Pharmacology Level 2
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Transcript of Pharmacology Level 2
1
The respiratory system in health and disease
Tyra Zetterström [email protected]
PHCO2308, 2011
Aim of lectures • To review the physiology of the lungs and
respiration
• How this relates to two common respiratory diseases: asthma and chronic obstructive pulmonary disease (COPD)
• To examine the molecular and cellular events that that relates to lung function and dysfunction
• How drugs can modify these events
Recommended reading (if you want to do well look in the Kimberlin Library or
Campus book shop !)
• Rang and Dale’s Pharmacology 6th edition chapter 23, Churchill-Livingstone, 2007
• Also Rang and Dale’s Pharmacology 7th edition
(2012), chapter 27
• Widmaier EP, Raff H & Strang KT Vander’s Human Physiology, McGraw-Hill, 2008
• Fox SI, Fundamentals of Human Physiology,
McGraw-Hill, 2008
2
The Respiratory System
Detailed branching of the Bronchial Tree
The respiratory system
Starts at the mouth and nose, where air enters
Terminates in the alveoli, where oxygen and carbon dioxide are exchanged
3
Alveoli: terminal parts of the Bronchioles
The diaphragm Role in respiration
• Major importance for respiration
• A sheet of muscle that divides the chest cavity from the abdomen
• Contraction of the diaphragm causes the lungs to expand and air to be drawn in
Anatomical illustration
The Respiratory Centre • The autonomic nervous
system controls breathing • The respiratory system is
located in the medulla at the base of the brain (Brain Stem)
• Connections between the medulla and cerebral cortex makes is possible to influence breathing
4
Respiration
Ventilation of the lung
Exchange of O2 and CO2;
- Intake and utilisation of O2
- Elimination of CO2
Respiration and
1. Route for water loss & heat elimination
2. Acid base balance (elimination of CO2)
3. Vocalization
4. Facilitates sense of smell
Function of the respiratory system
Protective mechanisms in the upper respiratory tract
The lungs are exposed to a range of chemicals microorganisms and dust
• Tiny hairs within the nose
• The nose is also lined with mucus producing cells
• Sticky mucus traps small particles for removal
5
Defence mechanism in the lower respiratory tract
• The tracheobronchial tree is lined with cilia
• Small projections from cells that sweeps secretion produced by goblet cells and bronchial glands
• “Sweeping” of secretion (mucus) towards the throat to be swallowed
• Damage of the cilia is a significant contributor to respiratory disease
Bronchiolar Epithelium
Goblet cells & Ciliated cells
Damage leads to respiratory disease
6
Summary Lecture 1
• The respiratory system terminates in the alveoli where O2 and CO2 are exchanged.
• Contraction of the diaphragm causes the lungs to expand and air to be drawn in.
• The autonomic nervous system originates in the brain stem and controls breathing.
• Connections between the medulla and cerebral cortex can influence breathing.
• Cilia are small projections from cells that sweep secretion produced by goblet cells and bronchial glands.
Lecture 2
The role of the Alveoli
Bronchiolar smooth muscle control
Function of the Alveoli • Most distal part of the
bronchioles
• Alveoli in direct contact with blood vessels
• Exchange of gases O2 & CO2
7
Detailed branching of the Bronchial Tree
Alveoli are in intimate contact with pulmonary capillaries
Note: 90% of alveolar surface* is covered with capillaries. * ~80 m2
Blood and air volume during the respiratory cycle
• The right ventricle of the heart pumps blood through the pulmonary arteries and arterioles
• Blood then enters the capillaries surrounding each alveolus
• At rest approximately 4 litre of air enters and leave the alveoli/minute
• In comparison 5 litre of blood flows through the pulmonary capillaries
• During heavy exercise, the air flow can increase 20 fold and the blood flow 5-6 fold
8
Smooth muscle and the respiratory tract
• The trachea & the bronchial tree are surrounded by muscles (wrapped in a double helix).
• Lower down the tree, muscle amount increases and cartilage decreases.
• Muscles are innervated by sympathetic and parasympathetic nerves.
• Sympathetic relaxation and parasympathetic constriction.
