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Drugs for asthma and chronic bronchitis

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					Drugs for asthma and
 chronic bronchitis
   A crammer session
                 This talk
•   Asthma
•   Anti-inflammatory drugs
•   Bronchodilators
•   Acute severe asthma
•   COB
•   Controlled oxygen therapy.
•   (Then you requested some additional
    material)
                  Asthma
• An inflammatory condition.
• Early-onset asthma:
  – Inhaled antigen, to which there is a Type-1
    immune response, involving IgE.
  – Tendency to remit with age.
  – Paroxysmal, especially at night.
• Late onset asthma:
  – Inhaled antigens less obvious.
  – Often more chronic
Smooth muscle


Mucosa
Muscle contraction
Muscle contraction

Mucosal oedema
Muscle contraction

Mucosal oedema

   Sticky mucus
     Muscle contraction

     Mucosal oedema
R2
        Sticky mucus




          R2
                       Muscle contraction

                       Mucosal oedema
                R2
                          Sticky mucus




PEFR and FEV1               R2

Wheeze
Cough ® green sputum
Overinflated chest
Anti-inflammatory drugs: steroids
                Membrane
                phospholipid
                       Phospholipase A2
                Arachidonic
                acid

                   COX-I       COX-II

Leukotrienes:
B’constrictor    PGs with       PGs with
                 gastric        inflammatory
                 protective     effects
                 effects
               Membrane
                                          roids
               phospholipid
                                   st   e
                               X
                      Phospholipase A2
               Arachidonic
               acid

                  COX-I       COX-II

Leukotrienes
                PGs with       PGs with
                gastric        inflammatory
                protective     effects
                effects
               outside

                             SLOW
   cytoplasm




nucleus                  Macrocortin
Anti-inflammatory drugs: steroids

• Life-saving.
• Take at least 12 h to work: so start
  early in severe cases.
• Systemic steriods: acute severe
  asthma.
• Inhaled steroids: maintenance
Anti-inflammatory drugs: steroids

• Systemic steroid:
  –   Osteopenia
  –   Glucose intolerance
  –   ‘Cushingoid’ features
  –   Hypertension
  –   Salt and water retention
  –   Psychoses
  –   Infection
• Topical steroid
  – Hoarseness
        Anti-inflammatory drugs:
              cromoglycate

•   By inhaler only.
•   Useful maintenance therapy.
•   No role in severe episodes.
•   Few, if any, adverse effects.
    Anti-inflammatory drugs:
leukotriene receptor antagonists

               Arachidonic
               acid



Leukotrienes
                  PGs with gastric   PGs with
                  protective         inflammatory
    x             effects            effects
 Receptors
     Anti-inflammatory drugs:
  leuotriene receptor antagonists
• Leukotrienes cause capillary leakiness
  and bronchoconstriction.
• Used by mouth for maintenance
  therapy (e.g. montelukast).
• Additive with inhaled steroids.
• BTS has yet to include in their
  asthma guidelines
Bronchodilators
Catecholamines, receptors and effects.

 • a receptors vasoconstrict
 • b1 receptors increase heart rate
 • b2 receptors vasodilate and bronchodliate

 •   Adrenaline      a, b1, b2.   ­ R, ­ Bdilate
                                  H     BP,
 •   Noradrenaline   a, b1.       (¯HR), ­­BP
 •   Dobutamine      (a) b1.      H
                                  ­ R, ­BP
 •   Isoprenaline    b1, b2.      H
                                  ­ R, (? BP)
 •   Salbutamol      (b1) b2.      H
                                  (­ R), Bdilate
            b2-agonists.
• Salbutamol, terbutiline
• Inhalers (of various types).
• Maintenance:
  – Pro rata necessitatis
  – Regularly in more severe cases
• Acute severe asthma
• Tachycardia and tremor
           Aminophylline
• Is not a catecholamine, but has
  analgous effects.
• Narrow therapeutic range.
• Given by mouth or by IV infusion.
• Toxic:
  – Fatal if injected too fast.
  – Convulsions.
  – Tachyarrhythmias
         Antimuscarinics.
• Atropine is the classical
  antimuscarinic, and this is b’dilator.
• Atropine: too many diverse effects.
• Ipratropium.
• By inhaler.
• Add to salbutamol.
• Dry mouth.
      Acute severe asthma
• See BTS guidelines on severity and
  management.
• Arterial gas monitoring: O2
• Systemic steroid early
• Nebulised salbutamol
• (IV aminophylline)
• Usually no antibiotic
• Ventilate
    Chronic obstructive bronchitis:
 maintenance and minor exacerbations

