Pharmacology RCR1 Respiratory

The ANS and respiratory system

 Airways include outer SM, submucosa and an inner mucosal layer,

allergens, irritants, chemicals and cigarette smoke can cause contraction
of the airway SM  to a narrowing of the airway lumen and broncho-
constriction
 ASTHMA  is characterized by intermittent bronchoconstriction’s caused
by allergen or a non-specific stimuli such as cold, dry air (80% due to
allergens)
 Irritants such as cigarette smoke, air pollution and isocyanates (in house
fires) can cause to broncho-constriction and long term exposure
contributes to the development of COPD/ CHRONIC OBSTRUCTIVE
PULMONARY DISEASE
 Bronchial SM has only PNS innervation but is relaxed by actions of
circulating adrenaline on ß-adrenoceptors, ß agonists mimic the effects of
adrenaline and will relax SM regardless of the contractile stimulus,
muscarinic antagonists also relax bronchial SM
 Noradrenaline works on only alpha adrenoceptors but is less effective on
ß adrenoceptors, however adrenaline is potent for both alpha and beta
 ACTIONS OF ADRENALINE
 Constriction of blood vessels in skin and gut (alpha 1)
 Dilation of blood vessels in skeletal muscle (beta 2)
 Dilation of pupil (alpha)
 Increased renin secretion in kidney (beta 2)
 Glycogenolysis in liver (alpha and beta 2)
 Decreased GI motility (alpha and beta 2)
 Increase HR and force of contraction (beta 1)
 Relaxation of bronchial SM (beta 2)
 Uses of adrenaline  in status asthmaticus, when rapid reversal of
bronchoconstriction is required, also in anaphylaxis where there is an
explosive release of histamine
 ANS and the <3  has both sympathetic and parasympathetic
innervation, stimulation of ß1-adrenoceptors  increased force of
contraction, increase HR, but reduced cardiac efficiency
  Selective ß agonists = Noradrenaline = >ß
= Adrenaline = =∫
= Isoprenaline = ß>
= Salbutamol = ß2>ß1>>
 ß2 agonists relax airway SM, inhibit mediator release from mast cells,
inhibit release of TNFincrease mucus clearance via actions on cilia
 SALBUTAMOL = is used to relieve symptoms of asthma, it is rapid acting,
and relaxes bronchial SM regardless of stimulus, they are usually given as
an aerosol, powder or nebulised solution
 ß2-adrenoceptor agonists do not affect the underlying airways
inflammation and over reliance should be avoided, over use can down-
regulate ß-adrenoceptor expression, it can also lead to skeletal muscle
tremor, hyperglycaemia in diabetic patients, arrhythmias acutely and
potentially MI in long term, and hypokalaemia
 SALMETEROL = is a longer acting ß2-agonist, with a duration of action of
12 hours so can be used twice daily, can also combine with steroid to
reduce inflammation
 DO NOT GIVE BETA BLOCKERS TO ASTHMATIC PATIENTS, these
antagonise ß-agonists and can cause severe bronchoconstriction
 Bronchial SM and PNS  irritants eg cigarette smoke can stimulate PNS
and cause bronchoconstriction
 MUSCARINIC ANTAGONISTS eg OXITROPIUM and IPRATROPIUM block
this and relax the airways, they have limited use in allergic asthma, they
inhibit mucus secretion, take 20-30mins to act and last 4-6 hours, more
useful in COPD
 Usually in COPD, patients are considered to have irreversible airways
obstruction however any patients have a small (100-150ml) amount of
reversible airways obstruction which can improve their quality of life
 SE OF MUSCARINIC ANTAGONISTS  are not ell absorbed into the
systemic circulation so the SE should be minimal but do not give to
patients with glaucoma, prostate or bladder conditions  SE usually
include constipation, tachycardia and atrial fibrillation
 Other drugs to use in Asthma = xanthines, steroids, anti-leukotrienes
 Other drugs to use in COPD = limited therapeutic options