Actions of parasympathetic and sympathetic nervous systems
Anatomy of a bronchiole
9
Cross section of a bronchiole
bronchiolar smooth muscle, Innervations control airways
resistance:
Bronchiolar s.m. wrapped around bronchiole
Bronchiolar epithelium
Mucous
Post ganglionic parasympathetic neuron
ACh
Muscarinic m3 acetylcholine receptor
Functional radius reduced by 1. Bronchiolar s.m. contraction 2. Increased mucous secretion. 3. Tissue inflammation
Stimulation of m3 ACh receptors → s.m contraction
Adrenaline from circulation
β2 adrenoceptor
Stimulation of β2 adrenoceptor → s.m. relaxation
β2AR → Gs → αs-GTP → ↑cAMP
mAChR → Gq → αq-GTP → PLC → IP3 →↑Ca2+
CONTRACTION
DECREASED
INCREASED
10
Adrenaline
β2
α β γ
Gs protein
adenylyl cyclase
ATP
↑ cAMP activation of cAMP-dependent kinase
(PKA)
Bronchiolar s.m. membrane
Decreased contraction
β2
α β γ
Summary slide L2 • Alveoli are in intimate contact with pulmonary capillaries
• At rest approximately 4 L of air enters and leave the alveoli/minute and 5 L of blood flows through the pulmonary capillaries
• These volumes changes dramatically during exercise
• The trachea & the bronchial tree are surrounded by muscles (wrapped in a double helix)
• Muscles are innervated by sympathetic (relaxes) and parasympathetic (constricts) nerves
• Β2 adrenergic receptors relaxes and m3 cholinergic type receptors constrict smooth muscles tissue surrounding the bronchi
Lecture 3
Lung Disorders
Airflow obstruction Asthma & COPD
11
Airflow Obstruction
• Seen in: asthma, COPD, chronic bronchitis, emphysema and cystic fibrosis
A reduction in airway diameter • Increased parasympathetic activity • Change in bronchial smooth muscle tone
Effects on bronchial secretions • Increased mucus viscosity and reduced
clearance
Tests of airflow obstruction
• Peak flow meter, used to test Peak Expiratory Flow (PEF); the greatest airflow that can be sustained for 10 millisec on forced expiration.
• Spirometer, used to measure Forced Expiratory Volume in 1 sec (FEV1) and Vital Capacity (VC); maximum total volume of air that can be exhaled under force.
With diseases of airways obstruction both PEF and FEV1/VC are decreased.
Normal Peak Expiratory Flow (PEF) depends on: gender, age and height
Handheld peak flow meter
12
Spirometry
• A lung function tests
• Helps to diagnose various lung conditions, including chronic obstructive pulmonary disease (COPD)
• Spirometry is also used to monitor the severity of some other lung conditions, and their response to treatment
http://www.aafp.org/afp/2004/0301/p1107.html
Lung Disorders
• Airflow obstruction – Asthma & COPD
• Restrictive lung disease (reduced volume and total lung capacity)
• Abnormalities of diffusion
• Abnormalities of pulmonary blood vessels
Asthma and COPD
• Asthma is very common and may be distressing, disabling and dangerous - good drug therapy is the key
• COPD is increasingly common throughout the world – it kills large numbers of people and is mainly caused by smoking – good drug therapy helps enormously, but doesn’t prevent progression to death
13
Asthma Defining signs & symptoms
1. Widespread narrowing of airways
2. This narrowing changes spontaneously or as a result of treatment (i.e. it is reversible)
3. Characterised by increased responsiveness of bronchi to various stimuli (known & unknown).
All 3 are important in diagnosis & treatment
What is it like to have asthma?
GRAB A DRINKING STRAW BLOCK YOUR NOSE
… and TRY TO BREATH IN AND OUT THROUGH THE STRAW.
don’t try this if you actually have asthma!!
Typical triggering stimuli
• Upper respiratory tract infection
• Exercise
• Cold air
• Inhaled irritants, allergens & drugs (e.g. β-blockers)
14
Bronchiolar s.m. wrapped around bronchiole
Bronchiolar epithelium
Mucous
Post ganglionic parasympathetic neuron
ACh
Muscarinic acetylcholine receptor
Functional radius reduced by 1. Bronchiolar s.m. contraction 2. Increased mucous secretion. 3. Tissue inflammation
Stimulation of m3ACh receptors → s.m contraction
Adrenaline from circulation
β2 adrenoceptor
Stimulation of β2 adrenoceptor → s.m. relaxation
Symptoms of Asthma • Wheezing
• Chest tightness
• Difficulty in breathing
• Coughing
• Blue colour of the lips
Prevalence of Asthma • 8-10% of adults • 10-15% of children (UK and Australia) • In the UK 5.2 x 106 asthma sufferers • 1.1 x 106 are children • 0.5 X 106 have an asthma attack every day
Indicates unacceptably poor control Leicester city has highest incidence of asthma emergency
admissions per capita in the UK
15
• Peak age of onset ~ 5 years
• In young children more common in boys (3:2)
• Later ages equal between sexes
• 1500 patients die each year in UK (5-10 deaths/year in Leicestershire
• Mortality often due to incorrect management
• Incidence increasing in developed countries.
