Tell Me About… Flashcards
2,3 - DPG
2, 3, diphosphoglycerate
* highly anionic organic phosphate
* shifts the ODC to the right
* promotes release of oxygen from haemoglobin
* produced by a side-shunt reaction of glycolysis
* present in large quantities in the erythrocyte
* one 2,3-DPG molecule binds between the beta-globin chains of deoxyHb, altering the protein structure and reducing oxygen affinity
* production of 2,3-DPG increased in anaemia and pregnancy
Adrenocorticotropic Hormone (ACTH)
Polypeptide hormone
Production: Anterior pituitary
Secretion: Anterior pituitary
Site of action: Adrenal cortex
Effects: Mainly stimulates the synthesis of glucocorticoids (stimulate gluconeogenesis, promote breakdown of dates and damp down inflammatory response) in the zona fasciculata. Also stimulates the synthesis of mineralocorticoids (e.g aldosterone - promotes Na and H2O retention by the kidneys) in the zona glomerulosa.
Release stimulated by: CRH, stress (including surgery), ADH
Release inhibited by: glucocorticoids
Hypersecretion: Adrenal hyperplasia, Cushing’s disease if pituitary tumour is the source
Hyposecretion: Secondary adrenocortical insufficiency
Action Potentials
Neuronal Action Potential - duration 1ms
- Resting membrane potential (usually -70 in nerves and -90mV in muscles) - maintained by Na+/K+ ATPase pump
- Threshold potential -55mV
- Depolarisation - voltage gated sodium ion channels open due to an electrical stimulus
- Sodium enters the cell, making it more positive
- If a threshold potential is reached, then an action potential is produced
- Once depolarised, the voltage gated sodium ion channels begin to close
- Positive potential inside the cell causes voltage-gated potassium channels to open and K+ ions to move out of the cell
- As K+ leave the cell, the membrane potential becomes more negative and usually overshoots (hyperpolarisation)
- Absolute refractory period - once sodium channels close, they enter an inactive state during which they cannot be reopened
- Relative refractory period - as sodium channels come out of inactivation, a larger stimulus than usual may generate an action potential
- Normal ion distribution restored via Na+/K+ ATPase pump - restores RMP
Cardiac Mycocyte Action Potential - duration 300ms
* Phase 4 - baseline - open potassium channels, resting membrane potential tends towards the equilibrium potential for K+ (RMP ~-90mV)
* Phase 0 - fast depolarisation - opening of voltage gated sodium channels with influx of sodium ions
* Phase 1 - notch - transient opening K+ channels rapidly repolarise before the plateau. Threshold potential ~-85mV
* Phase 2 - plateau - calcium enters the cell through L-type Ca2+ channels in the T-tubules, this calcium binds to RyR triggering massive calcium release from the SR
* Phase 3 - repolarisation - timed closure of Ca2+ channels, K+ channels repolarise the cell
Cardiac Pacemaker Cell Action Potential
* Phase 4 - spontaneous depolarisation as sodium enters via voltage gated channels and calcium enters via T-type channels
* Phase 0 - rapid depoalrisation once threadshold potential is reached, L-type calcium channels open allowing calcium entry into cell
* Phase 3 - repolarisation - as potassium permeability of cell increases, potassium exits
* Threshold potential -40mV
* Cycle length 1s for HR60, 0.5s for HR120
* Intrinsic SA rate 60-100, AV rate 40-60
Actions of Hormones
- Permeability e.g. GH, prolactin, insulin
- via G-proteins that increase cAMP e.g. oxytocin, ADH, LH, FSH, TSH, ACTH, PTH, glucagon, adrenaline at beta receptors
- via G-proteins that decrease cAMP e.g. somatostatin, adrenaline at alpha-2 receptors
- via PIP2, IP3 and DAG e.g. adrenaline at alpha-1 receptors, ADH
- via mRNA e.g. thyroxine, tri-iodothyronine, steroid hormones
Adrenaline
Amine hormone
Production: Adrenal medulla + small number of neurons in the medulla oblongata from tyrosine
Secretion: Adrenal medulla
Site of action: Adrenergic receptors on nearly all tissues, beta > alpha at lower doses, at high doses alpha 1 effects dominate
Effects: Increased inotropy, increased HR, SVR and PVR, BP, CO and increased myocardial oxygen consumption, coronary vasodilation, arrhythmogenic, decreased RBF, increased BMR, increased lipolysis and gluconeogenesis, initially increased insulin secretion then decreased, increased MV, bronchodilation
Release stimulated by: Stress - physical threat, excitement, noise, bright lights, high or low ambient temperature, sympathetic stimulation
Release inhibited by: Alpha and beta antagonists
Metabolism: Mitochrondrial MAO and COMT within liver, kidney and blood to VMA and metanephrine, urinary excretion
Hypersecretion: Phaeochromocytoma
Hyposecretion: Autonomic neuropathy, adrenalectomy
Adverse Drug Reactions
Type A - Pharmacological/augmented
Exaggeration for a drugs normal pharmacological actions when given at a usual therapeutic dose
Type B - Idiosyncratic/bizarre
Cannot be predicted from the known pharmacology of the drug
Type C - “Continuing” reactions
Persist for a relatively long time e.g. osteonecrosis risk in bisphosphonates
Type D - “Delayed” reactions
Become apparent some time after
Type E - “End of Use” aka withdrawal
Type F - Failure of therapy
Aldosterone
Mineralocorticoid steroid hormone
Production: zona glomerulosa of adrenal cortex
Secretion: adrenal cortex
Site of action: mineralocorticoid receptors in distal tubules and collecting ducts
Effects: increase blood volume by reabsorption of sodium in the kidneys, salivary glands, sweat glands and colon; secretion of potassium and H+ in the kidney, indirectly influencing water retention/loss and BP
Release stimulated by: renin, angiotensin II, ACTH, raised serum K+, angiotensin III, plasma acidosis, stretch receptors in the atria
Release inhibited by: low serum K+
Hypersecretion: Conn’s Syndrome
Hyposecretion: primary adrenal insufficiency, congenital adrenal hyperplasia
Angiotensin II
Polypeptide hormone
Production: conversion of ATI by ACE from the surface of pulmonary and renal endothelium
Site of action: arterioles, kidney, sympathetic nervous system, adrenal cortex, hypothalamus
Effects: increases sympathetic activity, increases tubular Na/Cl reabsorption and K excretion, H2O retention, stimultes adrenal cortex to increase aldosterone secretion, arteriolar vasoconstriction, stimulates pituitary gland to secrete ADH - increased water reabsorption from the CD
Release stimulated by: renin (in response to low Na, low renal perfusion, beta stimulation)
Release inhibited by: ANP
Angiotensinogen
Polypeptide hormone
