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
Functions of Lungs
- Gas exchange
- Vascular reservoir
- Filtration
— physical
— chemical - Humidification
- Immunological - macrophages/neutrophils
- Acid-base balance
- Metabolism
— removal/inactivation - bradykinins, serotonin, noradrenaline, leukotrienes, prostaglandins E2/F2a
— conversion - ATI —> ATII (ACE) - Defence mechanism - cough, mucociliary escalator
Functions of the Kidneys
- Regulation
— Extracellular volume and electrolyte composition
— Total body water
— Acid-base balance
— Arterial blood pressure - Excretion
— Endogenous and exogenous waste products - Production
— Renin
— EPO
— Gluconeogenesis
— Activation of vitamin D (1,25 dihydroxycholecalciferol)
Functions of the Liver
Metabolism
* carbohydrate - gluconeogenesis, glycogenesis, glycogenolysis
* protein - amino acid degradation
* lipid - fatty acids
* nitrogenous compounds - recycling of NH3/NH4+ compounds
* breakdown of insulin, bilirubin and various hormones
Digestive
* bile production
* absorption of lipids and fat soluble vitamins
Synthesis
* coagulation factors I, II, V, VII, IX, X, XI
* antithrombin, protein C and S
* immunoglobulins
* amino acids
* albumin and globulins
* acute phase proteins
* cholesterol and triglycerides
* prostaglandins
* fatty acids and lipoproteins
* ketone bodies
* activates vitamin D
Drug Biotransformation
* Catabolic - phase I –> oxidation, reduction, hydrolysis to form water-soluble compounds
* Anabolic - phase II –> conjugation to increase polarity and water solubility
Storage
* Vitamins A, B12, D, E, K
* Copper
* Iron
* Glycogen
Capacitance
* 15% of circulating volume (reservoir)
Homeostatic functions
* immunological functions - Kuppfer/Pitt cells perform phagocytosis of bacteria, erythrocytes, antigens etc)
* hormones - IGF1, thrombopoietin, angiotensinogen etc
* erthyropoiesis in fetus until 32/40
Functions of the Spleen
- Immune
– antigen presentation
– storage of lymphocytes and exposure to the circulation - Filtration and metabolism
– Removes old and damaged erythrocytes and particulate matter
– splenic macrophages release haem from haemoglobin - Storage
– 240ml of RBCs can be stored and mobilized via splenic contraction in time of hypoxia or hypovolaemia
– 30% of platelets
– iron - Production
– Opsonins, such as properdin (complement activation) and tuftsin (immunostimulatory peptide) - Haematopoiesis
– after 5th gestational month, haematopoiesis continues in the bone marrow, except in some pathological disorders of bone marrow disruption e.g. myelofibrosis
G Protein Coupled Receptors
Gs - stimulates production of adenylate cyclase –> conversion of ATP to cAMP –> activation of protein kinase A
Gi - inhibits production of adneylate cyclase –> decreases levels of cAMP and suppresses cAMP dependent pathway
Gq - activates phospholipase C which catalyses the hydrolysis of PIP2 –> DAG + IP3. IP3 opens calcium ion channels –> activates PKC
cAMP - smooth muscle relaxation, heart muscle contraction, glycogenolysis
PKA - phosphorylates many targets including troponin I, L type Ca channels, K channels
IP3 - mobilises calcium ions from storage organelles
PKC - phosphorylates many targets with cell type specific effects
Gastric Regulation
- Sympathetic nervous system input T5-L3
- Parasympathetic nervous system input S2-S4
- Enteric nervous system
– submucous (Meissner’s) plexus - responsible for secretory function
– myenteric (Auerbach’s) plexus - responsible for peristalsis and movements - C5-6 - upper oesophageal sphincter (cricopharyngeus)
- Lower oesophageal sphincter - physiological sphincter at the entrance to the stomach 15-25mmHg
- LOS tone increased by ACh stimulation, histamine, gastrin, motilin
- LOS decreased by ACh inhibition, dopamine, CCK, oestrogen, secretin
- Neuroendocrine cells (in the gastric pits)
– G cells - secrete gastrin (stimulates ECL-like cells to release histamine thereby increasing HCl production)
– ECL-like cells - secrete histamine in response to gastrin, mainly in the fundus
– D cells in the pylorus - secrete somatostatin which suppresses gastrin and production of gastric acid
– EC-cells - secrete serotonin, involved in regulating GI motility and fluid secretion
– P/D1 cells - secrete ghrelin (hunger hormone) - increases appetite and promotes fat storage - Chief cells (in the base of gastric glands in the fundus) - secrete pepsinogen (converted to pepsin by HCl) - digest proteins
- Goblet cells (in the gastric mucosa) - secrete mucus to protect the epithelium
- Parietal cells (present in the gastric pits, mainly in the fundus) - release HCl into the stomach lumen, also secrete intrinsic factor
– stimulated by gastrin, acetylcholine and histamine - Acid secretion increased by food/brain/mouth/stomach, stress, gastrin, ETOH, caffeine
- Acid secretion decreased by fatty acids/glucose/amino acids, H2 blocker/PPI, CCK, GIP, secretin, vagotomy
- Gastric emptying increased by ACh stimulation, metoclopramide, neostigmine, erythromycin
- Gastric emptying decreased by food, stress, pain, increasing age, pregnancy, diabetes, obstruction, opioids, alcohol, anticholinergics, sympathomimetics
Gate Control Theory of Pain
A mechanism in the spinal cord in which pain signals can be sent up to the brain to be processed to accentuate the possible perceived pain, or attenuate it at the spinal cord. The gate is the mechanism where pain signals can be let through of restricted.
Things which open the gate:
* stress/tension,
* focussing on the pain,
* lack of activity,
* catastrophising,
* anxiety and depression and
* belief of harm.
Things which close the gate:
* relaxation,
* contentment,
* distraction,
* activity (pacing),
* counter-stimulation (heat/massage/TENS),
* ACT/CBT.
Growth Hormone (GH)
Polypeptide hormone
Production: Anterior pituitary
Secretion: Anterior pituitary
Site of action: All body systems
Effects: Protein synthesis, lipolysis, skeletal and fetal growth, gluconeogensis, Na retention and reduced sensitivity to insulin. Some effects are mediated by insulin-like growth factors I and II (produced by the liver in response to GH).
