who cannot avoid exposure to their allergen (Veterinarians etc.) also benefit from this.
Anti-IL-5 Monoclonal Antibody
FDA approved for severe steroid refractory asthma - 100 mg S/C every 4 weeks
Mepolizumab
Drugs you don’t want to give an asthmatic
Absolutely NEVER
- Beta antagonists (blockers); propanolol > metoprolol Never, ever, ever in acute asthma !!!
- Cholinergic agonists; e.g. carbachol
- Adenosine (causes severe bronchospasm)
- Aspirin & NSAIDs (2-7% asthmatics)
(Maybe, watch closely)
ACE-Inh (e.g. Lisinopril) (causes dry hacking cough) (but not such a problem with ARBs e.g. Losartan)