Production: Alpha2-globulin precursor of angiotensin, produced in the liver, kidney, adrenal glands, brain, heart, blood vessels and adipose tissues - converted to AT1 following catalytic cleavage by renin
Effects: vasoconstriction and regulation of blood pressure via RAAS
Release stimulated by: Renin
Release inhibited by: ANP
Anion Gap
([Na+]+[K+])-([Cl-]+[HCO3-])
4-12mmol
High anion gap - accumulation of organic acids or impaired H+ excretion
* CO, CN
* Alcoholic ketoacidosis or starvation ketoacidosis
* Toluene
* Metformin, Methanol
* Uraemia
* DKA
* Pyroglutamic acidosis, paracetamol, phenformin, propylene glycol, paraldehyde
* Iron, isoniazid
* Lactic acidosis
* Ethylene glycol
* Salicylates
Normal anion gap - loss of bicarbonate from ECF
* Chloride excess
* GI causes - D+V, fistulae (including ileostomy)
* Addisons
* TPN
* CA inhibitors
* Dilutional acidosis
* Renal tubular acidosis
Low anion gap
- Analytical errors (increase Na+, increased viscosity, iodide ingestion, increased lipids)
- Decrease in unmeasured anions (albumin, dilution)
- Increase in unmeasured cations (multiple myeloma, hypercalcaemia, hypermagnesaemia, lithium OD, polymixin B)
- Bromide OD (causes falsely elecated Cl measurements)
Anti-Diuretic Hormone (ADH)
Polypeptide hormone
Production: Hypothalamus - supraoptic nucleus
Secretion: Posterior pituitary
Site of action: Distal tubule and collecting ducts in the kidney, blood vessels
Effects: Water reabsorption in the kidney, arteriolar vasoconstriction, release of ACTH from anterior pituitarym synthesis of factor VIII
Release stimulated by: Increased osmolarity of extracellular fluid, pain, haemorrhage, stress, thirst, activation of the RAAS
Release inhibited by: Alcohol, reduced osmolarity of extracellular fluid
Metabolism: Degraded by the liver and excreted through the kidneys
Hypersecretion: SIADH
Hyposecretion: Cranial DI
Apnoeic Oxygenation
Apnoeic mass transfer of oxygenation in healthy people under ideal circumstances, can maintain PaO2 for up to 100 minutes without a single breath.
- O2 consumption remains fairly constant at 250ml/min
- 250ml/min of oxygen will move from the alveoli into the bloodstream
- only 8-20ml/minute of carbon dioxide moves into the alveoli, the remainder being buffered in the bloodstream
- net pressure in the alveoli becomes slightly subatmospheric, generating a mass flow of gas (240ml/minute) from pharynx to alveoli
- lack of ventilation will eventually cause marked hypercapnia and significant acidosis
- with nasal cannulae, the pharynx is filled with high FiO2 gas and functions as an oxygen reservoir
Factors influencing time of onset of critical hypoxia in apnoea
* FRC - decreased in obesity, lung disease, kyphoscoliosis, pregnancy, children - hypoxia more rapid
* Pre-oxygenation - denitrogenation greatly increases the time for hypoxia after apnoea
* Maintenance of patent airway
– closed airway, alveoli collapse quickly
– patent airway - allows oxygen to diffuse into the apnoeic lung
* Hb level - anaemia will cause a small reduction in time to critical hypoxia
* Basic metabolic demand - higher demand = quicker hypoxia
Arterial BP Waveform
3 distinct components to waveform
* systolic phase - anacrotic limb - rapid increase in pressure to a peak, followed by a rapid decline (begins with opening of aortic valve and corresponds to left ventricular ejection)
– systolic upstroke - ventricular ejection
– systolic peak pressure - maximum pressure in central arteries
– systolic decline - efflux of blood from central arterial compartment is faster than the influx of blood from the emptying left ventricle
* dicrotic notch (closure of aortic valve/vascular resistance of the peripheral vessels)
* diastolic phase - dicrotic limb (run-off of blood into the peripheral circulation
– diastolic fun-off
– end-diastolic pressure - pressure exerted by the vascular tree back upon the aortic valve
Information derived from the arterial pressure waveform:
* From the measurements
– HR
– systolic pressure - peak of wave
– diastolic pressure (coronary filling) - trough of wave
– MAP (systemic perfusion) - area under the pressure curve
– pulse pressure (high in AR, low in cardiac tamponade or cardiogenic shock) - difference between systolic and diastolic
– changes in amplitude associated with respiration (PPV)
– slope of anacrotic limb associated with AS
* From the waveform shape
– slope of anacrotic limb represents aortic valve and LVOT flow
– slurred wave in AS
– collapsing wave in AS
– rapid systolic decline in LVOTO
– bisferiens wave in HOCM
– low dicrotic notch in states with poor peripheral resistance
– position and quality of dicrotic notch as a reflection of the damping coefficient
Atrial Natriuretic Peptide
Polypeptide hormone
Production: atrial myocytes
Secretion: atrial myocytes
Site of action: apical ENaC and basolateral Na-K-ATPase in the collecting duct, afferent arterioles, vascular smooth muscle, adrenals, adipose tissue
Effects: increase sodium excretion and GFR, antagonize venal constriction, inhibit renin secretion and renal sympathetic system, reduces aldosterone secretion
Release stimulated by: increased stretching of the atria wall due to increased atrial blood volume, beta stimulation, hypernatraemia, endothelin
Release inhibited by: NO, cGMP and cAMP
Metabolism: neprilysin
Becks Triad
3 signs of cardiac tamponade
1. Hypotension
2. Elevated JVP
3. Muffled heart sounds
Body Compartments
- Total body water (TBW) = 0.6/kg
- Intracellular fluid (ICF) = 0.4/kg
—> Levels higher than in plasma —> K+, Mg2+, HPO4-, Sulphate-, proteinate- - Extra cellular fluid (ECF) = 0.2/kg
- Interstitial fluid (ISF) = 0.15/kg (=3/4 of ECF)
- Intravascular fluid (IVF)/Plasma = 0.05/kg (=1/4 of ECF)
—> Levels higher than in ECF —> Na+, Ca2+, Cl-, HCO3- - Transcellular fluid
Brain Natriuretic Peptide
Polypeptide hormone
Production: Cardiomyoctes in the ventricles
Secretion: Cardiomyocytes
Site of action: ANP receptors (to a lesser degree than ANP) - apical ENaC and basolateral Na-K-ATPase in the collecting duct, afferent arterioles, vascular smooth muscle, adrenals, adipose tissue
Effects: increase sodium excretion and GFR, antagonize venal constriction, inhibit renin secretion and renal sympathetic system, reduces aldosterone secretion
Release stimulated by: increased stretching of the atria wall due to increased atrial blood volume, beta stimulation, hypernatraemia, endothelin
Release inhibited by: NO, cGMP and cAMP
Metabolism: neprilysin
Breathing Cycle
Rest - no air movement in/out of lungs due to absence of pressure gradient. Diaphragm is relaxed.