Release stimulated by: GHRH, exercise, hypoglycaemia, stress, glucagon, dopamine
Release inhibited by: Somatostatin, GH
Hypersecretion: Acromegaly (adults), gigantism (children)
Hyposecretion: Dwarfism
Glucagon
Polypeptide hormone
**Production: ** Synthesised in the A cells of the pancreas
Secretion: From the pancreas
Site of action: liver, CVS, fat, metabolism
Effects: glycogenolysis, glucoeogenesis, glucose release, ketone formation, inotropy, lipolysis, increased metabolic rate, GH release, somatostatin release, insulin release
Release stimulated by: hypoglycaemia, starvation, amino acids, physiological stress, beta agonists, cortisol, acetylcholine, theophylline
Release inhibited by: somatostatin, secretin, free fatty acids, alpha agonists, insulin, ketones, GABA
Metabolism: predominantly in the liver
Hypersecretion: glucagonoma, MEN 1
Hyposecretion: total pancreatectomy
Glucose Metabolism
Glycolysis = generation of ATP from glucose in the cytoplasm
–> glycolyis - breakdown of glucose into glucose-6 phosphate –> pyruvic acid
–> Kreb’s cycle (aka citric acid cycle) in the mitrochondria + electron transport chain/oxidative phosphorylation in the presence of oxygen - pyruvate is converted to acetyl CoA which enters the Krebs cycle –> 34 ATP per molecule of glucose + CO2 + H2O
–> in the absence of oxygen - pyruvate is metabolised in the cytoplasm to lactate –> liver clears >50% of lactate from blood, kidneys and muscles metabolise the remainder
Gluconeogenesis = generation of glucose from other substrates e.g. pyruvate, lactate, glycerol, amino acids
- usually takes place in the liver and in the cortex of the kidneys
Glycogenesis = synthesis of glycogen to store
- primarily takes place in liver, skeletal muscles and kidney
- consumes energy
- enhanced by high levels of insulin
Glycogenolysis = breakdown of glycogen to provide glucose
- takes place in the liver, muscles and kidney
- stimulated by glucagon in the liver or adrenaline in the skeletal muscle
Gonadotropin-releasing Hormone
Polypeptide hormone
Production: Hypothalamus (preoptic area)
Secretion: Hypophysial portal bloodstream
Site of action: Anterior pituitary
Effects: release of FSH and LH from the anterior pituitary
Release stimulated by: Kisspeptin, sex hormones
Release inhibited by: Sex hormones, dynorphin, inhibin, prolactin
Growth Hormone Releasing Hormone
Polypeptide hormone
Production: Hypothalamus
Secretion: Hypothalam-hypophyseal portal system
Site of action: Anterior pituitary
Effects: Stimulates GH production and release
Release stimulated by: pulsatile secretion, a2-adrenergic stimulation, hyoglycaemia
Release inhibited by: activation of GABAergic neurons, IGF-1, somatostatin
Heat Loss under GA
- Theatre environment - temperature, humidity, air circulation
- BMR decreased - decreased heat generation by metabolically active tissues eg the liver
- Spontaneous respiration - decreased heat generation by respiratory muscle contraction secondary to NMBAs/opioids
- Open, moist body cavities
- Cold irrigation fluid
- Decreased resting muscle tone –> decreases heat production
- Physiological response to hypothermia is blunted by anaesthetic agents –> inability to generate heat by moving/shivering, impaired vasoconstriction and piloerection
- Behavioural responses removed
- Administration of cold fluids/blood products
- Pathological conditions e.g. hypothyroidism
Human chorionic gonadotropin
Glycoprotein hormone
Production: in the human placenta by the syncytiotrophoblast
Site of action: ovary, corpus luteum
Effects: promotes maintenance of the corpus luteum, may facilitate trophoblast invasion
Release stimulated by: implantation of fertilised egg into the wall of the uterus, GnRH, IL-1B, activin
Release inhibited by: endorphins, inhibin, follistatin
Hypothermia and it’s causes
Core body temperature less than 35 degrees C (mild 32-35, mod 28-32, sev <28).
Swiss staging system - I - clearly conscious and shivering, II - impaired consciousness without shivering, III - unconscious, IV - not breathing, V - death due to irreversible hypothermia
Mechanisms
- increased heat loss
- decreased thermogenesis
- impaired thermogenesis
Risk factors
- Age (elderly and infants)
- Environmental - exposure, drowning, alpine environment, poverty
- Drugs/toxins - alcohol, sedatives, vasodilators
- Sepsis
- CNS disorders - hypothalamic lesions, hypopituitarism
- Endocrine/metabolic - hypothyroidism, adrenal insufficiency, malnutrition
- Trauma - burns, spinal cord injury
- Shock
- Skin disorders - psoriasis, exfoliating conditions
- Iatrogenic - cold fluid administration, intraoperative, therapeutic hypothermia
- Psychiatric (may lead to exposure)
Ideal Breathing Circuit
- simple and safe to use
- robust, small and lightweight
- efficient, requires low FGF
- delivers appropriate gas mixture
- allows all methods of ventilation in all age groups
- easy removal of waste gases
- easy to maintain, low running costs
- protects patients from barotrauma
- environmentally friendly
Ideal Induction Agent
Physical properties
- water soluble
- stable in solution
- stable on exposure to light or heat
- long shelf life
- no pain on IV injection, no thrombophlebitis
- painful on IA injection
- non irritant on SC injection
- cheap
- easy to manufacture
- environmentally friendly
Pharmacokinetics
- rapid onset, rapid redistribution to vascular rich group
- rapid clearance and metabolism
- no active or toxic metabolites
Pharmacodynamics
- high therapeutic ratio
- safe in porphyria/MH
- no histamine release/hypersensitivity
- minimal CVS/RS effects
- anti-emetic
- analgesic
- no SEs of current IV agents
Ideal Irrigation Fluid
- Transparent (for good visibility)
- Electrically non-conductive (to prevent dispersion of the diathermy current)
- Isotonic
- Non-toxic
- Non-haemolytic when absorbed
- Easy to sterilize
- Inexpensive
Ideal NMBA
Physical properties
- cheap, easy to manufacture
- long shelf life without refrigeration
- compatible with other drugs/solutions
- heat/light stable at room temperature
- environmentally friendly
Pharmacological properties
- non depolarising action
- rapid onset
- short duration, suitable for infusion
- rapid metabolism to inactive products
- reversible (cholinesterase inhibitors)
- actions confined to neuromuscular junction
- no local/systemic side effects
Ideal Opioid (for epidural use)
Physical properties
- no preservatives needed
- compatible with other agents
- can be sterilised
- cheap, easy to manufacture
- stable at room temperature
- light stable
Pharmacological properties
- cross dura rapidly and enter cord
- bind with strong affinity to opioid receptors in substantia gelatinosa (increased lipid solubility)
- poor CSF solubility
- effective analgesia at low dose (high potenct)
- minimal side effects
- minimal systemic absorption
Ideal Suction Tubing
Physical properties
- clear
- disposable
- flexible
- easy to use
- wide inner diameter
- non compressible
- low resistance
- thick wall - avoid collapse at maximum negative pressure
Ideal TIVA agent
Physical properties
- long shelf life
- stable at room temperature
- cheap, easy to manufacture
- no interaction with plastic tubing/needle
- compatible with other drugs/solutions
Pharmacological properties
- no/minimal effects on cardiovascular/respiratory systems
- no/minimal SEs
- rapid, predictable onset and offset
- clear end point
- low risk of anaesthetic awareness
- non toxic/active metabolites
- organ independent metabolism and excretion
Ideal Vaporiser
Physical properties
- light
- robust
- small liquid requirement
- minimal maintenance
- easy to maintain
- safe to use (safety features)
- performance not affect by change in temperature/pressure/FGF/volume of agent
- low resistance to flow
- cheap, easy to manufacture
- economical
- environmentally friendly
- corrosion and solvent reistant
- delivers precisely required agent
