Respiratory Medicine Flashcards
How can the nervous system be divided?
Main divisions of the nervous system
1.Somatic nervous system - controls organs under voluntary control (mainly muscles)
- Autonomic nervous system (ANS) which regulates organ function and homeostasis, and for the most part is not subject to voluntary control (the visceral or automatic system).
Can be subdivided into…
a) Sympathetic nervous system (fight or flight) - response to stress, danger and other alerts
b) Parasympathetic nervous system (rest and digest) - background housekeeping functions (e.g. digestion)
What role do afferent and efferent autonomic nerves play?
Afferent autonomic nerves
- Transmit information from the periphery to the CNS (to inform activity of efferent system)
- Sensors in many organs, notably the baroreceptors and chemoreceptors
- Information carried to the CNS by major autonomic nerves (e.g. vagus, splanchnic or pelvic nerves)
Efferent autonomic nerves
- Transmit impulses from the central nervous system (CNS) to peripheral organ systems
- Control heart, blood vessels, gut, bladder, eyes, exocrine and endocrine glands
- Response include smooth muscle contraction/ relaxation, glandular secretion etc.
Explain the anatomy of the parasympathetic nervous system.
Parasympathetic NS divided into pre- and post-ganglionic fibres
Parasympathetic preganglionic fibres
- Leave the brainstem (midbrain, pons, medulla) and sacral segments (S2–S4) of the spinal cord.
- Travel long distances to synapse with postsynaptic fibre in ganglia (clusters of synapses) located in effector organs
- Myelinated
Parasympathetic postganglionic fibres
- Unmyelinated
- Much shorter than preganglionic fibres
- Most located near to or within effector organs
Explain the anatomy of the sympathetic nervous system.
Sympathetic preganglionic fibres
- Cell bodies in lateral horns of the spinal segments T1-L2 – ‘thoraco-lumbar outflow’
- Myelinated
- Sympathetic paravertebral ganglionic chains run from the cervical to the sacral region
synapse in ganglia with a postsynaptic fibre
Sympathetic postganglionic fibres
- Unmyelinated
- Much longer than preganglionic fibres
- Run all the way to the effector organ
Note - Some preganglionic fibres do not synapse in the sympathetic chains but terminate in separate cervical or abdominal ganglia or travel straight to the chromaffin cells in the adrenal medulla (greater splanchnic nerve)
Whats special about the adrenal medulla (sympathetic nervous system)?
Adrenal glands located on superior aspect of each kidney
- Adrenal medulla chromaffin cells synthesise and store catecholamines (mainly adrenaline) in a similar way to sympathetic postganglionic nerve endings - act as a an post-ganglionic effector
- Hence, the adrenal gland responds nervous impulses from the sympathetic cholinergic preganglionic fibres by secreting hormones into circulation
- Allows large quantities of catecholamines to be release when under physical and/or psychological stress
What are the neurotransmitters/receptors used by the parasympathetic nervous system?
Parasympathetic Nervous System
Preganglionic parasympathetic nerves -
acetylcholine (ACh) is the neurotransmitter, which acts at nicotinic receptor at the preganglionic synapse
Postganglionic parasympathetic nerves -
acetylcholine (ACh) is the neurotransmitter, which acts at muscarinic receptors at effector organs
How do nicotinic and muscarinic receptors function?
Nicotinic cholinergic receptors depolarise the postsynaptic cell membrane by opening ion channels increasing permeability to sodium and potassium - driving action potential creation
Muscarinic cholinergic receptors are G-protein-coupled receptors that are linked to either inositol triphosphate (IP3) or cyclic adenosine monophosphate (cAMP) as secondary messengers
Type 1, 3 and 5 muscarinic receptors - increase IP3 - increase calcium availability or decrease potassium conductance - excitatory effect
Types 2 and 4 muscarinic receptors - inhibit cAMP generation - reduces calcium availability and is inhibitory.
Note - these receptors can also be located pre-synaptically - negative feedback loop to control ACh release
What is acetylcholine? How is it created/broken down?
Cholinergic neurotransmitter - Acetylcholine (ACh)
ACh synthesised in neurones from acetyl-CoA and choline by the enzyme choline acetyltransferase
ACH can be broken down by acetylcholinesterase (AChE) to form acetate and choline.