Inspiration - active process. Diaphragm contracts (innervated by phrenic nerve) –> moves downwards
External intercostal muscles contract (innervated by intercostal nerves) –> elevate ribs outwards and upwards
Thoracic cavity enlarges, increasing lung volume and generating negative pressure in lungs
pressure gradient causes air to flow into lungs
Expiration - passive process.
Elastic forces of lungs compress alveolar air volume
Pressure in lungs increases causing air to flow out of lungs
Diaphragm and external intercostal muscles relax –> decreasing thoracic cavity size –> decreased lung volume –> increased pressure in lungs
Buffers
- mixture of a weak acid and the salt of it’s conjugate base
- resists change in pH when acid or base is added
- efficacy determined by pKa of buffer, pH of solution, amount of buffer and whether it is an open or closed system
- bicarbonate/carbonic acid (pK 6.1) - most important ECF buffer system
— bicarbonate formed in erythrocyte and secreted into plasma
— bicarbonate diffuses into interstitium and is dominant fluid buffer in interstitial space
HCO3- + H+ -> H2CO3 —> CO2 + H2O (catalysed by carbonic anhydrase) - phosphate (pK 6.8)
HPO42+ + H+ —> H2PO4+
H2PO4+ + OH —> HPO42+ + H2O - plasma protein (pK 7.3)
— imidazole groups of histidine buffer at physiological pH in the intracellular space e.g. albumin contains 16 histidines - haemoglobin
— each molecule contains 38 histidine residues
— Hb exists as a weak acid as well as its potassium salt - ammonia
NH3 + H+ —> NH4+
Buffer Systems
* Extracellular fluid
— bicarbonate/CO2
— inorganic phosphate
— plasma proteins
* Intracellular fluid
— cell proteins e.g. Hb
— organic phosphates
— bicarbonate/CO2
* Bone
— mineral phosphates
— mineral carbonates
* Urine
— phosphate
— ammonia
* Blood
— bicarbonate
— haemoglobin
— proteins
* CSF
Calcium
- Normal range 2.2-2.6mmol/L (50% unionised, 40% protein bound, 10% unionised but combined with anions)
- 99% bone
- 1% intracellular fluid
- 0.1% extra cellular fluid
0.2mmol/kg required per day
Functions
- bone formation and metabolism (contributes to strength and structure)
- strong cation in acid-base balance
- coagulation of blood (cofactor in coagulation pathway
- cellular functions
— excitation-contract coupling in cardiac, skeletal and smooth muscle
— cardiac action potentials and pacemaker activity
— regulation of cell growth and apoptosis
— cofactor for many enzymes (e.g. lipase) and proteins 9calmodulin)
— membrane integrity and permeability
— ciliary motility
- cellular communication
— intracellular secondary messenger systems
— secretory processes including release of neurotransmitters and hormone release
— catecholamine responsiveness
Homeostasis
High blood Ca level —> stimulates thyroid to release calcitonin
—> simulates calcium deposition in bones by inhibiting osteoclast activity
—> reduces calcium reabsorption by kidneys
—> reduces calcium uptake in intestines
Low blood Ca level —> stimulates parathyroid glands to release PTH
—> increases calcium uptake in kidneys and from the intestines via vitamin D synthesis
—> stimulates calcium release from bones by promoting osteoclast activity
Carbonic Anhydrase
- Enzymes that catalyse interconversion of CO2 and H2O and the dissociated ions of carbonic acid
- CO2 + H2O ⟶ H2CO3 ⟶ H+ + HCO3-
- Active site of most carbonic anhydrases contains low molecular weight zinc
- 11 known isoenzymes found in humans in different locations
Role
* maintains acid-base homeostasis
* regulation of pH (buffering)
* regulation of fluid balance
* transport of CO2
Locations
- RBCs- converts CO2 gas to ions that can travel to the lungs to be breathed out
- gastric mucosa of the stomach –> assists with formation of HCl used in digestion
- pancreatic cells - pH balance in digestion to make secretions alkaline
- kidneys - reabsorption of bicarbonate ions from the renal tubules to acidify the urine and reduce high acid levels
- saliva - pH balance to make saliva neutral
- eyes - regulation of aqueous humour produced by the epithelium of the ciliary body
Cerebral Autoregulation
A homeostatic process that regulates and maintains cerebral blood flow constant and matched to cerebral metabolic demand across a range of blood pressures - usually a CPP 50-150 in the normotensive population. Also affected by PaCO2 and PaO2.
Cerebral blood flow (50ml/100g/min or 14% of CO) is supplied by the carotid (70%) and vertebral (30%) arteries.
Cerebral perfusion pressure = MAP - (ICP or CVP whichever is higher)
Metabolic Theory
A negative feedback system based on the use of vasoactive substances in order to balance blood flow to its demand.
Myogenic Theory
Vascular smooth muscle in arterioles detects BP changes and adjusts the calibre of its vessels to maintain constant flow.
Neurogenic Theory
Vascular smooth muscle actuators in the resistnace arterioles are controlled via sympathetic innervation, receiving the input from the appopriate brainstem autonomous control centre. NO released by parasympathetic fibres may also play a role.
Chloride
- Major Extracellular anion
- Daily requirement 1.0-2.0mmol/kg/day
- Important for osmolality and acid-base balance
- Found in a 1:1 ratio with sodium
- Freely filtered by the glomeruli
- Over 60% of chloride is absorbed along the proximal tubule
- PCT - as other ions move out of the filtrate, the chloride concentration increases, allowing it to be absorbed back into the blood down it’s concentration gradient
— early PCT - chloride absorption also occurs via apical chloride-anion exchanges
— exits cell via basolateral membrane transporters - Thick ascending limb of LOH - NKCC2 - chloride is reabsorbed
- DCT - sodium-chloride co-transporter transports the ions from the lumen into the cell (gradient maintained by Na-K-ATPase)
- CD - paracellular chloride absorption driven by lumen negative transepithelial potential generated by sodium flow through ENaC
— also transported via a chloride-bicarbonate exchanger - CNS - inhibitory action of glycine and some of the action of GABA relies on the entry of Cl- into specific neurones
- Cl/HCO3 exchanger biological transport protein relies on chloride to increase the blood’s capacity of CO2, in the form of bicarbonate (chloride shift)
- GI - major contributor to stomach acidity
- Responsible for maintenance of the GI osmotic gradient and fluid secretion
Classification and causes of pulmonary hypertension
Class 1: disease of the pulmonary arterial vasculature/Pulmonary artery hypertension
* Idiopathic
* Heritable
* Drugs/toxins
* Others: CTDs, portal hypertension, congenital heart disease
Class 2: attributable to left heart disease
* LV systolic/diastolic dysfunction
* Valvular heart disease
* Congenital heart disease
Class 3: attributable to lung disease and/or hypoxia
* COPD
* ILD
* Sleep-disordered breathing
* Chronic high altitude
Class 4: due to pulmonary artery obstruction
* Chronic thromboembolic pulmonary hypertension (CTEPH)
* Other pulmonary artery obstructions e.g. angiosarcoma
Class 5: unclear or multifactorial mechanisms
* Haematological e.g. myeloproliferative disorders
* Systemic e.g. sarcoidosis
* Metabolic disorders
Classify Pain
By chronicity
* Acute - recent onset, limited duration, identifiable cause e.g. injury/disease process
* Chronic - persists beyond time of injury, or no clearly definable cause
By nature
* Nociceptive - response to noxious stimulant of nocicptors
— superficial somatic - skin
— deep somatic — ligaments/muscles
— visceral —organs
* Neuropathic - due to dysfunction of the nervous system
Carbon Dioxide
The body contains approximately 120L of CO2.