Ideal Ventilator (Portable)
- lightweight
- robust
- able to function in demanding environments with minimal maintenance
- use available gas/electric supplies sparingly
- cheap, easy to manufacture
- environmentally friendly
- simple to operate
- range of effective ventilatory modes
Immune Mechanisms
Non Specific/Innate
* surface barriers - mechanical, chemical, biological
* inflammatory response
* activation of alternative complement pathway
* phagocytosis
Specific/Adaptive
* T lymphocytes
* B lymphocytes and antibodies
* Plasma cells
* Classic complement pathway
* Immunological memory
Implications of intraoperative hypothermia
- increased perioperative blood loss and coagulopathy - clotting cascade is enzyme dependent and platelet function is temperature dependant
- longer post anaesthetic recovery due to altered drug metabolism
- post operative shivering and increased oxygen consumption
- prolonged action os some NMBAs
- thermal discomfort
- cardiac events including MI, arrhythmias
- delayed wound healing (secondary to reduced tissue oxygenation and immunosuppression)
- increased rates of SSI
- longer hospital stay
- death
- increased transfusion requirements
Insulin
Polypeptide hormone
Production: synthesised from proinsulin in the rough ER of B cells in the Islets of Langerhans (pancreas)
Secretion: via exocytosis from the pancreas
Site of action: specific insulin receptor on the cell membrane, effects mediated by tyrosine kinase
Effects: increases glucose (active transport via GLUT4), amino acid, ketone and K+ uptake by the muscle, increased anabolism, decreased catabolism, increased glycerol phosphate and fatty acid synthesis, decreased gluconeogenesis and ketogenesis by the liver, increased glycogen synthesis, glycolysis, protein synthesis and lipid synthesis by the liver, general increased cell growth
Release stimulated by: glucose, GLP-1, GI hormones, ACh, fatty acids, glucagon, GH, cortisol, beta adrenergic stimulation
Release inhibited by: adrenaline, noradrenaline, fasting, somatostatin, low blood sugar, leptin
Metabolism: liver, muscle and kidney by glutathione insulin transhydrogenase, with renal elimination of inactive metabolites
Hypersecretion: Hyperinsulinaemia, insulinoma
Hyposecretion: Type 1 Diabetes mellitus
Isomers
Structural
* Positional e.g. enflurane/isoflurane
* Chain e.g. butane/isobutane
* Functional e.g. propranolol/methyl ethyl ether
Tautomerism
* thiopentone
* midazolam
Stereoisomers
* Geometric (cis-trans) e.g. mivacurium
* Optical e.g. bupivacaine/L-bupivacaine, ketamine/S-ketamine
Lactic Acidosis
Type A - Due to tissue hypoxia
* Tissue hypoperfusion
* Abnormal vascular tone or permeability
* LV failure
* Decreased cardiac output
* Reduced arterial oxygen content e.g. asphyxia, hypoxaemia, CO poisoning, life-threatening anaemia
Type B - Not due to tissue hypoxia
* Sepsis
* Hepatic/renal failure
* DM
* Cancer
* Malaria/cholera
* Drugs or toxins e.g. biguanides, ethanol, salicylates, isoniazid, methanol, ethylene glycol, cyanide, TPN, nitroprusside, lactulose, theophylline, catecholamines, cocaine, vitamin deficiency, paraldehyde
* Strenuous muscular exercise
* Grand mal seizures
Leukotriene Synthesis
Membrane phospholipids/DAG
↓
(Cytosolic phospholipase A2/Phospholipase C)
↓
Arachidonic Acid
↓
(Lipo-oxygenases)
↓
HPETE (hydroperoxyeicosatetraenoic acid
↓
(Lipo-oxygenases)
↓
Leukotriene A4 → (with H2O) → LTB4 induces adhesion and activation of leukocytes on the endothelium
↓
Glutathione (Glutathione-S-transferase)
↓
Leukotriene C4 + Glutamic Acid mediator of smooth muscle contraction
↓
(transpeptidase)
↓
Leukotriene D4 triggers contractions in smooth muscles lining the bronchioles
↓
(dipeptidase)
↓
Leukotriene E4 smooth muscle contraction and proliferation, vascular permeability and oedema, increasing expression of adhesion molecules and monocyte activation
Leukotrienes
Eicosanoid hormones
Production: Leukocytes, by oxidation of arachidonic acid and eixosapentaenoic acid by arachidonate 5-lipoxygenase
Secretion: Plasma
Site of action: leukotriene receptors (GPCR) in the lung, peripheral blood leukocytes and spleen
Effects: inflammatory response, bronchoconstriction, increase vascular permeability
Release stimulated by: inflammation
Release inhibited by: leukotriene antagonists
Metabolism: partly degraded in local tissues, ultimately become inactive metabolites in the liver
Hypersecretion: asthma, allergic conditions
Luteinising Hormone (LH)
Glycoprotein hormone
Production: Anterior pituitary
Secretion: Anterior pituitary
Site of action: Testes and ovaries
Effects: Testosterone secretion in the male, luteinisation of ovarian follicles and ovulation in the female.
Release stimulated by: GnRH, oestrogen
Release inhibited by: Oestrogen and progesterone (after ovulation), testosterone (in men)
Hypersecretion: menopause, Turner syndrome, Klinefelter syndrome, PCOS
Hyposecretion: Kallmann syndrome, Pasqualini syndrome, hypothalamic suppression
LVEDP and PAWP/PAOP
LVEDP
* Left ventricular end diastolic pressure
* Normal range 4-12mmHg
* >15-18 = potential for decreased LV function and pulmonary congestion
* >20 = probable pulmonary congestion
* >25 = pulmonary oedema
* Measured by PAWP in normal heart with normal mitral valve and normal pulmonary vasculature
PAWP/PAOP
* Pulmonary arterial wedge/occlusion pressure
* Normal range 4-12mmHg
* Estimates LVEDP in most patients –> an indicator of preload (LVEDV)
* >18 in the context of normal oncotic pressure suggests left heart failure
PAWP > LVEDP
* mitral stenosis
* atrial myxoma
* mitral regurgitation
* non zone III position
* left to right shunt
* COPD
* IPPV +/- PEEP
* pulmonary venous obstruction
PAWP < LVEDP
* LVF
* high PEEP
* aortic regurgitation
* non compliant LV e.g. hypertensive cardiomyopathy
Magnesium
- Naturally occurring intracellular calcium antagonist
- Normal plasma level 0.7-1.1mmol/L
- Approximately half of total body magnesium is in muscle and other soft tissues, remainder within bone and a small amount in erythrocytes
- Around 1% in ECF, 99% intracellular
- Approx 1/3rd of dietary Mg is absorbed, mostly in the small intestine via a passive and saturatable transport system
- Most of Mg is reabsorbed in the ascending limb of the loop of Henle
- PTH enhances gut absorption of Mg and reabsorption in ascending limb of the loopn of Henle and distal tubule to maintain plasma concentration
- Aldosterone can increase renal excretion of Mg
- Effects:
- – CVS - direct depressant effect on myocardial and vascular smooth muscle, inhibitis release of catecholamines –> reduced CO and tone, slows rate of impulse formation at SA node and prolongs SA conduction and AV node refractory period
- – CNS - antagonises Ca ions at presynaptic junction, reducing release of ACh at NMJ, reduces excitability of nerves, anticonvulsant, reverses cerebral vasospasm, blocks NMDA channels –> analgesia
- – MSK - involved in terminating contraction, intiating relaxation in skeletal muscles
- – Resp - bronchodilator, does not effect respiratory drive
- – GU - powerful tocolytic - decreasing uterine tone and contractility, mild diuretic properties
- – Haem - reduces platelet activity
Hypomagnesaemia
* decreased intake - malabsorption, dietary deficiency
* increased loss - diuretics, nephrotoxics, diarrhoea, alcohol abuse, genetic renal disorders
* redistribution - massive transfusion of citrated blood, hyperparathyroidism, insulin administration
Early symptoms - anorexia, nausea, muscular weakness, cramps, lethargy, weight loss
Later - hyperirritability, hyperexcitability, muscle spasms, stridor, tetany, convulsions, hypertension, SVT/VTs
Hypermagensaemia
* exogenous overadministration
* antacids
* chronic renal insufficiency
2-3mmol/L - headache, N+V, diarrhoea, decreased tendon reflexes and GCS
3-5mmol/L - muscle weakness, decreased GCS, hypotension, ECG changes (prolonged AV condution, widened QRS)