Respiratory Pharmacology 1 & 2

 More people die to respiratory disease in UK than HD or cancer, costs NHS

5-6 billion/year, it can be genetic, infections, cancer, occupational or
cancer, every year 1,600 people die from asthma in the UK
 ASTHMA  reversible airflow obstruction (expiratory wheeze), airways
inflammation (mast cells, eosinophil’s and oedema), bronchial hyper
responsiveness
 Two types being
1. EXTRINSIC = identifiable external trigger, allergic reaction to
common environmental agent, typically develops in childhood,
85% childhood asthma is allergic asthma
 2. INTRINSIC = no obvious external trigger, often develops in
adults after a viral infection, smoking plays a role, tends to be
more sever
 Triggers include allergies, exercise, cold air, food additives and acid
reflux
 PATHOPHYSIOLOGY OF ASTHMA  Early Phase is the Mast Cell
Degranulation of histamine, leukotriene C4, prostaglandin D2, constricts
bronchial SM, Late Phase, is the Eosinophil recruitment, where
leukotriene C4, cytokines and eosinophil granule proteins are released,
which occurs 4-12 hours after and is a later wave of bronchoconstriction
 There are two pharmacological approaches to asthma treatment
 RELIEVERS that block or reverse the bronchial SM contraction, but
have no effect on underlying inflammation, given by inhalers for rescue
in acute attacks, long acting drugs also work for chronic
bronchoconstriction especially nocturnal asthma
 PREVENTERS are taken everyday for prophylaxis and they reduce
airway inflammation or BHR
 FEV1 = the forced expiratory volume in 1 second

 ß2-adrenoceptor agonists  given as an inhaler for relief of symptoms,

nebuliser in status asthmaticus or IV if very sever, often combined with a
steroid for moderate asthma, SE include skeletal muscle tremor,
restlessness, hypokalaemia, cardiac arrhythmias, and receptor down
regulation with over use
 Salmeterol = binds to an exo-site via a flexible tail and repeatedly
stimulates the receptor, can be taken once or twice a day, so useful for
nocturnal asthma
 Formoterol = is dissolved into the plasma membrane and diffuses out to
stimulate the receptor
 Salbutamol but be taken every 4-6 hours to maintain bronchodilation
 If a patient is using the ß2 agonists inhaler regularly then you need to
add in a steroid
 Methylxanthines 

 Theophylline = oral administration only, variable gut absorption and

hepatic metabolism, plasma concentration should be 10-20mg/ml, it is
increased by HF, liver disease and some drugs, many SE above 20mg/ml,
decreased by smoking, alcohol, SE include nausea, insomnia and
dysrhythmia due to narrow therapeutic index
 Anti Muscarinics 

 Ipratropium, oxitropium and tiotropium, all are similar to ATROPINE =

inhaled muscarinic M1/M3 antagonists, block PNS bronchoconstriction
and mucus secretion, low efficacy in asthma so used as an adjunct in
moderate or severe asthma, SE include poor absorption so SE are rare
 RELIEVERS =

 PREVENTER = target the inflammation which underpins persistent

asthma, increasingly important, most important preventers are the
corticosteroids
 Corticosteroids  decrease # eosinophils (apoptosis), mast cells and
dendritic cells, decrease cytokines produced by T-lymphocytes and
macrophages, also decrease cytokines and other mediators produced by
 epithelial cells, decrease leak from endothelial cells, increase the # of
ß2=receptors in airway SM while also decreasing their secretion of
cytokines, and decrease mucus secretion from mucus glands

 Beclomethasone/budesonide = daily inhalers

 Fluticasone = daily inhaler, most potent, first pass hepatic metabolism will
reduce SE
 Oral prednisolone in sever asthma but IV hydrocortisone in status
asthmaticus
 NB there is very poor compliance with steroid inhalers due to steroid
phobia due to negative media
 SE of chronic oral steroid (not inhaled if used properly)  abnormalities
in fat, protein and carbohydrate metabolism, rare with inhaled steroids
used properly, long term use can lead to CUSHINGOID SYNDROME
 Steroids in children is recommended, risk is reduced by giving the lowest
dose and limiting systemic SE by ensuring effective inhaler technique and
using drugs such as fluticasone that are inactivated by first pass
metabolism, no evidence of growth restriction in inhaled steroids
 Cromones = eg SODIUM CROMOGLYCATE (INTAL) and NEDOCROMIL
SODIUM (TILADE)  dry powder inhaler for prophylaxis, also as eye
drops and nasal spars for other allergic conditions, most effective in
children, take 4 times daily, prevent the degranulation of mast cells ∆
release of histamine
 Anti-leukotrienes = antagonists of Cys-LT receptors on SM and
eosinophils, used for prophylaxis of persistent asthma, broncho-dilation
(reduced frequency and severity of asthma attacks) and anti-
inflammatory (reduce eosinophilia), reduce comorbidities such as allergic
rhinitis (hay fever), paediatric formulations, minimal SE
 Anti-IgE = OMALIZUMAB (XOLAIR), humanised IgE, bings to IgE in plasma
and doesn’t cause mast cell degranulation, for moderate and severe
asthma, however v expensive and can  anaphylaxis