CO2 Production
* produced by cell metabolism in the mitochondria
* dependent on rate of metabolism and relative amounts of carbohydrate, fat and protein metabolised
* approx 200ml/min when at rest and eating a mixed diet –> utilises 80% of O2 consumed (RQ 0.8 - carb diet 1.0 and fat diet 0.7)
CO2 Transport
1. Dissolved as gas in plasma (7-10%)
- 20x more soluble than O2 (Henry’s Law)
2. Bound to haemoglobin and other plasma proteins as carbamino compounds (20%)
- CO2 binds readily with Hb at a lower partial pressure than oxygen
- Hb carries less than 1/4 of the amount of CO2 compared with O2
3. Present as bicarbonate ion in plasma and transported as bicarbonate (70%)
- CO2 + H2O –> H2CO3 –> HCO3- + H+ (catalysed by carbonic anhydrase)
- CO2/H2O/HCO3 readily pass through cell membranes but H+ can’t
- Chloride shift occurs with exchange of Cl ions into the cell as HCO3 diffuses out
- H+ ions bind easily to reduced Hb
Control of Breathing
Inputs
- central chemoreceptors - ventral medulla - stimulated by fall in CSF pH (indirect response to changes in arterial PaCO2)
- peripheral chemoreceptors - carotid (CN IX) and aortic (CN X) bodies stimulated by low PaO2, high PaCO2 and acidemia
- mechanoreceptors - stretch receptors in bronchial muscle stimulated by overinflation and stimulate the apneustic centre to reduce inspiratory volumes (Hering-Breuer reflex)
- other effects - juxtacapillary receptors in alveolar walls, irritant receptors, pain receptors, thalamus (temperature), limbic system (emotional response), cerebral cortex (conscious control of breathing), muscle spindles
Integration and control centres
- dorsal respiraory group in the medulla –> controls the diaphragm (inspiratory)
- ventral respiratory group in the medulla –> controls the intercostal muscles (inspiratory and expiratory)
- apneustic centre in the lower pons - modulates DRG function to prevent overexpansion
- pneumotaxic centre in the pons –> also modulates DRG, increasing RR and decreasing VT to maintain MV (fine-tuning inspiration)
Effectors
- diaphragm
- intercostal muscles
- abdominal muscles
- accessory muscles - sternocleidomastoid
Coronary Autoregulation
Capacity of the heart to maintain steady myocardial perfusion across a range of perfusion pressures.
Coronary blood flow (250ml/min or 5% of CO) remains constant between MAP 60-140 - beyond this range, flow becomes pressure-dependent.
Metabolic theory - vasodilatation in the presence of increased metabolic substances e.g. pCO2, pO2, H+, K+, adenosine
Myogenic theory - alteration in caliber of vessel when stretch/relaxation is detected
Neural - response to ACh (vasodilation of intact endothelium) or NAd (sympathetic stimulation increasing blood flow)
Humoral - vasoactive hormones can cause endothelium mediated vasodilation or constriction (e.g. angiotensin II vasoconstricts and releases endothelin which also constricts; ACE inactivates bradykinin which is a vasodilator)
Corticotropin-releasing Hormone
Polypeptide hormone
Production: Hypothalamus (paraventricular nucleus), T lymphocytes, placenta
Secretion: Neurosecretrory terminals into the primary capillary plexus of the hypothalamo-hypophyseal portal system
Site of action: Anterior pituitary
Effects: Stimulates synthesis of ACTH and beta endorphin
Release stimulated by: Stress
Release inhibited by: Glucocorticoids provide a negative feedback loop
Cortisol
Glucocorticoid steroid hormone
Production: Adrenal cortex - zona fasciculata (from cholesterol)
Secretion: Adrenal cortex
Site of action: Liver, kidneys, small intestine, adipose tissue
Effects: Stimulation of gluconeogenesis. Inhibition of glucose uptake. Mobilisation of amino acids from extrahepatic tissues. Stimulation of fat breakdown in adipose tissue. Anti-inflammatory and immunosuppressive
Release stimulated by: ACTH, cytokines, exercise, stress, trauma, ghrelin
Release inhibited by: raised cortisol inhibits release of ACTH and CRH
Metabolism: liver and kidney
Hypersecretion: Cushing’s syndrome
Hyposecretion: Addison’s Disease
CSF Production and Circulation
Production - continuously in the choroid plexus (covers two lateral ventricles, roof of 3rd and 4th ventricles), ~500ml/day (around 150ml present in the body at any given time
Circulation - lateral ventricle –> third ventricle via foramen of Munro–> fourth ventricle via aquaduct of sylvius –> subarachnoid space and central canal via foramina of Luschka and Magendie –> arachnoid granulations in dural venous sinuses
Functions of CSF
* Buoyancy - reduced net weight of brain, preventing excessive pressure on the base of the brain
* Protection - limits neural damage in cranial injuries
* Homeostasis - buffering, maintain low extracellular K+ for synaptic transmission
* Waste clearance - from brain cells
Cushing’s Triad/Reflex/Reaction
- Systolic hypertension (widened pulse pressure
- Bradycardia
- Respiratory depression (irregular, decreased respirations)
Combination of activation of both the sympathetic and parasympathetic nervous system in response to cerebral ischaemia. The body induces hypertension in an attempt to restore cerebral blood flow. Baroreceptors detect the increase in BP and trigger a parasympathetic response via the vagus nerve, inducing bradycardia.