5-7.5mmol/L - respiratory paralysis
10-12.5mmol/L - cardiac arrest
Give calcium gluconate IV if concerns
Mechanisms of drug action
- Receptors
- Ion channels e.g. lignocaine at Na+ channels
- Enzymes e.g. aspirin and COX-1
- Hormones e.g. carbimazole
- Neurotransmitters e.g. TCAs decreasing noradrenaline reuptake
- Transport systems e.g. digoxin acting on Na+/K+
- Physiochemical e.g. sugammadex chelating rocuronium
Mechanisms of Drug Interactions
- Physiochemical - occur due to the physical properties of the drugs themselves
— chelation e.g. sugammadex/rocuronium
— neutralisation e.g. heparin/protamine
— precipitation e.g. thiopentone/suxamethonium
— adsorption e.g. halothane/rubber - Pharmacokinetic - occur when one drug alters the way the body handles another
— absorption e.g. LA/adrenaline
— distribution e.g. Aspirin displaces warfarin
— metabolism e.g. CYP450 enzyme inducers and inhibitors
— excretion e.g. alkalinisation of urine to increase excretion of salicylates, probenecid inhibit is tubular secretion of penicillins, thereby increasing plasma levels - Pharmacodynamic - action of one drug is altered by the administration of another
— summation e.g. nitrous oxide/volatiles
— synergism e.g. remifentanil/propofol
— potentiation e.g. probenacid/penicillin
— antagonism e.g. morphine/naloxone
Mechanisms of Heat Loss
- Radiation (~45%)
Loss of heat through electromagentic radiation
increase theatre temperature,
vasodilatation,
exposure of patient,
reflective blankets,
Bair Hugger - Conduction (3-5%)
Transfer of heat (as kinetic energy) by direct contact from a higher temperature object to a lower temperature object
warming mattress,
fluid warmer - Convection (25-30%)
Transfer of heat energy through a liquid/gas by movement of the medium itself
theatre air circulation/laminar flow,
vasodilatation,
exposure of patient,
Bair Hugger - Evaporation
Loss of heat energy due to the latent heat of vaporisation
theatre humidity,
body cavity exposure,
HMEF,
skin prep - Respiration
HMEF (70% efficient),
low FGF,
soda lime
Melatonin
Amine hormone
Production: Pineal gland
Secretion: Pineal gland
Site of action: suprachiasmatic nucleus, throughout the body
Effects: regulation of circadian rhythm, antioxidant ad fere radical scavenger, inhibition of leptin, inhibition of LH and RSH release
Release stimulated by: darkness
Release inhibited by: blue light
Metabolism: proteasomal proteolysis, excreted in urine
Hypersecretion: seasonal affective disorder
Hyposecretion: pineal disorders
Muscle Contraction
- Acetylcholine released from the axon terminal binds to receptors on the sarcolemma
- An action potential is generated and travels down the T tubule, depolarising the cell membrane
- Calcium is released from the SR in response to the change in voltage (L type calcium channels allow calcium into the cell leading to activation of ryanodine receptors)
- Calcium binds to troponin leading to exposure of actin active sites; cross-bridges form between actin and myosin
- ADP and inorganic phosphate are released from the myosin head allowing the power stroke - the myosin head pivots and bends, pulling on the actin and moving it - muscle contraction
- A new molecule of ATP binds to the myosin head, causing it to detach from the actin
- Acetylcholinesterase removes acetylcholine from the synaptic cleft
- Calcium is transported back into the sarcoplasmic reticulum by active transport
- Tropomyosin binds active sites on actin causing the cross-bridge to detach
Nitrogen
- 3% of body weight
- 0.2g/kg required intake per day
- Improtant component of amino acids –> required for peptides and proteins
- Essential component of nucleic acids DNA and RNA
- Required for synthesis of ATP
Nitrogen Balance
* Nitrogen intake should = nitrogen loss
* Nitrogen intake from meat, fist, dairy foods, eggs, nuts, legumes, grains and cereals
* Nitrogen loss in urine, faeces, sweat, hair and skin
* Positive nitrogen balance associated with periods of growth, hypothyroidism, tissue repair and pregnancy
* Negative nitrogen balance associated with burns, serious tissue injuries, fever, hyperthyroidism, wasting diseases and periods of fasting
Noradrenaline
Amine hormone
Production: Adrenal medulla from tyrosine
Secretion: Adrenal medulla
Site of action: Adrenergic receptors on nearly all tissues (alpha»_space; beta effects)
Effects: Increased SVR, venoconstriction, increased preload, increased myocardial oxygen consumption, increased coronary flow, reflex decrease in HR
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: Mitochondrial MAO and COMT within liver, kidney and blood to VMA and normetanephrine, urinary excretion of metabolites + 25% pulmonary uptake
Hypersecretion: Phaeochromocytoma
Hyposecretion: Autonomic neuropathy, adrenalectomy
Nutrition on ITU
Nutritional requirements
* Calculate BMR using an equation/formula
* Usually need ~25kcal/kg/day in afebrile, healthy individuals
* Modify caloric needs depending on resting energy expenditure - fever, sepsis, surgery, burns
* Protein - 1.5-2g/day (provides 5.3kcal/g)
* Lipid - provides 9.3kcal/g (max 40% caloric intake)
* Carbohydrate - provides 3.75kcal/g
* Recommended calorie:nitrogen ratio 100:1
Electrolyte requirements (in mmol/kg/day)
* Na and Cl 1.0-2.0
* K 0.7-1.0
* PO4 0.4
* Ca and Mg 0.1
* Trace elements - chromium, copper, manganese, selenium, zinc, vitamins A/D/E/K/B1/B2/B3/B5/B6/B7/B9/B12/C
Routes
1. Oral
2. Enteral - OG, NG, enterostomy post-pyloric +/- pro-kinetics (erythromycin, metoclopramide)
3. Parenteral - supplemental or sole nutrition
Complications
* Refeeding syndrome - drops in phosphate, magensium, potassium, calcium (start with 25-50% of energy requirements and increase gradually, monitor electrolytes, give thiamine and B vitamins)
* Overfeeding - uraemia, hyperglycaemia, hyperlipidaemia, fatty liver, hypercapnia, fluid overload
* Hyperglycaemia - insulin resistance as part of stress response
* Specific complications of enteral nutirion - aspiration, pneumonia, diarrhoea
* Specific complications of PN - CVC risks, sepsis, hepatobiliary disease, electrolyte imbalances and micronutrient deficiencies
Osmolar Gap
Calculated osmolarity = (2 x [Na+]) + [glucose] + [urea])
Osmolar gap = Osmolality (measured) – Osmolarity (calculated)
Normal = < 10
Causes of high osmolar gap:
* Mannitol
* Methanol
* Ethylene glycol
* Polyethylene glycol (IV lorazepam)
* Propylene glycol (IV lorazepam, diazepam, phenytoin)
* Sorbitol
* Glycine (TURP syndrome)
* Maltose (IVIG)
* Presence of other osmotically active particles
Oxygen Cascade
Transfer of oxygen from air to the mitochrondria
In each step of the cascade, the PaO2 falls. It demonstrates that oxygen delivery to tissues relies on the passive transfer of gas down partial pressure gradients
- Air (dry atmospheric gas) - pO2 = FiO2 x Patm
- Trachea (humidified gas) PiO2 = FiO2 (Patm-PH2O) - heated to 37 degrees and has 100% relative humidity
- Alveolar gas PAO2 = PiO2-PaCO2/R - dependent on alveolar ventilation
- Capillary blood - diffusion
- Arterial blood - shunt
– extrapulmonary - bronchial veins, thebesian veins, R–> L cardiac defect
– intrapulmonary - alveolus full (blood, fluid, pus, tumour), atelectasis - Mitochondria - metabolism (oxidative phosphorylation
– Pasteur point - the partial pressure of oxygen at which oxidative phosphorylation ceases - Venous blood - PO2 is greater than mitochrondial PO2 as not all arterial blood travels through capillary beds
Oxytocin
Polypeptide hormone
Production: Hypothalamus - paraventricular nucleus
Secretion: Posterior pituitary
Site of action: Breast, kidneys, uterus (from day 22 of pregnancy onwards, increasing as gestation progresses)
Effects: Stimulates contraction of myoepithelial cells surrounding the milk ducts, therefore causing secretion of milk. Also stimulates contraction of the uterus and water retention by the kidney.