Process of events
1. Synthesis using enzyme choline acetyltransferase pre-synaptically
2. Loaded/stored in vesicles
3. Release into synaptic cleft
4. Acts on receptors
5. Diffuses off receptor
6. Targetted and broken down by AChE
7. Choline and acetate pumped back into the pre-synaptic terminal
What are the two sub-divisions of cholinergic receptors?
ACh acts on cholinoreceptors - two sub-divisions
Nicotinic receptors
- Directly coupled to increased permeability of cation channels (Na+, K+) depolarising
- Autonomic ganglia (and neuromuscular junction)
- Also located pre-synaptically
Muscarinic receptors
- G-protein-coupled receptors coupled to phospholipase C (generates IP3, DAG), adenylate cyclase (generates cAMP), activation of K+ channels or inhibition of Ca2+ channels
- M1 - neural, M2 - cardiac, M3 - glandular/smooth muscle
- Also located pre-synaptically
Summary table of nicotinic and muscarinic receptors - Effector, secondary messenger, agonist, antagonist.
What are the main endogenous
mediators and receptors involved in the regulation of the sympathetic nervous system?
Preganglionic sympathetic nerves
- Acetylcholine (ACh) is the neurotransmitter
acts, and it acts on nicotinic receptors at the preganglionic synapse
- The adrenal medulla is innervated by preganglionic fibres and therefore adrenaline is
released from the gland by stimulation of nicotinic ACh receptors
Postganglionic sympathetic nerves
- Noradrenaline (NA) is the chemical transmitter, which act on alpha-1 and beta-1 receptors
- Sweat glands are an exception - postganglionic
sympathetic fibres release ACh at muscarinic receptors
Outline the downstream mechanisms of alpha-1 and beta-1 receptors.
Noradrenaline (NA) - main neurotransmitter in post-ganglionic fibres
Receptors
1. Alpha-1 receptors that are linked to inositol triphosphate (IP3) as a secondary messenger and, in smooth muscle cells, cause constriction
2. Beta receptors are linked to cyclic adenosine monophosphate (cAMP) as a secondary messenger and, in smooth muscle cells, cause relaxation.
Note - pre-synaptic alpha-2 adrenergic receptors are responsible for the negative feedback loop that down-regulates noradrenaline release
What are catecholamines? How are they synthesized and broken down?
Catecholamine = neurotransmitters - adrenaline (A), noradrenaline (NA)
Catecholamines synthesised from the essential amino acid phenylalanine and tyrosine - enzymes tyrosine hydrolase and dopamine beta-hydroxylase
Stored in terminal branches of postganglionic fibres visible as varicosities (‘string of beads’ appearance)
Following release and binding at the post-synaptic receptor…
- Metabolism by catechol-O-methyl-transferase (COMT)
- Re-uptake into pre-synapse - where it is further metabolised by monoamine oxidase (MAO) in mitochondria
What are the different actions of alpha-1, alpha-2, beta-1 and beta-2, adrenergic receptors?
Alpha1-adrenoceptors - blood vessels - vasoconstriction (IP3)
Alpha2-adrenoceptors - located in the presynaptic membrane - feedback inhibition by noradrenaline on its own release from presynaptic terminals
Beta1-adrenoceptors- heart - increased force and rate of contraction (cAMP)
Beta2-adrenoceptors - lung – bronchial smooth muscle relaxation (cAMP) & blood vessels - vasodilatation (important during exercise)
Summary table of the adrenergic receptors - Effector, secondary messenger, agonist, antagonist.
Adenylate cyclase classically linked to Beta receptors
Agonists for the alpha receptors – mainly noradrenaline
Beta receptors – adrenaline
What are the genereal consequences of activation of the sympathetic and parasympathetic nervous systems?
Parasympathetic - housekeeping activity and antagonizes sympathetic NS
Sympathetic - Prepares body for ‘fear, flight or fight’
What are the actions of the parasympathetic and sympathetic NS on the heart?
What are the actions of the parasympathetic and sympathetic NS on blood vessels?
The sympathetic nervous system is the dominant influence on the smooth muscle tone in blood vessels.
However, some specific vascular beds have a rich supply of muscarinic M3 receptors.
What are the actions of the parasympathetic and sympathetic NS on the lungs?