Cyclic Adenosine-mono-phosphate (cAMP)
- Second messenger role in regulating cardiac muscle contraction - increases contractility, heart rate and conduction velocity
- Important role in regulating contraction of vascular smooth muscle - causes smooth muscle relaxation
- Regulation of glycogen, sugar and lipid metabolisms
- Synthesised from ATP via adenylyl cyclase (in the presence of magnesium ions) in response to catecholamines binding to b1 and b2-adrenoceptors (coupled to Gs-proteins)
- Inhibited by agonists of adenylate cyclase inhibitory Gi-protein couple receptors
- Activates protein kinase A
– stimulates calcium ion movement across the sarcolemma and sarcoplasmic reticulum via activation of ion channels
– phosphorylation of contactile and regulatory proteins - allowing them to act on ion channels or become inhibited - Degraded by phosphodiesterase (PDE-3) into AMP
CYP2D6
Substrates
tricyclic antidepressants, beta-blockers, chlorphenamine, opioids, SSRIs/SNRIs, flecainide, , haloperidol, promethazine, risperidone, tamoxifen, tolterodine
Inhibitors - decrease efficacy of drugs that require transformation by CYP2D6 to their active metabolites and increase levels of drugs that are eliminated by CYP2D6 metabolism
amiodarone, bupropion, chloroquine, cinacalcet, fluoxetine, haloperidol, imatinib, protease inhibitors, paroxetine, quinidine, systemic terbinafine
Inducers
not very susceptible to enzyme induction
CYP3A4
- Responsible for the metabolism of >50% of medicines
- Activity is absent in newborns - reaches adult level around 1yr of age
- Considerable variability of activity in the population
- Women have higher CYP3A4 activity than men
Inhibitors - decrease efficacy of drugs that require transformation by CYP3A4 to their active metabolites and increase levels of drugs that are eliminated by CYP3A4 metabolism
Macrolides, Ca channel blockers, anti-fungals, protease inhibitors, RT inhibitors, mifepristone, grapefruit juice, cimetidine, goldenseal
Inducers - increase efficacy of drugs that require transformation by CYP3A4 to their active metabolites and decrease levels of drugs that are eliminated by CYP3A4 metabolism
Anti-epileptics, rifampicin, glucocorticoids, modafilin, st john’s worts
Cytokines
Pro-inflammatory
* IL-1, IL-6, IL-12, IL-18
* TNF alpha
* Interferon gamma
* GM-CSF
Anti-inflammatory
* IL-10, IL-11, IL-13, IL-1ra
* TGF beta
* STNF-R
Dopamine
Amine hormone
Production: Neurons (predominantly substantia nigra), medulla of adrenals, from L-DOPA (from tyrosine or phenylalanine)
Secretion: Stored in synaptic vesicles until it is ejected via exocytosis
Site of action: Dopamine receptors throughout the body - postsynaptic dopamine receptors on dendrites or presynaptic autoreceptors on the membrane of the axon terminal
Effects: Regulation of cellular cAMP levels, prolactin antagonist, increase blood flow, GFR, natriuresis and diuresis in the kidney, inhibits renin release, facilitates vasopressin release, renal vasodilation
Release stimulated by: activites that make you feel good
Release inhibited by: dopamine through D2 autoreceptors
Metabolism: MAO, COMT and aldehyde dehydrogenase
Hypersecretion: ?schizophrenia
Hyposecretion: Parkinson’s Disease
Dopamine Pathway
Dopamine is a neurotransmitter of the catecholamine family and is formed by removing a carboxyl group from a molecule of L-DOPA
Phenylalanine
↓
(Phenylalanine hydroxylase)
↓
L-Tyrosine
↓
(Tyrosine hydroxylase - rate limiting step)
↓
L-DOPA
↓
(DOPA decarboxylase)
↓
Dopamine
↓
(Dopamine beta-hydroxylase)
↓
Noradrenaline
↓
(Phenylethanolamine N-methyltransferase)
↓
Adrenaline
Metabolised by Catechol-O-Methyltransferase (COMT) and Monoamine Oxidase (MAOs)
Drug Targets
- G protein coupled receptors - act via 2nd messengers e.g. opioid, adrenoceptor
- Ion channel receptors
–ligand gated e.g. nACH, 5HT3, NMBD, ketamine
–voltage gated e.g. RYR1 receptor
–other e.g. aquaporins - Nuclear hormone receptors aka steroid receptors aka intracellular receptors - act via gene transcription e.g. thyroid, oestrogen
- Kinases - act via phosphorylation e.g. tyrosine kinase (insulin)
- Enzymes e.g. COX-1 (aspirin), CA inhibitors (acetazolamide)
- Catalytic receptors e.g. GP2b3a
Drugs displaying zero order kinetics
First order kinetics - when a constant proportion of drug is eliminated per unit time. T1/2 is fixed - for every half life that passes the drug concentration is halved. Most drugs are eliminated this way. Elimination mechanisms are NOT saturable.
Zero order kinetics - when a constant amount of drug is eliminated per unit time. The rate of elimination is constant and is independent of the total drug concentration in the plasma. T1/2 is not constant - the higher the concentration, the longer the t1/2. Few drugs are eliminated this way although many will show zero order kinetics at high, or toxic, concentrations. Elimination mechanisms (enzymes or transporters) ARE saturable.
Examples
- ethanol
- phenytoin
- salicylates (at high doses)
- theophyllines
- thiopentone
- warfarin
Drugs excreted predominantly unchanged in the urine
Drug metabolism is defined as the biotransformation of lipid-soluble chemicals into water-soluble forms, so that they can be excreted in the urine.
Metabolism is divided into two phases - drugs may undergo one phase only, or may be metabolised through both phases sequentially.
Phase I reactions - introduction into or unveiling or a polar functional group on the drug molecule –> renders it a suitable substrate for conjudation with another molecule during phase II metabolism.
- oxidation
- reduction
- hydrolysis
Involve CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 in more than 90% of drugs undergoing phase I metabolism.
If high aqueous solubility is achieved, the derivative from phase I metabolism may be excreted via the urine immediately.
Phase II reactions - conjugation of the functional groups of a drug molecule to various hydrophilic endogenous compounds –> renders them sufficiently water soluble to facilitate renal secretion of .
May insert a large polar substrate to the molecule to make it more amenable for active secretion into the bile and subsequent excretion into the GI tract.
Drugs that do not undergo phase I or II metabolism and are excreted predominantly unchanged in urine include:
* aminoglycosides
* cephalosporins
* ephedrine
* digoxin
* lithium
* milrinone
* mannitol
* neostigmine
* oxytetracycline
* penicillins
* glycopeptides
Doses of these drugs may required adjustment in the event of renal impairment.
Duty of Candour
Every health and care professional must be open and honest with patients and people in their care when something that goes wrong with their treatment or care causes, or has the potential to cause harm or distress.