Metabolism: oxytocinase in the liver, kidneys and plasma (during pregnancy)
Release stimulated by: Suckling
Release inhibited by: Dopamine
Parathyroid Hormone
Polypeptide hormone
Production: Parathyroid glands
Secretion: Parathyroid glands (Chief cells)
Site of action: Bone, kidney, CNS, pancreas, testes, placenta
Effects: Regulation of serum calcium - enhances release of calcium from bone, prevents action of osteoblasts, reabsorption of calcium in the distal tubules and CDs, stimulates conversion of vitamin D to active form to increase calcium uptake from the intestine
Release stimulated by: low serum calcium, low magnesium, increased phosphate, adrenaline, histamine
Release inhibited by: high serum calcium, high magnesium, calcitriol, phosphate
Hypersecretion: Hyperparathyroidism
Hyposecretion: Hypoparathyroidism
Patient Blood Management
MDT, patient centred, evidence based approach aimed at optimising the care of patients who may need a blood transfusion, and minimising the blood products that need to be administered.
Pre-operative
* identify and correct anaemia - PO/IV iron, B12, folate (ideally at least 4 weeks pre-op)
* consider deferring elective (high blood loss) surgery until cause of anaemia addressed and treated
* ask about bleeding history to identify and manage patients with haemostatic disorders
* protocols for anti-coagulation/anti-platelet therapies used perioperatively
* determine expected blood loss
* confirm patient wishes regarding transfusion therapy and blood conservation modalities
* consider EPO
* consider preoperative autologous blood donation
Intra-operative
* cell salvage if blood loss anticipated to be >1000ml
* TXA
* controlled hypotension
* patient position (decreased CVP)
* maintain physiologic homeostasis - euvolaemia, avoid hypothermia
* minimise surgical blood loss - minimally invasive techniques, electrosurgery decides, meticulous haemostatic techniques, topical haemostatic agents/adhesives
* use evidence based transfusion guidelines
* consider acute normovolaemic haemodilution
Post-operative
* post op cell salvage
* minimise blood sampling
* use evidence based transfusion guidelines
* early surgical re-exploration for those with localised internal bleeding
* use of ROTEM/coagulation testing and haematology input to ensure correct products provide
* consider volume provided if Hb dropped
* consider alternatives to transfusion e.g. IV iron
Pharmacogenomics
- Inherited genetic differences in drug metabolic pathways which can alter individual response to drugs
- Can affect receptors, enzymes or transport processes
- Acetylator status - rapid or slow
– autosomal dominant/recessive
– hydralazine, sulphonamides, dapsone, isoniazide, phenelzine, procainamide - Sux apnoea (autosomal recessive)
– autosomal recessive
– 4 alleles - butrylcholinesterase (BChE) - BChE gene on chromosome 3
– Eu - normal (100% activity)
– Ea - atypical (30% activity)
– Ef - fluoride resistant (40% activity)
– Es - silent (0% activity) - CYP2D6 - metabolism of codeine
– autosomal codominant
– about 7-10% of whites have poor CYP2D6 metabolism
– 1-7% of whites and >25% of Ethiopians are classified as having ultrarapid metabolism
– poor metaboliser, intermediate metaboliser, extensive metaboliser, ultra rapid metaboliser - Malignant Hyperthermia
– autosomal dominant
– mutation in RYR1 gene on chromosome 19 (up to 70% of affected individuals) - MTHFR gene variants
– cause reduced ability to convert folic acid or folate into a usable form
– avoid N2O/entonox - CYP2C9 variants - VKORC1 gene
– autosomal dominant
– warfarin resistance or sensitivity - CYP2C19 variants
– autosomal codominant
– clopidogrel resistance (inability to convert clopidogrel to active form)
Pharmacologic Management of Pulmonary Hypertension
Prostacyclin receptor agonists (eg selexipag, epoprostenol, iloprost)
- selectively bind the PGI2 receptor causing direct vasodilatation and inhibition of platelet activation
Endothelin receptor antagonists (eg Bosentan)
- inhibit action of endothelin-1 produced by endothelial cells that mediates vascular constriction
Guanylate cylase activators (eg riociguat/vericiguat)
- increase production of intracellular cGMP leading to vascular smooth muscle relaxation
PDE5 inhibitors (eg sildenafil
- prevent breakdown of intracellular cGMP
Calcium channel blockers
Digoxin
Diuretics
Oxygen
Anticoagulation
Pharmacological and physiological interactions of muscle relaxants
Pharmacological
* Volatile anaesthetics - prolong blockade by depressing somatic reflexes in CNS thereby reducing transmitter release at the NMJ
* Aminoglycosides (large intraperitoneal doses), polymixins and tetracyline - prolong blockade by decreasing ACh release, possibly by competition with calcium ions
* Local anaesthetics - variable effect on blockade - low doses may enhance blockade through sodium channel blockade
* Lithium - prolong blockade through sodium channel blockade
* Diuretics - variable effect through impact on cAMP, may have effects via serum K+ in addition
* Calcium channel antagonists - prolong blockade by reducing calcium influx, leading to reduced ACh release
* Magnesium - decreased ACh release by competition with Calcium ions, and stabilisation of the post-junctional membrane
Physiological
* Hypothermia - prolongs blockade by reducing metabolism of muscle relaxant
* Acidosis - usually prolongs blockade
* Hypokalaemia - acute hypokalaemia increases the resting membrane potential (makes it more negative) - non depolarising relaxants are potentiated while depolarising relaxants are antagonised
* Hyperkalaemia - resting membrane potential becomes less negative leading to antagonism of non depolarising relaxants and potentiation of depolarising relaxants
* Hypermagnesaemia - prolongs blockade by decreasing ACh release through competition with calcium ions, and stabilisation of the post-junctional membrane. When used at suprenormal levels, Mg ions can cause apnoea via a similar mechanism
Phases of Hypoxic Pulmonary Vasoconstriction
Phase 1 - within a few seconds, maximal at 15 minutes
- probably mediated by K channels
Phase 2 - moderate hypoxia sustained for more than 30-60 minutes, further increase in PVR, peaks at 2hrs
- probably a result of increased release of endothelin
When normoxia returns - it can take several hours for PVR to return to baseline
Physiology of Vomiting
Inputs
* Systemic toxins and drugs –> chemoreceptor trigger zone –> CTZ –> NTS and VC
* Vagal (GI tract mechano and chemoreceptors), glossopharyngeal, facial nerve stimulation –> visceral afferents –> NTS and VC