• See BTS guidelines.
• Inhaled salbutamol (consider other
  devices)
• Inhaled ipratropium
• Oral aminophylline (TDM)
• Antibiotic for green sputum
 Controlled oxygen therapy
           Acute causes: PE, pneumonia
• Respiratory failure:
             than 8.0kPa at sea level.
  – pO2 less Chronic causes: COB (pink OD
                 Acute causes: sedative
  – Type-1: pCO2 low or normal
                     puffers)
  – Type-2: pCO2 high causes: COB (blue
                 Chronic
                        bloaters)
• Type-1: partial pressure of O2
  unimportant
• Type-2: partial pressure of O2 very
  important
    Controlled oxygen therapy
             Oxygen flow rate determined
•   Respiratory failure:
                       by gases
             Failure to maintain sea level.
                     8.0kPa at satis pO2
    – pO2 less than CHRONIC CASES: Oxygen
                 IN
                  flow or normal
    – Type-1: pCO2 lowto ventilation by pH:
                  Leadsrate determined
             Resp stimulants not indicated
    – Type-2: pCO2 high
                 acidosis and respiratory arrest
• Type-1: partial pressure of O2gases
             Failure to maintain satis
  unimportant and pH leads to DOXAPRAM
• Type-2: partial pressure of O2 very
  important
Basics.
        How do drugs work?
• At the molecular level:
  –   receptors
  –   enzymes
  –   structural macromolecules
  –   physiochemical effects
• At the whole tissue/animal level
  –   dose-response relationship
  –   agonists and antagonists
  –   therapeutic window
  –   interindividual variation in response
 Dose-response relationship
• Agonists
  – bind to a receptor and stimulate it
  – full agonists
  – partial agonists
• Antagonists
  – bind to a receptor without stimulating it
  – competitive antagonists: can be overcome by ­
    agonist concentration
  – non-competitive antagonists: cannot be
    overcome
EFFECT




                  EC50


         LOG DRUG CONCENTRATION
EFFECT




         LOG DRUG CONCENTRATION
         POTENCY AND EFFICACY
Effect


                          B       C


              A




         Log drug concentration
      Therapeutic window
• The terms ‘therapeutic’ and ‘toxic’ are
  arbitrary, and are simply two ends of
  a continuity.
• There is inter-subject variability in:
  – the dose needed for benefit
  – the dose needed for harm
• And drugs differ in the ‘gap’ between
  benefit and harm
% requiring dose to achieve


                                Therapeutic   Toxic
                                effect        effect
effect




                              DRUG DOSE
% requiring dose to achieve




                              Therapeuti     Toxic
                              c effect       effect
effect




                                 DRUG DOSE
 Absorption: lipid solubility.
• Most drugs are weak acids or bases
• Drugs cross membranes when unionised

So acid drugs cross membranes
best in an acidic medium
…and alkaline drugs cross
membranes best in alkaline
conditions
Look up the Henderson-Hasselbach
equation
BIOAVAILABILITY
           First pass effect

                     Metabolised



                                          Acid
The proportion                            labile
of a dose that
gets from
                                   Lipid insoluble
point of
delivery to
systemic
circulation
 Distribution: plasma protein
           binding
Diffusion down
concentration                  R
gradients




                 Drug in
                 free
  Albumin        solution in
                 plasma
             Tissue distribution.
             LEAKY         TIGHT
             JUNCTIONS:    JUNCTIONS:
             e.g. muscle   e.g. brain


                              Thiopentone


Penicillin
    Hepatic drug metabolism:
           principles
• Most drugs are relatively lipid soluble
• Readily absorbed, but more difficult
  to eliminate.
• Metabolism converts lipid soluble to
  more water soluble molecule
• This usually terminates biologic
  activity
• …But sometimes the reverse
   Hepatic drug metabolism
• Phase I:
  – oxidation, reduction, deamination, hydrolysis
  – can be INDUCED and INHIBITED.
  – Metabolite may retain biological activity
• Phase II:
      Carbamazepine               Cimetidine
  – conjugation
        Rifampicin               Erthromycin
  – usually with glucuronate, acetate or sulphate
       Barbiturates             Ciprofloxacin
  – metabolite lacks biological activity
         Phenytoin                 Isoniazid
     Irreversible elimination
•   Mainly kidney
•   Glomerular filtration
•   Tubular secretion
•   Tubular re-absorption
GFR

             GLOMERULUS



      Plasma
      protein
      binding

 ARTERIOLE          Water
                    solubility
 Arteriole

               Some strong
               acids/bases get
Filtration     actively secreted
is passive
                                   Nephron




         ….while others get
         actively reabsorbed
         (depends on pH)

         LOOK UP ASPIRIN OVERDOSE
reserve
   Anti-inflammatory drugs: 5-
     lipoxygenase inhibitors

                Arachidonic


         x
                acid
         5-LP

Leukotrienes
                   PGs with gastric   PGs with
                   protective         inflammatory
                   effects            effects
 Receptors
    Anti-inflammatory drugs: 5-
      lipoxygenase inhibitors
• Leukotrienes cause capillary leakiness
  and bronchoconstriction.
• 5-LP inhibitors reduce formation.
• Used by mouth for maintenance
  therapy.
• BTS has yet to include in their
  asthma guidelines

				
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posted:7/18/2013
language:English
pages:48