This means that health and care professionals must:
* tell the person when something has gone wrong
* apologise to the person
* offer an appropriate remedy or support to put matters right (if possible)
* explain fully to the person the short and long terms effects of what has happened
Ethical Duty
- low threshold for notification - any harm or distress to patients
- ethical duty to tell patients when things have gone wrong, apologise and try to put things right
Statutory Duty
- higher threshold for notification, includes prolonged psychological harm to patient
- duty applies to organisations rather than indiciduals
- patients shoud be told of a “notifiable safety incident” as soon as is practical
- NHS body definition - something unintended or unexpected in the patients care that, in the reasonable opinion of a healthcare professional, could result in or appears to have resulted in their death or them uffering severe or moderate harm, or prolonged psychological harm
- The organisation has to explain to the patient what’s known at the time, what further enquiries will be made, offer an apology and keep a written record of the notification to the patient. Failure to do so could be a criminal offence.
- The patient should be given reasonable support - practical or emotional
- The patient must get written notes of the initial discussion and of the notification, including details of further enquiries, their results and an apology. The organisation needs to keep copies of all correspondance.
Severe harm - a permanent lessening of bodily, sensory, motor, physiologic or intellectual functions, directly related to the incident
Moderate harm - needing a moderate increase in treatment, and significant, but not permanent, harm
Endothelin
Polypeptide hormone
Production: Vascular endothelial cells
Site of action: pituitary, vascular endothelium, heart, lungs, kidney, brain
Effects: smooth muscle contraction of medium sized cells, roles in cell survival, angiogenesis, bone growth, nociceptor function
Release stimulated by: angiotensin II, ADH, thrombin, cytokines, reactive oxygen species, shearing forces on vascular endothelium
Release inhibited by: NO, NO donor drugs, dilator prostanoids
Metabolism: predominantly pulmonary uptake, kidneys and liver
Hypersecretion: high blood pressure, heart disease
Enkephalin
Polypeptide hormone
Production: Brain, adrenal medulla (chromaffin cells)
Site of action: Opioid receptors - delta and mu
Effects: regulation of nociception
Release stimulated by: Pain
Erythropoietin
Polypeptide hormone
Production: Extraglomerular mesangial cells of the kidney, liver, pericytes in brain
Site of action: bone marrow
Effects: stimulates red blood cell production
Release stimulated by: Cellular hypoxia
Release inhibited by: Hb and iron levels
Hypersecretion: High altitude, polycythaemia
Hyposecretion: CKD
Exponential Processes
- The rate of change of quantity of a substance is directly proportional to the quantity of the substance present at that time
- Asymptote - a curve/line that constantly approaches but does not reach another line/curve (taken to be “complete” after 5 half lives or 3 time constants)
- The absolute amount varies, with a constant percentage
- Rate depends on the concentration
- Examples of exponential decay include nitrogen washout in pre-oxygenation, lung volumes during spontaneous expiration, drug wash-out, radioactive decay
- Examples of exponential growth include bacterial growth, drug wash-in, lung volumes during PCV
Factors affecting cerebral blood flow
Normal cerebral blood flow is 50ml/100g/minute. This is influenced by:
* cerebral metabolism (cerebral metabolic rate for oxygen is normally 3.5ml/100g/min) - increased by pyrexia, seizures; reduced by hypothermia, anaesthesia
* carbon dioxide - linear relationship between PaCO2 and CBF between 2.7 and 10.6kPa - mediated by pH of extracellular fluid surrounding central vasculature
* oxygen - hyperoxia has little effect, hypoxia (<6.7kPa) causes rapidly progressive increase in CBF
* autoregulation - CBF constant over the CPP range 50-150mmHg - myogenic mechanism, metabolic theory. Lower limit represents maximal vasodilatation, upper limit represents maximal vasoconstriction above which the BBB is disrupted, with oedema and ischaemia
* autonomic nervous system - more for anterior circulation than posterior via superior cervical ganglion for SNS and sphenopalatine and optic ganglia for PNS, sensory fibres from trigeminal. SNS contributes to vasoconstriction, protects brain in hypotension. PNS contributes to vasodilations, maximal in post ischaemic reperfusion and hypotension.
* blood viscosity - balance between reduced Hct improving blood flow and oxygen carrying capacity - 30% optimal
In a patient with a head injury, reduced MAP, increased ICP or both compromise cerebral blood flow.
Factors affecting choroidal blood volume
The choroid supplies the outer retina with nutrients, and maintains the temperature and volume of the eye.
The choroidal circulation is a high flow system with relatively low oxygen content - it accounts for 85% of the total blood flow in the eye.
The choroid circulation is controlled mainly by sympathetic innervation and not autoregulated.
- arterial PaCO2
- hypoxaemia
- vasodilatation
- venous pressure - cough/prone etc
- transient rise with acute increase in systolic BP
Factors affecting hepatic blood flow
Blood supply
* 25% of CO - 1200ml/min (100ml/100g/min), oxygen consumption 6ml/100g/min
* from hepatic artery (branch of coeliac trunk) - high pressure, high resistance, less of blood flow but higher oxygen saturations
* from portal vein (confluence of mesenteric and splenic veins) - low pressure, low resistance, 70% of total blood flow, lower oxygen saturations
Hepatic Blood Flow Regulation
* portal venous flow regulation - mainly determined by splanchnic arterial flow rate
* portal resistance changes in response to humoral signals (e.g. catecholamines) in shock and local endocrine signals (e.g. VIP) causing vasodilation following a meal
* standard arterial regulatory mechanisms of controlling hepatic arterial flow
– myogenic
– flow (shear)-mediated
– conducted vasomotor responses
– immunologically mediated by inflammatory molecules
* hepatic arterial buffer response - hepatic arterial flow increases if portal venous flow decreases, and vice versa
* external factors
– venous return e.g. during PPV/HF - impairs hepatic venous draining
– CO - influences hepatic arterial flow directly and portal flow indirectly
– shock states and exercise - decrease splanchnic blood flow
Factors affecting intraocular pressure
Normal IOP is 11-21mmHg with cyclic fluctuations of 2-3mmHg throughout the day. IOP >24mmHg is considered pathologic.