* Motion –> vestibular nuclei –> NTS and VC
* Pain, emotion, smell, sight –> higher cortex centres –> VC
Receptors
* M3 - vestibular nuclei, higher cortex centres, CTZ, NTS, VC, efferent nerves
* NK1 - vestibular nuclei, visceral afferents, CTZ, NTS, VC
* H1 - vestibular nuclei, NTS, VC
* 5HT3 - CTZ, visceral afferents, NTS, VC
* D2 - CTZ, NTS, VC
Processing centres
* Nucleus Tractus Solitarius - brainstem
* Chemoreceptor Trigger Zone - area postrema of the medulla, on the lateral walls of the 4th ventricle (outside the BBB)
* Vomiting centre - dorso-lateral reticular formation of the medulla
Outputs
* Vasomotor Nuclei - dorsal motor nucleus –> vagal efferents
* Respiratory Nuclei - Ventral Respiratory Group –> descending corticospinal tracts
* Salivary Nuclei - nucleus ambiguus –> CN 9 and 10
Process of Vomiting - co-ordinated by the vomiting centre in the medulla
* Pre-ejection phase
– prodromal nausea
– salivation
– retrograde intestinal contraction which forces intestinal contents into the stomach
* Retching phase
– deep inspiration and breath-holding to splint the chest
– epiglottic closure
– elevation of the soft palate to prevent nasal soiling
* Expulsive phase
– relaxation of oesophageal sphincters
– pyloric contraction
– violent contraction of the diaphragm and abdominal muscles
Potassium Regulation
- Extracellular potassium concentration - 3.5-5mmol/L
- Intracellular potassium concentration - 120-150mmol/L
- Intracellular K+ levels are important for enzyme function, cell division and growth, acid-base and cell volume regulation
- Freely filtered at the glomerulus
- Mostly reabsorbed at the PCT (2/3rds) and LoH (20%)
- Some reabsorption and some potassium secretion at the DCT and CD
- At PCT - passive reabsorption via a paracellular mechanism - directly proportional to water and Na+ movement (Na+-K+-ATPase)
— sodium moves out of the cell, driving K+ into the cell
— extrusion of sodium creates an osmotic gradient and an electrochemical radiant
— water moves out of the PCT down the osmotic gradient
— Cl- moves down the electrochemical gradient
— K+ is reabsorbed and follows Cl- into the bloodstream - At LoH - trans cellular and paracellular reabsorption
— Na+-K+-ATPase on the basolateral membrane pumps Na+ out into the bloodstream and pumps K+ into the thick ascending limb
— gradient created for the NKCC2 cotransporter on the apical membrane
— NKCC2 pumps Na+, K+ and 2Cl- into the cell from the lumen
— Intracellular K+ can enter the bloodstream through K+-Cl- symporter or through K+ uniporter
— movement of K+ through apical renal outer medullary K+ channels - leads to positive voltage in the lumen, providing a driving force for passive reabsorption - Approximately 10% of filtered potassium is reabsorbed in DCT and cortical CD when the body is attempting to preserve potassium
— mediated by alpha and beta intercalated cells
— apical H+-K+-ATPase mediates movement of H+ into the lumen, driving K+ into the intercalated cell
— basolateral K+ channel allows the K+ inside the intercalated cell to leak out into the bloodstream - If potassium is deplete, the number of H+-K+-ATPase pumps increase significantly in order to reabsorbed as much K+ as possible (drives H+ into the lumen generating hypokalaemic alkalosis)
- Potassium secretion in the late DCT and CD via principal cells
— principal cells contain ENaC on the apical membrane and Na+-K+-ATPase on the basolateral membrane
— K+ is driven into the principal cell from the bloodstream by Na+-K+-ATPase leading to intracellular accumulation of K+
— high intracellular K+ creates chemical gradient which allows for secretion of K+ via K+ channels on the apical membrane - Secretion affected by tubular and luminal factors
- Tubular factors
— High ECF K+ stimulates Na+K+ATPases, increasing permeability of K+ channels and increasing secretion of K+ into the lumen
— Aldosterone stimulates Na+K+ATPases in the basolateral membrane, stimulating K+ channels and ENaCs in the apical membrane leading to increased secretion
— Acidosis - increased H+ secretion into lumen to correct acidosis
— Alkalosis - kidneys try to decrease secretion of H+, increasing K+ in turn - Luminal factors
— High luminal flow washes away luminal K+, maintaining a constant concentration gradient and increasing K+ secretion
— Increased luminal flow also increases Na+ delivery to the tubule cells —> Na+ uptake through ENaC —> negative potential in the lumen, encouraging K+ secretion through the apical K+ channel
Potassium
- Predominantly intracellular cation
- Daily requirement 0.7-1.0mmol/kg/day
- Completely and passively absorbed in upper GI tract
- Excretion mainly in collecting ducts
- Involved in neuromuscular excitability
— gradient across cell membranes determines the excitability of nerve and muscle cells including myocardium - Affects tonicity
- Antiport molecule in Na/K transport and control of intracellular volume
- Regulation of some Intracellular processes (protein/glycogen synthesis, carbohydrate metabolism)
Hyperkalaemia
* muscle weakness
* lethargy
* ascending paralysis
* respiratory failure
* cardiac arrhythmias - peaked T waves, flattened P waves, increased PR interval —> widened QRS —> deep S waves, merging of S+T waves —> sine wave formation —> VF
* membrane stabilisation - calcium chloride/glauconite
* ECF—>ICF shift - sodium bicarbonate (in known CKD), insulin/dextrose, salbutamol
* removal of K from body - frusemide, resonium, dialysis
Hypokalaemia
* mild usually asymptomatic
* fatigue, muscle cramps, weakness
* constipation
* rhabdomyolysis
* ascending paralysis
* respiratory failure
* arrhythmias - U waves, T wave flattening, ST depression —> VT/VF, long QT and Torsades
* replace magnesium as this facilitates a more rapid correction of hypokalaemia
* non acute - 10-20mmol/hr
* life threatening can give quicker
Principles of anti microbial stewardship
- controlling the source of the infection
- prescribing antibiotics when they are truly needed
- prescribing appropriate antibiotics with adequate dosages
- using the shortest duration of antibiotics required based on evidence
- reassessing treatment when culture results are available
- educating staff
- supporting an interdisciplinary approach
- enhancing prevention and control of infection
- supporting surveillance of anti microbial resistance and HAI and monitoring of antibiotic consumption
Pro-Drugs
- A compound that has negligible, or lower, activity against a specified pharmacological target than one of its major metabolites.