What are the actions of the parasympathetic and sympathetic NS on the GI tract?
Parasympathic increases digestion
Sympathetic decreases digestion
What are the actions of the parasympathetic and sympathetic NS on the bladder and genitalia?
What are the actions of the parasympathetic and sympathetic NS on the eye?
Miosis - small/constricted pupils
Mydriasis - dilation of pupils
What effect does the sympathetic nervous system have on the kidneys?
Main thing - increases AngII which is a potent vasoconstrictor and stimulates aldosterone release (increase sodium/water retention)
What effect does the sympathetic nervous system have on the adipose tissue?
Summary of the main effects of the parasympathetic NS on the body?
Activation of the parasympathetic nervous system….
- Reduces heart rate
- Increases glandular secretion
- Increases peristalsis and relaxes sphincters in the gastrointestinal tract
- Supports emptying of the bladder
- Constricts the pupil
Summary of the main effects of the sympathetic NS on the body?
Activation of the sympathetic nervous system…
- Raises blood pressure
- Increases heart rate
- Preserves extracellular fluid volume
- Mobilises energy stores
- Inhibits many of the housekeeping functions of the parasympathetic system
What are the main airways that regulate airflow? What are the different inputs that influence broncho-constriction/dilatation?
Resistance to airflow is controlled at the bronchiole level
The most important influence on airway diameter and resistance is the tone of the smooth muscle around the bronchi and bronchioles
Fight between factors that drive contraction and dilatation - many drugs try to influence this balance
The main factor favouring contraction is the parasympathetic nervous system - post-ganglionic fibres secrete the neurotransmitter acetylcholine which acts at muscarinic M3 receptors on bronchial smooth muscle and glandular cells, and mediate bronchoconstriction and mucus secretion - main driver at rest
During inflammation - leukotrienes and histamine are released driving contraction
The main factor favouring dilatation is the sympathetic nervous system via circulating adrenaline released from the adrenal glands and acting at beta-2 adrenoceptors located on bronchial smooth muscle.
This mechanism is a minor influence at rest but becomes more important during exercise or the stress response to acute bronchospasm during asthma exacerbations
What are the main diseases affecting the respiratory system?
What drugs act as bronchodilators?
Bronchodilators are, by definition, drugs that increase the diameter of the respiratory airways by relaxing the layer of smooth muscle surrounding the bronchi and bronchioles - reduces the resistance to airflow and the work of breathing.
Important two…
Beta-2 agonist drugs activate beta-2 adrenoceptors found on the surface of bronchial smooth muscle cells that are the physiological target of circulating catecholamines such as adrenaline - divided into…
a) Short duration of action (e.g. salbutamol, terbutaline)
b) Longer-acting (e.g. salmeterol, formoterol).
Anti-muscarinic drugs activate muscarinic M3 receptors that are the physiological target of the neurotransmitter acetylcholine
a) Short duration of action (e.g. ipratropium bromide)
b) Longer-acting (e.g. tiotropium, aclidinium bromide).
Note - Phosphodiesterase inhibitors target the enzyme phosphodiesterase (PDE) that is responsible for the breakdown of cyclic adenosine monophosphate (cAMP), which is a secondary messenger for beta-2 adrenoceptors
Why are bronchodilators delivered by inhalation?
Rationale
- Drug delivered directly to its site of action
- Limited collateral effects on other tissues
Inhaler devices are used
- Metered-dose inhaler (MDI) - requires a certain levels of technique/coordination - spacer device is an alternative
- Dry powder inhaler (DPI)
- Mechanical Nebulizer devices – drug put into a container which is driven in by airflow/O2 – used in emergency situations
Note - Size of aerosolized is important – 2.5 microns to reach site of action
Examples of Beta-2 agonists, mechanism of action, indications, adverse effects?
Adverse effects due to localisaiton of Beta-2 receptors on other tissues like muscles, heart, etc - interfer with contractions
Examples of anti-muscarinics, mechanism of action, indications, adverse effects?
Used for COPD – helps to reduce glandular secretion – big problem in COPD patients
Anti-cholinergic side effects are important to learn – classic group of adverse effects – inhibition of PS NS action
Glaucoma - eye conditions related to optic nerve damage
Examples of phosphodiesterase inhibitors, mechanism of action, indications, adverse effects?