Intraocular contents
- choroidal blood volume
- aqueous humour volume - balance between production and outflow rate
- vitreous humour volume
Scleral rigidity
- severe myopia
- old age
External pressure
- direct pressure
- retrobulbar haematoma
- extrinsic muscles
- venous congestion e.g. prone/steep trendelenberg positioning
Anaesthetic management
- regional anaesthesia contraindicated for penetrating eye injury (LA increasing IOP + distorted anatomy) unless vision not salvagable
- drugs usually decrease IOP (apart from sux but only very transiently increases it)
- avoid ketamine due to possibility of nystagmus/blepharospasm affecting surgical conditions
- avoid N2O if plan for gas injection/recent gas injection/other injuries of concern
- minimise repsonse to laryngoscopy - ?VL
- if AFOI required - sedation ++, generous topic anaesthesia
- ETT>LMA (limited access to airway and controlled ventilation preferable despite lower sympathetic response and lower increase in IOP with LMA)
- smooth emergence to avoid cough - ensure fully reversed etc, deep extubation if appropriate
- antiemetics, consider TIVA for high risk PONV
- avoid hypotension - arterial line monitoring?
Factors affecting jugular venous oxygen saturation
SjvO2 gives an assessment of global oxygenation and the adequacy of cerebral blood flow.
A catheter is inserted by retrograde cannulation of the internal jugular vein and advanced into the jugular bulb on the side of worst pathology or on the dominant side for venous drainage. The catheter tip should lie level with the C1/C2 disc in order to avoid error from admixture with extracranial blood.
Measurements can be taken intermittently using serial sampling or continuous measurement is possible with spectrophotometric catheters.
SjvO2 reflects the balance between the oxygen supply (CBF, SpO2) and demand.
Normal SjvO2 is between 55-75%.
Low SjvO2 = hypoperfusion with oxygen demand exceeding supply/cerebral ischaemia
* reduction in oxygen delivery
– raised ICP
– reduced CBF
– hypoxia
– profound hypocarbia
* increased cerebral oxygen demand
– seizures
– pyrexia
High SjvO2 = hyperaemia or reduced metabolic demand
* reduction in cerebral oxygen consumption
– coma
– hypothermia
– cerebral infarction
* increased oxygen delivery
– hypercapnia
– vasodilatation
Complications of it’s use include:
* errors in values
* positioning problems
* poor sampling technique
* subclinical thrombosis or clot formation on the catheter
* those associated with central venous cannulation
Factors affecting LA Toxicity
Site of injection
* Surface area
* Vascularity
* Location IV > tracheal > intercostal > caudal epidural > paracervical > lumbar epidural > brachial plexus > sciatic/femoral > subcutaneous
* Intra-vascular injection
Drug
* Choice of LA
bupivicaine > L-bupivicaeine > ropivicaine > mepivicaine > lidocaine
* LA dose
* Vasoactivity +/- vasoconstriction
Patient Factors
* Age - elderly, neonates have less a1-acid glycoprotein therefore an increase in unbound LA, as well as reduced clearance compared to adults
* Genetics
* Cardiac pathology - reduced volume of distribution and clearance
* Liver failure - reduced plasma clearance and prolongation of half life
* Renal failure - increased absorption, accumulation of metabolites
* Pregnancy - reduced plasma protein binding, increased absorption due to high CO, increased sensitivity of cardiac and nervous tissue
* Drug interactions - amides are metabolized by CYP450 enzymes in the liver, esters are metabolised by plasma esterases therefore can be affected by drugs that alter plasma esterase activity
* Acidosis
* Peripheral vasoconstriction
* Hyperdynamic circulation
* Hypoxia
* Hypercarbia
Factors affecting lung compliance
Classified into chest wall, lung or total lung compliance.
Lung compliance - increased
- lung surfactant
- lung volume: compliance is at its highest at FRCA
- posture (supine, upright)
- loss of lung connective tissue associated with age
Static lung compliance - decreased
- loss of surfactant (ARDS)
- decreased lung elasticity e.g. fibrosis, oedema
- decreased functional lung volume e.g. pneumonectomy or lobectomy, pneumonia, atelectasis, small stature
- alveolar derecruitment
- alveolar overdistension
Dynamic lung compliance - decreased
- increased airway resistance e.g. asthma
- increased airflow e.g. increased RR
Chest wall compliance - increased
- EDS and other connective tissue diseases associated with increased elasticity
- rib resection
- cachexia
- flail segment, rib fractures
- open chest e.g. clamshell
Chest wall compliance - decreased
- structural abnormalities - kyphosis/scoliosis, pectus excavatum, circumferential burns, surgical rib fixation
- functional abnormalities - seizure, tetanus
- extrathoracic influences on chest/diaphragmatic excursion - obesity, abdominal compartment syndrome, prone position, pregnancy
Physiological
- posture - lungs are more compliant when upright than supine
- age - compliance is reduced at extremes of age
- pregnancy - less compliant lungs, reduced FRC
Factors affecting onset of a LA block
Drug
- pKa (less basic pKa = faster onset due to greater proportion of unionised form)
- lipid solubility (increased lipid solubility allows more rapid diffusion and greater Vd, alsoaffects potency)
- protein binding (increased binding –> longer duration)
- chirality
- molecular weight (smaller molecules diffuse through membranes faster)
- vasoactivity - (more rapid absorption after lidocaine compared to bupivicaine)
- adjuvants
- dose used (concentration/volume)
Type of block
- proximity to nerve (diffusion through tissue to reach nerves delays onset of block)
- type and size of nerve fibres - smaller diameter, unmyelinated nerves affected first (C fibres > A-a)
Tissue factors
- pH of tissue - inflamed or infected tissue is more acidemic, reducing the unionised amount of drug
Factors affecting onset of inhalational anaesthesia
Alveolar concentration of agent
- inspired concentration - FGF, breathing system volume, circuit absorption
- alveolar ventilation (MV) - increased dead space will prolong induction
- FRC - large FRC dilutes amount of agent inspired with each breath
- second gas effect - use of N2O concentrates the gas in the alveoli, increasing the pressure gradient driving diffusion into the blood
Drug uptake from the lungs
- blood:gas partition coefficient - agents with a low coefficient reach equilibrium more rapidly - affected by temperature, Hct
- alveolar blood flow - rate of onset reduced when alveolar blood flow is high due to reduction in concentration of agent in alveoli - affected by CO and shunt
- alveolar-venous partial pressure gradient - dependent on tissue blood flow, blood:tissue solubility coefficients
Factors affecting Oxygen Demand
Increased demand
* fever
* pain
* agitation
* shivering
* hyperdynamic state
Decreased demand
* hypothermia
* anaesthesia/analgesia