 In acute sever asthma/status asthmaticus, give oxygen, nebulised ß2-

agonists, and oral prednisolone or IV hydrocortisone, if no improvement
in 15-20mins, continue O2 and ß2-agonist, give ipratropium (muscarinic
antagonist) and Mg2+ (antagonists to calcium so ∆ decrease muscle
contraction) and admit them to hospital
 Keep adding treatment until asthma is controlled, ensure you check if a
patient continues to adhere to treatments, and ensure they have good
inhaler technique

 Most asthmatics have mild asthma or early onset atopic asthma (allergic
asthma) which as inflammation increases so does symptoms but some
sufferers have inflammation predominant asthma, obese non-eosinophil
asthma or symptom predominant asthma
 Asthma severity varies over time, some patients have high sputum
eosinophil’s or neutrophils
 30-70% of asthma patients do not adhere to their treatment regimen, can
be because patient feels better so stops, has SE, doesn’t feel the drug is
working, doesn’t like the formulation, controversy about drug in news,
patient attitude or for cost reasons, but it could also be unintentional due
to poor inhaler technique or if a regimen is too complex
 Cold weather triggers mast cells, FVC – forced vital capacity
 NB in obstructive conditions FEV/FVC is 70-80%, where FEV is reduced
and FVC is reduced or normal
 NB in restrictive conditions FEV and FVC are both significantly reduced
and the FEV1/FVC is below 80%
 Skin prick tests allow you to determine what they are allergic to
  Lung has 23 generations of distributing aitways and SA or 100m2
OVER VIEW OF ASTMA DRUGS
RELIEVER DRUGS = ß2-agonists, methlyxanthines, anti-muscarinics
PREVENTER DRUGS = corticosteroids, cromones, anti-leukotrienes and anti-IgE
 COPD is in two branches = EMPHYSEMA (loss of alveolar structure) and
CHRONIC BRONCHITIS (excess mucus production), 30,000 die in UK/year
 Treatment for COPD is to stop smoking, give antibiotics for infections, use
anti-muscarinics as bronchodilators, or ß-agonists, thephylline, steroids,
supplementary oxygen

Adverse Drug Reactions

 ADR complicates 2.43% of hospital admissions, 3.5X increase in mortality

and doubles length of stay, huge cost for NHS
 Classification (NB CDE are all very rare)
o Type A – Augmented – dose related, predictable, due to known
pharmacological actions of the drug (95%)
o Type B – Bizarre – not dose related, unpredictable, idiosyncratic
and drug hypersensitivity
o Type C – Chemical eg Azanthiprine
o Type D – Delayed eg carcinogenesis or teratogenesis
o Type E – End of Dose = effects following cessation of drug
 Mechanisms of type A  exaggerated therapeutic responses at the target
site (eg bleeding on warfarin), desired pharmacological effect at another
site (eg headache on GTN), additional or secondary pharmacological
actions
  Type B  mainly cutaneous but due to drug hypersensitivity reactions,
they have immunological basis
o Type 1 – IgE effects on mast cells, basophils, immediate, eg
anaphylaxis, urticarial (angioedema), ß lactams (penicillin,
cephalosoprins), anaesthetic drugs (suxamethonium &
vecuronium)
o Type 2 – cell suface antigen IgG/IgM eg pemphigus (blistering)
o Type 3 – immune complexes, IgG/IgM eg vasculitis
o Type 4 – lymphocyte mediated – delayed, DRESS, EM, SIS, TEN,
often due to skin, developed in 2-3% of in-patients, multiple
symptoms