- Can be used to improve drug delivery or pharmacokinetics, to decrease toxicity, or to target the drug to specific cells or tissues
- 2 major types based on how the body converts the prodrug into the final active drug form
- Type 1 prodrugs are bioactivated inside the cells (intracellular)
- Type 2 prodrugs are bioactivated outside cells (extracellular), especially in digestive fluids or in the blood
- Subtypes based on whether the bioactivation site is also the site of therapeutic action
Examples
* diamorphine –> morphine + 6-acetylmorphine (via blood esterases)
* codeine –> morphine + codeine 6-glucuronide (via CYP2D6)
* enalapril –> enalaprilat (hydrolysis by esterases)
* prednisone –> prednisolone (liver by 11-beta-hydroxysteroid dehydrogenase)
* parecoxib –> valdecoxib (enzymatic hydrolysis)
* omeprazole –> acid or sulfonamide form (acidic environment in the stomach)
* levodopa –> dopamine (DOPA decarboxylase)
* methyldopa –> alpha-methylnorepinephrine (decarboxylation)
* terlipressin –> lysine vasopressin (endothelial peptidases)
* carbimazole –> methimazole (hydrolysis and enzyme decarboxylation in the blood)
* aspirin –> salicylate (stomach, intestinal mucosa, blood, liver)
* valaciclovir –> aciclovir monophosphate (viral thymidine kinase) –> acivlovir triphosphate (host cell kinases)
Prolactin
Polypeptide hormone
Production: Anterior pituitary, dicidua, myometrium, breast, lymphocytes, leukocytes, prostate
Secretion: Anterior pituitary
Site of action: Breasts, ovaries, pituitary glands, heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal gland, uterus, skeletal muscle, skin, CNS
Effects: Development of the breasts ready for lactation, stimulates milk production, reduces fertility, sexual gratification
Release stimulated by: PRLH, dopamine antagonists, suckling, prolactin (positive feedback mechanism), stress, exercise
Release inhibited by: Dopamine (aka prolactin-inhibitory hormone)
Hypersecretion: Hyperprolactinaemia, polactinomas
Hyposecretion: Hypoprolactinaemia (uncommon in isolation)
Prostacyclin aka Prostagland I2
Eicosanoid hormone
Production: Endothelial cells which line the walls of arteries and veins
Secretion: Endothleial cells
Site of action: platelet prostacyclin receptors
Effects: inhibits platelet activation, vasodilation, antiproliferative, antiinflammatory
Release stimulated by: vascular damage
Release inhibited by: NSAIDs
Metabolism: broken down into a weaker vasodilator
Prostaglandin Synthesis
Membrane phospholipids
↓
(Cytosolic phospholipase A2)
↓
Arachidonic Acid
↓
(COX 1, COX 2) (PGH synthase)
↓
Prostaglandin G2
↓
(PGH synthase)
↓
Prostaglandin H2
↓
PGD2 (PGD2 synthases) → allergic response - mast cells, brain, airways
PGE2 (PGE2 isomerases) → uterine contraction, inhibition of sodium absorption, patency of PDA, vascular smooth muscle contraction
PGF2 (PGF2 synthase) → uterine contraction, bronchoconstriction, vascular smooth muscle contraction, increase sclera’s permeability to aqueous fluid
PGI2 aka Prostacyclin (PGI2 synthase) → vasodilation, inhibition of platelet activation
TXA2 (TXA2 synthase) → stimulates activation of new platelets + increases platelet aggregation
Prostaglandins
Eicosanoid hormones
Production: Derived enzymatically from arachidonic acid in almost every tissue in the body
Secretion: Via prostaglandin transporter and passive diffusion
Site of action: Most tissues and organs
Effects: locally acting vasodilators (smooth muscle relaxation), inhibit aggregation of platelets, involved in inflammation
Release stimulated by: activation of COX 2 by injury or inflammation
Release inhibited by: NSAIDs and corticosteroids
Metabolism: rapidly metabolised in the lungs by a dehydrogenase enzyme
Pulmonary Vascular Resistance
Factors affecting PVR - increased PVR
* Decreased pulmonary blood flow
* Low and high lung volumes (compression or larger and smaller vessels respectively)
* HPV
* Catecholamines
* Serotonin
* Arachidonic acid metabolites
* Histamine
* Hypercapnia
* Hypothermia
* Acidemia
* Alpha 1 receptors - cause vasoconstriction
* Increased Hct
* Pulmonary vasoconstrictors - adrenaline, noradrenaline, adenosine
Factors affecting PVR - decreased PVR
* Increased pulmonary blood flow
* Lung volume - “U” shaped curve, PVR is lowest at FRC
* Alkaelaemia
* Hyperoxia
* Hypocapnia
* Beta 2 and muscarinic 3 receptors - cause vasodilation
* Pulmonary vasodilators - NO, milrinone, levosimendan, vasopressin, Ca-channel blockers, sildenafil, ACE-I, prostacyclin, Bosentan
QT Prolongation
- Normal QTc = 440ms (M) or 460ms (F)
- QTc >500ms is associated with increased risk of torsades de pointes which may be fatal
Aetiology
- Pharmacological
- Long QT syndrome
- Jervell and Lange-Neilson syndrome - rare autosomal recessive disorder (bilateral sensorineural hearing loss + prolonged QTc)
- Romano-Ward syndrome - most common form of congenital long QT syndrome causing abnormalities in transport of positive ions through cardiac ion channels
- Electrolyte abnormalities - hypocalcaemia, hypokalaemia, hypomagnesaemia
- Hypothyroidism
- Hypothermia
Many commonly used medications exhibit QT prolonging effects, however, the degree of QT prolongation is not severe enough to warrant caution in health patients.
* Antiarrhythmics - sotalol, amiodarone, quinidine, flecainide
* Antihistamines - terfenadine, astemizole
* Prokinetics - cisapride
* Neuroleptics/antipsychotics - phenothiazines, haloperidol, chlorpromazine, proclorperazine, olanzapine, risperidone, droperidol
* TCAs - amitriptyline, doxepin, desipramine, imipramine, clomipramine
* Antibiotics - macrolides (erythromycin, clarithromycin), fluoroquinolones
* Antifungals
* Antimalarials
* Ondansetron
* Sumatriptan
* Methadone
Management
* Caution is advised when combining QT prolonging medications or using these medications in those with electrolyte abnormalities.
* Patients with long QT syndrome (or other genetic causation) should use QT prolonging medications with caution.
RBCs and Haemoglobin
Red Blood Cells
* formed in the bone marrow by erythropoiesis
* biconcave discs measure 7.5 microns in diameter
* thicker outer rim, thher centre
* deformable - squeeze thorugh narrow capillaries without disrupting cell membrane
* enhances diffusion of gases due to greater surface area
* reduces wall tension as the cells well after taking up CO2 from the tissues
* contain approximately 30pg of Hb
* erythrocytes survive approximately 120 days
Haemoglobin
* 4 globin chains (2 alpha, 2 beta)
* Each contains a haem molecule which reversible binds to oxygen, containing a Fe2+ ion
* Fe2+ ion forms 6 bonds within the haem moiety
Functions of Hb
* transport of oxygen from the lungs to the tissues - to facilitate oxidative phosphorylation in the mitochrondroa
* carriage of CO2 from tissues to lungs as carbaminohaemoglobin
* buffering of H+ formed in the erythrocyte from conversion of CO2 into bicarbonate
* NO metabolism
Regulation of Blood Pressure
- High pressure baroreceptors respond to decreased vessel stretch and decrease firing
— carotid sinus (CN IX)
— aortic arch and heart (CN X) - Vasomotor centre (nucleus tractus solitarius in the rostral ventrolateral medulla) detects decreased afferent impulses
—> decreased parasympathetic outflow
— increased heart rate (SA node)
AND —> increased sympathetic outflow
— increased contractility and increased HR —> increased CO
— vasoconstriction —> increased MAP —> increased CO
— venoconstriction —> increased venous return - Low pressure (cardiopulmonary) baroreceptors detect changes in blood volume
— vena cava
— pulmonary arteries
— atria - Chemoreceptors in the aortic and carotid bodies detect changes in blood pH, O2 and CO2 levels
—> respond to decreased arterial pO2 by increasing firing of afferent nerves —> increased sympathetic outflow (vasoconstriction), increased parasympathetic outflow (transient decreased HR) and increased ventilation - Central chemoreceptors in the medulla respond to changes in pCO2 and pH
—> respond to decreased pCO2 by increasing vasoconstriction in the brain, decreasing cerebral blood volume and therefore ICP - RAAS
- Renin - released from granular cells in the juxtaglomerular apparatus in espouse to increased concentration of salt in the blood, reduction in renal blood flow, or stimulation from the SNS acting on B1 receptors
— converts angiotensinogen into angiotensinogen I which is converted by ACE (from the lungs) into angiotensin II - Angiotensin II - causes vasoconstriction, increases salt reabsorption through activation of aldosterone and increases plasma volume through stimulation of ADH release
- Aldosterone - acts on the cells in the DCT and CD to increase Na+ reabsorption while increasing K+ secretion into tubules