Asthma Epidemiology
Why? Possible explanations
• Overuse of β2-bronchodilators
• Childhood environment too clean
• Changes in diagnostic practice:
Previous under diagnosis? Current over diagnosis?
Summary L3 • Airflow obstruction seen in: asthma, COPD
chronic bronchitis, emphysema and cystic fibrosis
• Spirometry is used to diagnose various lung conditions including COPD
• Common reasons for lung disorders: reduction in airway diameter and/or effects on bronchial secretions
• In the UK 5.2 x 106 asthma sufferers • High mortality; 1500 patients die each year
in UK
16
Lecture 4 Lung Disorders II
Asthma & inflammation
Central to asthma:
Bronchial s.m. hyper-responsiveness
Inflammation
Airflow obstruction
QUESTION: IS ASTHMA PRIMARILY AN INFLAMMATORY DISEASE?
Inflammation-Introductory comments
• A common set of responses to infections (viral or bacterial) tissue damage (bruises) or allergens
• A protective mechanism; removes infections and damaged tissue
• Helps to repair tissue
17
Inflammation; mediators and drug treatment • Mediators of inflammation: histamine prostaglandins and leukotrienes
• Antiinflammatory drugs: stereoids such as, hydrocortisone, prednisolone and betamethasone
• Also non-steroidal antiinflammatory drugs-NSAIDS: aspirin, diclofenac and ibuprofen
Inflammation involves; • Attracting a type of white blood cells (eosinophils) which
remove bugs and damaged tissue
• Activation of inflammatory cells (mast cells) by allergen binding to antibodies (IgE) on mast cell surface
• Releasing mediators of inflammation from mast cells and eosinophils
• Protein leakage from blood vessels causing swelling (oedema)
• Increasing local blood flow, stimulation of pain nerve terminals-pain and itching
Histamine a mediator of inflammation and bronchoconstriction
• Histamine derives from mast cells
• Acts at H1 receptors and causes bronchoconstriction
• Drugs: H1 ANTAGONISTS (the antihistamines)
Antihistamines are NOT used in the treatment of asthma
18
Mast Cells & IgE
.
Mast Cell
IgE from sensitized
Release of mediators of inflammation histamine, prostaglandins and leukotrienes
IgE receptors in mast cell membrane
More mediators of inflammation and bronchoconstriction
1. From mast cells and eosinophils
• Prostaglandins (e.g. PGD2) Precursor - arachidonic acid Acts at PG receptors → BRONCHOCONSTRICTION
DRUGS: Antiinflammatory steroids reduce synthesis
• Leukotrienes, especially cysteinyl leukotrienes (cysLTs) - LTC4, LTD4, & LTE4. Precursor arachidonic acid.
Act at cysLT receptors → bronchoconstriction & eosinophilia
DRUGS: 1. Antiinflammatory steroids reduce synthesis 2. cysLT receptor antagonists (LTRAs)
More mediators of inflammation and bronchoconstriction - 2
2. from eosinophils
• Eosinophil derived proteins. These cause epithelia damage, enhancing disease progression.