Factors affecting Oxygen Supply
Increased supply
* hyperoxygenation
* augmented cardiac output
* mild peripheral acidosis
Decreased supply
* hypothermia
* anaemia
* profound alkalosis
Factors affecting seizure threshold
- Medications
- Sleep deprivation
- Illicit drug use
- Malnutrition
- Uncontrolled diabetes
- Withdrawal
- Fever
- Fasting/starvation
- Menstruation
- Photic triggers
Drugs that lower seizure threshold include:
* opioids e.g. pethidine, tramadol
* chemotherapeutic agents
* antimicrobials e.g. carbapenems, cephalosporins, quinolones
* hypoglycaemic agents
* immunosuppressants
* psychiatric medications
* other - aminophylline, stimulants, phenylephrine
Factors affecting vapouriser output
- Proportion of gas passing through vaporising chamber (use of bypass)
- Efficiency of vaporisation (surface area available - use of wicks/baffles)
- Temperature (increased output with increased temperature)
- Time (reduced output with increased time due to cooling associated with vaporisation)
- Gas flow rate (at high flow rates, gas leaving the chamber will be less saturated)
- Carrier gas composition (changes in viscosity and density of the gas mixture)
- Ambient pressure (if ambient pressure reduced, output concentration rises)
Factors affection myocardial oxygen supply
Coronary blood flow
* coronary perfusion pressure - aortic diastolic blood pressure and ventricular end-diastolic blood pressure
* perfusion time (heart rate –> diastolic time)
* vessel patency and diameter
* blood viscosity
Arterial oxygen content
* CaO2 = [Hb x sats x 1.34] + [PaO2 x ).023]
Oxygen consumption by heart
* HR
* Contractility
* Temperature
* Ventricular wall tension - preload and afterload
* Tissue mass
Factors shifting the OxyHb Dissociation Curve
Left shift of the curve = increased oxygen affinity, thereby decreasing oxygen delivery to the tissues
* alkalaemia
* hypothermia
* decreased 2,3-DPG
* fetal Hb
* methaemoglobinaemia
* carboxyhaemoglobinaemia
* high oxygen affinity Hb variants
Right shift of the curve = decreased oxygen affinity, thereby increasing oxygen delivery to the tissues
* acidaemia
* hypercarbia
* pyrexia
* increased 2,3-DPG
* low oxygen affinity Hb variants eg. sickle Hb
* sulfhaemoglobin
* chronic iron deficiency anaemia
Factors that Affect Hypoxic Pulmonary Vasoconstriction
Inhibition
* COPD
* pregnancy
* alkalaemia
* haemodilution
* cirrhosis
* female gender
* hypocapnia
* sepsis
* exercise
* hypothermia
* drugs: N2O, verapamil, hydralazine, GTN, halothane, nitroprusside, ACEI
Promotion
* Hypertension
* lung retraction
* acidaemia
* hypercapnia
* pyrexia
* lateral positioning
* epidural
* iron deficiency
* drugs: phenylephrine, noradrenaline
No effect
* supine positioning
* drugs: NO, iso/sevo/desflurane, ketamine, opioids, diltiazem, sildenafil, dopamine
Factors which affect minimal alveolar concentration (MAC)
MAC is a measure of potency - the EC50 of an agent, where the outcome is movement in response to surgical stimulation. The SD is 0.1 - so 95% of patients will not move in response to a stimulus at 1.2 MAC.
MAC is inversely proportional to potency - more potent agents require smaller alveolar concentrations to produce anaesthesia.
MAC is estimated clinically using end-tidal gas measurement - it is not based on arterial partial pressure of an agent therefore can be inaccurate where there is VQ mismatch in particular.
Factors which decrease MAC
- age (~6% every 10yrs older) and neonates
- hypothermia
- hypocapnea
- hyponatraemia
- hypothyroidism
- acute alcohol and other CNS depressant intoxication
- chronic amphetamine intake
- hypovolaemia/hypotension
- lithium
- hypoxia
- anaemia
- pregnancy
- N2O/IV anaesthetics/benzos/opioids
Factors which increase MAC
- youth
- hyperthermia
- hypercapnoea
- hypernatraemia
- hyperthyroidism
- chronic ETOH and CNS depressant abuse
- acute amphetamine intake
- SNS activation and anxiety
- increased atmospheric pressure
- red hair
Filters
Epidural filter
* disc shaped with hydrophilic supported membrane
* filter pore size usually 0.22 microns
* filters viruses, bacteria and foreign bodies
HMEF
* hygroscopic membrane pleated to decrease the dead space
* mechanical or electrostatic filters
* 0.2 microns pore size
* 60-70% humidity
* adds up to 100mls dead space
* can increase PEEP
Filter needles
* prevent particular and organism contamination
* 0.2 microns
Fluid filter
* 15 microns to prevent particularte contamination
Blood filter
* whole blood - 170-250 microns
* 70-80% leucocyte depleted - 20-50 microns
* electrostatic filters - 100% leucodepletion
Filters used in renal haemofiltration
Forming a Clot
Initiation
* on a tissue factor bearing cell
* damage to endothelium exposes TF and vWF
* vWF binds to platelets through the GP1b receptor
* platelet membrane provides phospholipid surface on which coagulation factors are active
* TF binds to circulating factor VII and activating it, catalysing conversion of FIX → FIXa and FX → FXa
Amplification
* platelets and co-factors are activated in order to prepare for large-scale thrombin generation
* FXa catalyses small amounts of IIa from II
* thrombin (IIa) binds to GP1b receptors on the platelet surface, activating FXI, FVIII and FV
* FXIa helps to amplify the conversion of FIX to FIXa
Propagation
* on the surface of platelets
* FVIIIa binds to FIXa and generates large amounts of FXa from FX
* FXa combines with FVa to form prothrombinase complex
* Complex catalyses the conversion of prothrombin (II) to thrombin (IIa) in large amounts
* thrombin converts fibrinogen (I) to fibrin (Ia) which cross-links platelets via the GP2b/3a receptor
* formation of platelet plug, stabilised by fibrin mesh at the site of vessel injury
Termination
3 mechanisms
* TFPI (tissue factor pathway inhibitor) - inactivates the complex produced by factor Xa in initiation
* Antithrombin - endothelial injury results in heparan sulphate being exposed to the blood - induces a conformational change in circulating antithrombin - binds to IIa and Xa, inactivating them
* Thrombomudulin - thrombin binds to thrombodmodulin (expressed on endothelial cell surfaces) - conformational change in TM, allowing it to bind to protein C and activate it. aPC binds to FVa, inactivating it. Protein S is a co-factor for protein C.
Follicle-stimulating Hormone (FSH)
Glycoprotein hormone
Production: Anterior pituitary
Secretion: Anterior pituitary
Site of action: Testes and ovaries
Effects: Stimulates spermatogensis in the male and ovarian follicle growth in the female.
Release stimulated by: GnRH
Release inhibited by: Oestrogen, testosterone (in men)
Functions of Endothelium
- Diffusion
- Osmosis
- Filtration e.g. Bowman’s capsule
- Barrier e.g. BBB
- Vasomotor tone - produces NO
- Inflammation - synthesises prostaglandins
- Coagulation - release of tissue factor triggering the clotting cascade
- Secretion - ACE