Phosphodiesterase inhibitors – prevent the breakdown of cAMP – increasing its ability to activate PKA and thus preventing contraction driven by MLC kinase
Adverse side effect – similar to the potentiation of B2 receptor – acting on the same system
How is magnesium used as a bronchodilator, mechanism of action, indications, adverse effects?
Small print stuff
Smooth muscle relaxant
Last stage drug used – acute severe bronchospasm
How are leukotrine receptor antagonists used as a bronchodilator, mechanism of action, indications, adverse effects?
Inhibit the activity of leukotrines - prevents smooth muscle contraction, decreases immune chemotaxis and decrease vascular permeability
How does the asthma treatment pathway look like?
SABA - short acting beta agonist
ICS - inhaled corticosteroid
LRTA - Leukotrine receptor antagonist
LABA - long acting beta agonist
LAMA - Long-acting muscarinic antagonists
Corticosteroids examples, mechanism of action, indications and adverse effects?
Examples:
Inhaled: beclometasone, fluticasone
Oral: hydrocortisone, prednisolone
IV/IM: hydrocortisone, methylprednisolone, dexamethasone
Topical: hydrocortisone, betamethasone
Mechanism of action
- Bind to intracellular receptors to alter translation of DNA
- Macrophages and T cells are key cell targets in inflammation
Indications
- inflammatory diseases such as asthma, COPD exacerbations, RA, etc.
- allergic emergencies, adrenal insufficiency
Adverse effects
- Wide range of effects including osteoporosis, weight gain, diabetes, susceptibility to infeciton, muscle wasting (myopathy), dyspepsia, psychosis and hypertension
Which type of drugs effects would have adverse effects on the respiratory system?
What are examples of drugs that cause bronchoconstriction?
- Beta blockers (drive bronchoconstriction) - never given to patients with troublesome asthma - block activity of beta-2 receptor – note even though Beta-1 antagonists are selective there is overlap!
- NSAIDS – stop prostaglandin production - interference with COX drives increases leukotrine production - promoting bronchoconstriction and inflammation
- Cholinesterase inhibitors - increase pool of ACh resulting in increase M3 activity and thus bronchoconstriction
- Beta-2 agonists (paradoxical bronchospasm) - phenomenon that is sometimes observed
What are examples of drugs that suppress respiration?
Examples of drugs that have direct inhibitory effects on the respiratory centre and chemoreceptors that drive breathing
Hypnotics - promote sleep
Drugs that cause paralysis - paralysis of respiratory musculature
Why is particle diameter important for understanding particle penetration and deposition in the lungs?
Diameter is important as it dictates how a particle acts in airflow - influence a particles ability to penetrate and deposit in the lungs
Large particles settle higher in the airway, compared to smaller particles
A lot of forces involved - airflow, diffusion, electrostatic, etc.
Can particles in the lungs move to other tissues?
Yes, particles can move around to other tissues – e.g. liver and spleen
How do macrophages clear particles that are deep in the lungs?
Lower respiratory tract - lack of cilia
Hence, macrophages can engulf the particles and migrate to the lymph node or move up to the mucocilliary escalator to be pushed out the lung
Anything larger than 10microns – difficult to phagocytose for macrophage
What factor dictates how far fibres travel down the lung?
Fiber doesn’t tumble – travels straight as a arrow/javelin
Movement up and down as it travels – will dictate the length down the lung it reaches - determined by fibres physical diameter not length
What are some conditions associated with fibres accumulating in the body?
Why are fibres pathogenic for the body?
Fibre Pathogenicity Paradigm
They are thin, bio-persistent (doesn’t breakdown/resistant to acidification) and long
What happens when phagocytse get fustrated and are unable to clear fibres?
Start to produce proteolytic enzymes and low pH – because this vesicle is open it will be released into the surroundings – resulting in excessive inflammation
What are the different outcomes for fibres based on their length?
Can fibres enter the pleura space?
Yes, movement into pleural space is possible – drains present (stomata) in the pleural space to drain debris/dead cells.
This allows some of the small fibres to be moved out, but fibres that are too large build up if they can’t be filtered out - irritating/inflammation of the mesothelium
What does pleural inflammation/fibrosis in the short term mean in the long term?