No drugs directly relating to this process, but steroids attenuate recruitment and activation of eosinophils
19
Pathology of chronic-late phase asthma • Hypertrophy (increased size) and
hyperplasia (increased number) of the s.m. surrounding the bronchial tree
• Increased number of blood vessels, resulting in thickening of the airway wall
• Increased number of goblet cells, resulting in increased mucous secretion and mucous plugging
• Infiltration by leukocytes ie eosinophils
White Blood Cells • Leukocytes from leuco Ancient Greek
white • Cells of the immune system, defending the
body against infections, disease and foreign materials
• Five different types exist: neutrophil, eosinophil, basophil, lymphosite (T lymphocyte and B cells) and monocyte
• All produced and derived from the bone marrow
Eosinophils • A type of white blood cells not present in healthy
lungs but in lungs of asthma sufferer • Attracted to lungs by interleukins (from T
lymphocytes) • Once present in lungs they release meditators of
inflammation – These include leukotrienes – Leukotrienes cause bronchoconstriction – They attract more eosinophils into the lungs
which then release more leukotrienes Eosinophils contribute to both early and late
phases of asthma
20
Pathogenesis of asthma ~ 70% of asthmatics are atopic i.e. specific reactions to environmental stimuli
Allergen Lymphocytes
Mast cells & eosinophils
IgE antibodies from B cells Interleukins
from T lymphocytes Protect and activate mast cells Recruitment, infiltration and activation of eosinophils
Mediators of inflammation and bronchoconstriction
Summary L4
• Asthma is primarily an inflammatory disease
• Mediators of inflammation: histamine prostaglandins and leukotrienes • Mast cells release histamine which causes
inflammation and bronchoconstriction • Eosinophils contribute to both early and
late phases of asthma • Pathology and pathogenesis of asthma
Lecture 5
Drug treatment of Asthma
21
Recommended reading (if you want to do well look in the Kimberlin Library or
Campus book shop !)
• Rang and Dale’s Pharmacology 6th edition chapter 23, Churchill-Livingstone, 2007
• Also Rang and Dale’s Pharmacology 7th edition
(2012), chapter 27
• Widmaier EP, Raff H & Strang KT Vander’s Human Physiology, McGraw-Hill, 2008
• Fox SI, Fundamentals of Human Physiology,
McGraw-Hill, 2008
Phases of asthma acute/chronic Acute/immediate phase 1. Bronchoconstriction 2. Mediator release – histamine and leukotriene B4. 3. Infiltration of eosinophils –more LTB4.
RESULTS IN AIRWAYS NARROWING
Late/chronic phase • Mediator release from eosinophils • Long term inflammation • Long term structural changes to airways
Receptors • Proteins on the cell surface
• Agonists bind to the receptor and change the function of the cell
• For example, by stimulating enzymes e.g., adenylate cyclase and the formation of cyclic AMP
• Antagonists bind and block the receptors without activating them
• Agonists cannot bind in the presence of an antagonist
•
22
Drugs used in treatment of asthma
1. Bronchodilators
2. Anti-inflammatory Steroids
1. BRONCHODILATORS
• β2-adrenoceptor agonists
• Xanthines
• Muscarinic receptor antagonists
• cysLT receptor antagonists (LTRAs)
β2-adrenoceptor agonists
Act on bronchiolar s.m. β2-adrenoceptors → relax → bronchodilaton
Also: • inhibit mediator release from mast cells
• Increase mucus clearance by an action on cilia
23
Administration of β2-adrenoceptor agonists
• Most commonly by aerosol
• Also by powder or nebulisor
• Sometimes orally or i.v (eg in status asthmaticus) .
Ways to administrate β2-adrenoceptor agonists
Nebuliser (liquid) Aerosol (powder)
β2-adrenoceptor agonists; two classes
Short acting Salbutamol, terbutaline.
Rapid onset use on demand to relieve symptoms, lasts 4-6 h.
Long-acting Salmeterol Slow onset, lasts 12 hours. Used regularly to prevent symptoms.
Skeletal muscle tremor- A side effect of both types Side effects are reduced by keeping dose low and by using in combination with steroids Note: These drugs relieve symptoms but they leave the underlying disease process unchecked
24
Short and long-lasting β2-agonists
Xanthines Weaker brochodilators than salbutamol Phosphodiesterase inhibitors (i.e. inhibit cyclic AMPbreakdown)
… and … some anti-inflammatory effects
Side effects: 1. CNS stimulant 2. Stimulate the heart 3. Weak diuretic
Main clinical drugs: Theophylline & aminophylline NB Caffeine is a xanthine
Used orally, with inhaled steroids in β2 agonist unresponsive patients.
