Pharmcology Flashcards
NANC innervation nonadenergic/ noncholinergic
Bronchodilation
Transmitters: VIP and NO
In asthma substance P may cause bronchoconstriction
Parasympathetic innervation
Ach from vagus nerve stimulates M3 receptors
Bronchoconstriction
No sympathetic innervation but
B2 receptors on airway smooth muscle
Circulating adrenaline released from adrenal medulla causes bronchodilation
B2 receptors on mast cells (normally release bronchoconstrictors eg histamine) - inhibits activity
B2 stimulation promotes muco-ciliary escalator activity
Mechanical receptors
Rapidly adapting receptors RAR also known as irritant or cough receptors cause bronchoconstriction
Stimulation by foreign bodies or irritants initiates reflex with afferent and efferent arms in vagus result in contraction smooth muscle
Slowly adapting pulmonary stretch receptors PSR cause bronchodilation, stretch fibres in afferent vagus nerve
Mast cells
Present in airway walls
Mediators released on degranulation causing bronchoconstrction
Eg histamine, platelet activating factors , leukotrienes
Contribute to asthma pathology
CO2
Bronchodilation
Builds up in areas of lung that are under ventilated
Important for ventilation- perfusion matching
Radial traction
Airways embedded in lung parenchyma
Parenchyma splints airways open
Inflation increases radial traction and reduces airway resistance
During inspiration lung expands stretching parenchyma fibres increasing radial traction pulling out airways increasing diameter reducing airway resistance
Alveolar interdependence
Neighbouring alveoli share walls
Mechanical tethering keeps conducting airways open
Loss of radial traction and alveolar interdependence increases airway resistance in COPD
Asthma
Episodes of bronchoconstriction
Bronchial hypersensitivity- airway mucosa inflammation: infiltration of immune cells and thickening
Increased airway secretions
Pharmacological treatment can target bronchoconstrictor or inflammatory components
Anti-cholinergics/muscarinic antagonists
Block bronchoconstricting action of ACh
Ipratropium: inhaled quaternary nitrogen in structure prevents systemic absorption and reduces side effects (dry mouth and cough)
Tachycardia, relax bladder, inhibit intestine activities, inhibit salvia etc
Used in COPD with salbutamol
B2 agonists
Noradrenaline or adrenaline
Stimulates the AC/cAMP/PKA pathway to cause bronchodilation and reduce inflammation (mast cells inhibited)
Salbutamol: short acting inhaled, side effects: tachycardia, tremor, airway hyper responsiveness can develop tolerance
Salmeterol/turbutaline: long acting/ slow onset, used in pregnancy’s not appropriate in asthma attack
Methylxanthines
PDE(phosphodiesterase) inhibitors: increased cAMP and cause bronchodilation and reduce inflammation
Administered orally
Theophylline/aminophylline: oral, narrow therapeutic window side effects: headache, restlessness, abdominal symptoms, arrhythmias
Reported drug interactions use declined
Aspirin induced asthma
Sensitivity develops in adulthood women>men
Symptoms: rhinorrhea, nasal congestion, sinusitis
5-lipoxygenase unregulated increasing production leukotrienes
Montelukast used as a treatment- leukotriene receptor antagonist
Monoclonal anti-IgE antibodies
Omalizumab : s.c injection every 2-4 weeks, reduces circulating IgE and therefore reduces mast cell degranulation and inflammation, used in severe allergic asthma, in rare instances can cause anaphylaxis
Reduces bronchoconstriction
Histamine receptor antagonists
Ketotifen: oral H1 receptor antagonist, anti inflammatory after 6-12 weeks
Reduced reliance on steroids and bronchodilators
Few side effects: drowsiness
Targeting leukotriene pathway
Leukotriene formation antagonists: Zileuton (oral) inhibits 5-lipoxygenase, short half life not widely used in treatments asthma would need to be taken 3-4 times a day problem with compliance
Leukotriene receptor antagonists: montelukast (oral), single dose used in severe chronic asthma and exercise induced asthma, bronchodilates, decreases mucous production, reduces inflammation
Sodium cromoglicate/ cromolyn
Inhaled
Prophylactic treatment
Mechanism not fully understood
Inhibits release of inflammatory mediators from mast cells and RAR axon releases so prevents bronchoconstriction