Pleural mesothelioma
Pleural plaques
What are six conditions that might causes inta-pulmonary restriction?
What type of elasticity do the lung and chest wall normally exhibit?
Lung and chest wall are elastic
- Lungs natural tendency deflate
- Chest wall has a natural tendency to inflate
Difference in chest wall and lung elastic pressure is called the transpulmonary pressure
To inflate the lung we need to overcome the transpulmonary pressure (equilibrium) but either increase thoracic volume (normal breathin) in order to decrease pleural and alveolar pressure OR we could apply an inflation pressure (ICU setting)
Image uses the diagram alveoli as a conceptual framework for the lung
What does the term compliance refer to? What is the difference between a lung with a high or low compliance?
How does a fibrotic/restrictive lung with a decreased compliance impact its inflation & deflation?
Fibrotic lung/alveoli
a) Decreased compliance means that an increased pressure is required to inflate the lung - restricts inflation
b) Increased elastic recoil does mean that deflation is easier
Typical of fibrotic lung disease
How does an inelastic lung with a increased compliance impact its inflation & deflation?
Lung that is increasingly compliance
Decreased elastic tissue and increase complianced makes it…
a) Easier to inflate - less resistance
b) Difficult to deflate - less elastic tissue and recoil
Typical of emphysema
Apart from pleural and inflationary pressure, what other force do we need to consider?
Inward force generated by fluid layer surface tension (sT)
Force created by fluid lining the alveoli is dependant on the radius and shape of the alveoli:
a) Smaller radius - increased force
b) Bigger radius - decreased force
Hence, given that the inflationay pressure is constant - the total alveolar pressure (pressure driving collapse) will be larger in smaller alveoli.
What is the consequence of having different surface tensions between small and large alveoli?
Consequence - air will move from HIGH pressure area to LOW pressure areas
Small alveoli with higher pressure - empty in larger alveoli with lower pressures - resulting in instability
What prevents collapse (due to alveolar instability - surface tension) and keeps alveoli stable?
Surfactant
Produced by alveolar Type II cells - reduces surface tension
Composed of lipids (90%, mainly phospholipids) and proteins (10%)
What is the composition of the surfactant?
Outline the mechanism of action behind the surfactant - how does it reduce surface tension/pressure in small alveoli?
Surfactant molecules act to reduce surface tension but only when they are close togther
Hence….
1. In large alveoli or in expanded lungs - the surfactant only minimally reduces surface tension - minimal impact of pressure
2. In small alveoli or in in delated lungs - the surfactant significantly reduces surface tension - resulting in reduced alveolar pressure
Net result - equalises pressure between adjacent alveoli or differing sizes - removing alveolar instability
How do obstructive and restrictive conditions compare in terms of their impact on FEV1, FVC, TLC and VC?
Obstructive
- FEV1 reduced but FVC normal (exceptions in severe obstruction) – ratio decreased
- TLC (total lung capacity) increased and VC (vital capacity) decreased
Restrictive
- FEV1 may be reduced and FVC will almost always be reduced – ratio is normal or elevated – change in FEV1 is usually smaller than FVC change
- TLC (total lung capacity) and VC (vital capacity) are decreased
How can we distinguish between intra- and extra-pulmonary restriction?
Look at Gas Transfer Measurements
This entails looking at…
a) GAS EXCHANGE - use low levels of carbon monoxide (CO) - rapidly taken up by hemoglobin/high affinity, not produced by the body, not toxic and easy to measure
b) ALVEOLAR VOLUME - use helium gas - not taken up by hemoglobin, not produced by the body, non-toxic and easy to measure.
How do TLCO and KCO differ between intra- and extra-pulmonary diseases?
Looking at both alveoli and bood vessels
Extra pulmonary - TLCO is low but KCO is normal/high - normal alveoli + blood supply – total transfer of CO is reduced as lung is reduced in size/in-cased in a smaller area but each blood supply is normal or high (increase packing of blood vessels with alveoli)
Intra-pulmonary – TLCO and KCO are both low – lungs are smaller and alveoli are diseased and damaged – alveolar unit has an impaired ability to transfer gas
KCO looks at gas transfer, so it makes sense that is is lower in fibrotic/intra-thoracic restrictive diseases
KCO – is the distinguishing factor between intra and extra-thoracic restrictive diseases!