Problem: Narrow therapeutic window: plasma 10ug for therapy, over 20ug gives side effects – monitor plasma levels
Muscarinic receptor antagonists • Cholinergic muscarinic (m3) receptors → s.m
contraction & mucus secretion • Muscarinic receptor antagonists are used as
bronchodilators (ipratropium and tiotropium) • Both are nonselective also blocks the m2
autoreceptor (bad news, why?) • Quaternary nitrogen compound with minimal
absorption into the circulation (few side effects) • Used in combination with β2 agonists for aerosol
inhalation (mainly COPD) • Tiotropium more long acting than ipratropium
25
Leukotriene Receptor Antagonists (LTRAs)
Antagonise the action of all leukotrienes.
• Particularly effective in exercise-induced asthma
• Increasing role in general asthma therapy
Used with β2 agonists and inhaled steroids
Examples: Montelukast & Zafirlukast
2. Anti-Inflammatory Steroids
• Work by inhibiting expression of pro-inflammatory genes and inducing expression of anti-inflammatory genes.
• E.g. inhibit production of pro-inflammatory cytokines
• Increase production of β2 adrenoceptors
• Reduce numbers of eosinophils, T-lymphocytes & mast cells in airway tissues
Pathogenesis of asthma ~ 70% of asthmatics are atopic i.e. specific reactions to environmental stimuli
Allergen Lymphocytes
Mast cells & eosinophils
IgE antibodies from B cells Interleukins
from T lymphocytes Protect and activate mast cells Recruitment, infiltration and activation of eosinophils
Mediators of inflammation and bronchoconstriction
26
Steroids & Asthma (cont) • Usually administered by inhalation. Also used
orally in acute severe attacks
• Do NOT alleviate symptoms in short term
• Used in prophylaxis (PREVENTER) of asthma. Attacks underlying inlammatory disease
• Beclometasone is usual inhaler choice for mild asthma
• Fluticasone is more potent – for more persistent conditions
• Administered routinely – NOT on demand – typically twice/day
STRATEGY IN TREATMENT OF ASTHMA
• Recognise that symptoms may be treated (with β2 agonist) while leaving the disease process unchecked.
• This means that, except perhaps in the most occasional forms, asthma should always be treated with steroids.
Summary Lecture 5
• Bronchodilators • Anti-inflammatory Drugs • Symptoms are treated with β2 agonist • Steroids are treating the cause of the
disease • Steroids are prophylactics (PREVENTER)
of asthma. Attacks underlying inflammatory disease
27
Lecture 6
COPD and its treatment
COPD • Chronic obstructive pulmonary disease • 30,000 deaths/year in UK • 6th most common cause of death in UK • Most patients die after years of struggle • Epidemic of COPD spreads across the world
following the spread of the smoking epidemic. • In USA COPD is the only major cause of death
to increase significantly in recent years • COPD becoming the 4th leading cause of death
in Europe
COPD MORTALITY – GETTING WORSE
1. !In 2002 2.75 million people died from In 2002 2.75 million people died from COPD
2. !A substantial number of these were A substantial number of these were in South East Asia where the tobacco epidemic is only just beginning to hit
3. !Here COPD is still predominantly a Here COPD is still predominantly a male disease
28
Treatment of COPD • Stop smoking! • Short acting β2 agonists (salbutamol) • Short acting muscarinic agonist -
ipratropium often helpful as well • Steroids often help too - oral
prednisolone and inhaled • Also, oxygen, mucolytics,
antibacterials as necessary
Additional Lung Disorders
1. Chronic bronchitis
2. Emphysema
These disorders often co-exist with COPD
Chronic bronchitis • Productive cough on most days.
• Excess mucous formation
• Mucous plugs
• Inflammation of small airways
• Commonly with secondary infections.
29
Emphysema • Proteolytic destruction of tissue
• Damage to alveolar septa
• Elastin destruction
• Loss of elasticity
• Loss of capillary bed
Illustration of damaged Alveoli
Overlapping symptoms of lung diseases
30
Course Assessment The Respiratory System
Name :
P number :
PLEASE ANSWER THE FOLLOWING MULTIPLE CHOICE QUESTIONS BY WRITING THE NUMBER OF THE ANSWER WHICH YOU THINK IS CORRECT IN THE BOX.
ATTEMPT TO ANSWER ALL QUESTIONS.
HAND IN YOUR ANSWERS TO THE LECTURER AT THE END OF THE TEST.
Q1. Asthma is a disease of:
1. The brain 2. The respiratory System 3. The liver 4. The skin 5. The heart