Pharmacology of Steroids

 Non-hormonal steroids = cholesterol which is key in atherogenesis

 Steroid hormones
o Corticosteroids from the adrenal cortex
 Glucocorticoids – cortisol, metabolic and anti-inflammatory
functions
 Mineralocorticoids – aldosterone, renal regulation or
electrolytes and water
 Adrenal gland  In the adrenal cortex = Zona Glomerulosa
(mineralcorticoids eg aldosterone), Zona Fasciculata (glucocorticoids eg
cortisol), Zona reticularis (anderogens so some testosterone) and then the
Adrenal Medulla (catecholamines eg adrenaline)
 Cholesterol is the precursor for every phospholipid ∆ all glucocorticoids,
mineralocorticoids and sec hormones
 Cholesterol is vital in the fluidity and function of the phospholipid
membrane in all cell, it is a steroid, but lipophilic, it is nearly one
cholesterol/phospholipid, makes membrane less deformable and less
water-permeable, means no cell wall is necessary in animals, it is derived
from the diet or synthesised by hepatocytes by HMG CoA reductase, and is
transported between the liver and tissue in lipoproteins
 Excess LDL deposits cholesterol in atheromas  CAD, HMG CoA reductase
in the liver is inhibited by statins
 Corticosteroid Effects  act as though they are preparing the body for a
period of starvation and dehydration as they mobilise energy stores into
glucose and glycogen & conserve water by reducing urine production
 Glucocorticosteroid  hydrocortisone, mainly metabolic (mobilises
nutrients in catabolism ∆ weight gain) and anti-inflammatory
 Many synthetic GCS drugs have been develops to combat chronic
inflammatory diseases
o Prednisolone – systemic GCS eg arthritis
o Dexamethasone – systemic GCS eg arthritis
o Betamethasone – topical GCS eg eczema
o Fluticasone – inhaled GCS eg asthma
 The hypothalamo-pituitary-adrenal axis  catabolic effects include
hyperglycaemia, mobilisation of lipids and breakdown of proteins  anti-
inflammatory effects include decreased leucocyte activity and decreased
inflammatory mediators
 If on cortisol, need to come off slowly in order to
increase natural cortisol
 ACTH = adrenocorticotrophic hormone
 GCS bind to cytoplasmic receptors and modulate
transcription of hundred of inflammatory genes,
turns genes on and off, interact with gene
transcription, binds to a glucocorticoid receptor
and is transported into nucleus
 GCS blocks transcription of pro-inflammatory
genes:-
- Cyclooxygenase-2 (source of prostaglandins)
- Adhesion molecules (ICAM)
- Complement components and Immunoglobulins (IgG & IgE)
- Cytokines (TNFGM-CSF, interleukins)
 GCS induces anti-inflammatory genes
- Ribonucleases (break down inflammatory mRNAs)
- Interleukin 10, Annexin-1
 Consequences are slow in onset, reduces oedema in 2-6 hours, supresses
cytokines in 6-18 hours and inhibits leucocytes in 12-48 hours, but also
slow in offset
 Glucocorticoids are used in replacement therapy (eg Addison’s Disease),
also used in asthma, allergic disease (eg eczema, rhinitis), rheumatoid
arthritis, inflammatory bowel disease, after organ transplantation, some
types of leukaemia, cerebral oedema
 Excessive production of cortisol or over-use of GCS  CUSHINGS
DISEASE, endogenous over-production of cortisol can be inhibited by
metyrapone, GCS drugs should be given at lowest effective dose, for the
shortest duration, and topical if possible
 Mineralocorticoids  main endogenous one is aldosterone, released from
zona glomerulosa, triggered by low Na+ and indirectly by the RAAS
system, it acts on mineralocorticoid receptors mainly in the cytoplasm of
the kidney tubule epithelial cells, it increases gene transcription of
epithelial Na+ channels, increasing sodium and water re-absorption
across the luminal membrane into blood, and therefore K+ and H+ are
excreted instead
 Mineralocorticoid drugs include
o FLUDROCORTISONE (an MR agonist), used as replacement therapy
in adrenal insufficiency (Addison’s disease)
o SPIRONOLACTONE (a competitive MR antagonist), diuretic and
potassium sparing actions, used with other diuretics to reduce
blood volume and prevent hypokalaemia, also used in
hyperaldosteronism (Conn’s syndrome)
 GCS reduce the proliferation, adhesion, migration, activation and survival
of inflammatory leucocytes, they reduce oedema at the inflammatory site
and impair fibrosis and wound healing