4 weeks to become effective can be very effective
Mild side effects: low incidence, coughing, wheezing, dry throat
Corticosteroids
Inhaled
Reduces airway hyper responsiveness and inflammation
Prevents rather than relieves
Beclamethasone (inhaled): metabolised to active form in lungs reducing systemic side effects
Respiratory stimulants (analeptics)
Doxapram
- effective less 1 min helpful in crisis but metabolised quickly, short half life cant be used long term maintenance chronic health condition
Mechanism: simulates O2 and CO2 chemoreceptors, non specifically enhances electrical activity everywhere
Higher doses direct action on medulla
Adverse effects: cardiac arrhythmias, convulsions
Clinical use: acute ventilatory failure with hypercapnia (COPD)
Post operative respiratory depression
Mechanical assisted ventilation preferred
Respiratory depressants
General principle: any agent which has a generalised CNS depressant effect has the potential to depress respiration via action at the respiratory nuclei in the brain stem
Respiratory function is resistant doesn’t completely stop
Implications for drug use: legal/therapeutic and illegal, patient health status so how much reserve they have, patient age very young and old more sensitive to respiratory depression
General anaesthetics
Depressant
Volatile anaesthetics- isoflurane
Physiological action: decrease response of CO2 chemoreceptors, increases PaCO2
Mechanism: GABA? More inhibitory neurotransmission decreasing CNS activity, non specific
Long procedure- supported with oxygen
Injectable anaesthetics less understood- decrease CO2 response
Benzodiazepines
Depressant
Diazepam (Valium), temazepam
Preanaesthetics, anxiolytics- anxiety
Physiological:
- decreases hypoxic drive - peripheral effect, higher dose can affect central medulla, non fatal respiratory function doesn’t stop even in overdose. High dose and respiratory compromise= problem
Mechanism:
-GABAa receptors (Cl- ion channels) increase inhibitory affects, lots of areas in brain, GABA bound opens channels , GABA and BDZ increases GABA effect, Hyperpolarisation due to lots Cl- entering depression electrical activity
GABA is required for action
Barbiturates
Phenobarbital, thiopental
Physiological action: decreases response central chemoreceptors, decrease hypoxic drive
Anaesthetic dose Close to fatal dose difficult to use
Mechanism: increases inhibitory neurotransmission GABAa receptors, increases Cl- Channel open time neurones depressed activity
GABA unnecessary more toxic than benzodiazepines
Alcohol (ethanol)
Depressant
Physiological action: decreases CO2 response
Mechanism:
-increases GABAa transmission more inhibition
-decreases NMDA transmission (excitatory neurotransmission)
Voltage gated ca channels effected
Fatal dose rarely achieved
Opioids
Depressants
Morphine, fentanyl, heroin
Bind to opioid receptors GPCRs: mu, delta etc
Mu receptors: used in analgesia and respiratory depression, in medulla
Tolerance: start on low dose, repeated use increases dose to get therapeutic effect but no tolerance for respiratory depression so dose needed for analgesia can have negative impact respiratory function
Physiological action: decreases CO2 chemoreceptor response increase PaCO2
Mechanism: GPCRs, mu coupled to open K+ channels cause neurone hyperpolarisation decreases excitability
Opioid receptor antagonists
Naloxone
Opioid overdose
Can sometimes given without prescription- paramedics etc
Gets metabolised faster than heroin so need multiple doses until heroin metabolised
Life saving
People who abuse opioids build up tolerance then if go in remission, then relapse and use high doses they did before with no tolerance can be fatal
Drug interactions
Additive effect:
Benzodiazepine/opioid/alcohol potential fatal
Benzodiazepine and general anaesthetic- assisted ventilation during operation
Benzodiazepine antagonist
Flumazenil
Often not needed
Used if taken too many respiratory depressants
Respiratory stimulants others
Progesterone
Aminophylline (methylxanthines)
All increase VE and hence reduce PaCO2 useful in COPD, obesity hypoventilation syndrome
Sleep
Decreased response to hypoxia and hypercapnia
Decreased response to mechanoreceptors
Hypotonia of upper airways- OSA
Hypotonia of skeletal and respiratory muscle
PaO2 and PaCO2 can be altered up to 1kPa