*ADH - release triggered by increased plasma Osmolarity (osmoreceptors in the hypothalamus), reduced blood volume and increase in levels of angiotensin II
—> increases water reabsorption through insertion of aquaporins in the CD and DCT thereby increasing intravascular fluid volume
—> direct action on V1 receptors on vascular smooth muscle causing vasoconstriction
- ANP - released by increased stretch of atria due to increased BP
— causes generalised vasodilation —> increased GFR —> increased Na+ and H2O filtration and excretion —> decreased blood volume
— stimulates decreased renin, ADH and aldosterone release
*Other contributory factors
- Sodium - increased sodium leads to increased water reabsorption and therefore increased plasma volume
- Bradykinin - causes dilation of arterioles via release of prostacyclin, NO and endothelium-derived hyperpolarizing factor and makes veins constrict, via prostaglandin F2
- Nitric oxide - potent vasodilator produced in response to shear stresses in vessels
- Glucocorticoids - overstimulation of the mineralocorticoid receptor, resulting in sodium retention in the kidney, volume expansion and subsequent increase in BP
- Renal function - kidneys are responsible for regulating circulatory volume by controlling sodium and water balance, damaged kidneys are less able to do this
- Psychological stress - leads to temporary increase in sympathetic outflow
- Obesity - multiple mechanisms that impact on BP control - including renal medullary compression, increased RAAS activity and increased SNS activity (via release of leptins)
- Atherosclerosis - narrowing and stiffening of vessels, impairment of baroreceptor response
- Other hormones and neurotransmitters including thyroxine, histamine, acetylcholine and serotonin
Regulation of Sodium
- Sodium intake - dietary intake, absorbed in the colon and sitar small bowel
- Sodium output - urinary excretion, insensible losses (sweat, faeces)
- 99% of sodium ions which pass through the glomerulus are reabsorbed, driven across the basolateral membrane by Na-K-ATPase pumps
- Renal sympathetic nerve activity - stimulated by hypotension (carotid and aortic bodies) and hypovolaemia (atrial natriuretic peptide) —> activation of alpha-1 and alpha-2 receptors lead to increased Na reabsorption in the PCT and fluid retention
- RAAS - reduced renal perfusion and/or reduced sodium delivery to the nephron stimulates renin release —> ATII —> aldosterone secretion
- ATII stimulates the Na+/H+ antiporter in the PCT
- Aldosterone increases the expression of epithelial sodium channels (ENaC) in the collecting duct
- ANP/BNP - stretch as a result of increased blood volume leads to release of ANP/BNP - reduce aldosterone and renin secretion, thereby decreasing Na reabsorption
- Increase in plasma osmolality is detected by osmoreceptors in the hypothalamus —> release of ADH —> insertion of aquaporins in the DCT and CD —> increased water resorption by osmosis
Regulation of Temperature
Compartments
- Core (66% of adult body mass) - 37 degrees
- Peripheral - absorbs or releases thermal energy to maintain core normothermia - 28-36 degrees - neonates and infants have a very small peripheral compartment
Components
- Afferent thermal sensing from peripheral thermoreceptors via the lateral spinothalamic tract and central thermoreceptors
brainstem
hypothalamus
spinal cord
deep thoracic and abdominal tissue
free nerve endings in the skin - cold receptors and warm receptors
- Central Integration primarily in the hypothalamus
hot - anterior hypothalamus - preoptic nuclei
cold - posterior hypothalamus - shivering centre
- Efferent response
cardiovascular - vasodilation/vasoconstriction
CNS - behaviour modification e.g. clothing, relocation and skeletal muscle activity
MSK - sweating, piloerection, shivering
Metabolic - non shivering thermogenesis (hormonal and brown fat) and increase in BMR
Renal Autoregulation
- Renal blood flow and GFR are subject to autoregulation
- MAP 80-180mmHg
Myogenic Theory (faster response)
* stretch of smooth muscle in preglomerular arteriole wall leads to reflex constriction to maintain blood flow
Tubuloglomerular Feedback (slower response)
* alterations in GFR due to perfusion cause an altered composition of fluid due to a change in flow rate
* an increase in sodium chloride concentration in the early distal tubule is detected by the macula densa (at the end of the ascending limb) which acts to alter arteriole tone by
* increased sodium concentration leads to release of ATP and reduced prostaglandin E2 that act on the nearby juxtaglomerular cells –> constriction of afferent arteriola and decreased renin secretion from both afferent and efferent juxtaglomerular cells –> lower GFR
* further increase in Na concentration –> release of NO to prevent excessive vasoconstriction
* decreased sodium concentration results in juxtaglomerular cells being stimulated to release more renin –> RAAS –> increased angiotensin II –> preferential constriction of the efferent arteriole –> increased GFR
Also affected by sympathetic nervous system, RAAS, atrial naturietic peptide and prostaglandins.
Renal Replacement Therapy
Techniques
* Peritoneal dialysis
* Intermittent haemodialysis (IHD)
* Continuous renal replacement therapy (CRRT)
– continuous veno-venous haemofiltration (CVVH) - uses convection for solute removal
– continuous veno-venous haemodialysis (CVVHD)
– continuous veno-venous haemodiafiltration (CVVHDF) - uses a filter that allows a countercurrent of dialysate, combines diffusion with convection for solute
– slow continuous ultrafiltration (SCUF) - removal of plasma water with smaller molecules from the blood stream (corrects volume overload)
Aims
* Solute removal
* Water removal
* Correction of electrolyte abnormalities
* Normalization of acid-base disturbances
Mechanisms
* Ultrafiltration/haemofiltration - fluid can cross a semi-permeable membrane in response to a pressure gradient
– osmotic/onchotic/hydrostatic
– generated by increasing pressure on blood side or decreasing pressure at effluent pump to alter “transmembrane pressure” (TMP)
– allows removal of fuid from the patient
* Convection - one way movement of solutes across a semipermeable membrane with the flow of H2O (aka “solute drag”)
– filtration with larger membrane pores, allows water, electrolytes, urea and creatinine to be carried across the membrane and removed from the circulation
* Adsorption - adherence of solutes and other biological matter to the surface of the membrane e.g. cytosorb filters
– may decrease clearance of solutes as more are adhered to the membrane and decrease it’s efficiency
* Diffusion/haemodialysis - movement of particles from a higher concentration to a lower concentration across a semi-permeable membrane
– effective for small molecules due to pore size “selective diffusion”
– flow of dialysate in the opposite direction (countercurrent) to ensure a good concentration gradient
– slower process
Contents of Dialysate
* Sodium, chloride and magnesium - equivalent to normal serum levels
* Potassium - either at a decreased level to aid clearance of high potassium or a more equivalent level
* Bicarbonate - to aid addition of bicarbonate to the blood
* Urea and creatinine are not present in any volume
Anticoagulants for CRRT
* None - poor filter life, useful if risks of anticoagulation outweigh benefits or if anticoagulation is contraindicated
* Systemic anticoagulation - useful where systemic anticoagulation is indicated but high risk for bleedings - heparin/LMWH, direct thrombin inhibitors
* Regional anticoagulation
– citrate - binds calcium which is required for activation of factors 2, 9, 10 and therefore thrombin generation. Citrate/Ca complexes that reach the systemic circulation are rapidly metabolised but can accumulate if there is liver of skeletal dysfunction
– heparin/protamine
– prostacyclins
Complications of CRRT
* Risks associated with central vascular access
– catheter placement - infection, bleeding, bruising, haematoma, damage to vessels, PTX, arrhythmias, emboli
– catheter dysfunction - fibrin deposition, distortion, kinking
* Risks associated with extracorporeal circuit - air embolism, reduced filter life and dialysis dose, hypothermia, bioincompatibility, immunologic activation, anaphylaxis, hypotension
* Haematological complications - associated with anticoagulation
* Electrolyte disturbances - low phosphate, magnesium, calcium, potassium, sodium, high sodium
* Acid-base disturbances - metabolic acidosis/alkalosis, citrate induced alkalosis/acidosis
* Nutritional losses - amino acids, proteins, poor glycaemic control, vitamin deficiencies, trace minerals
* Volume management errors
* Altered drug removal
* Delayed renal recovery
Renin
Polypeptide hormone
Production: Juxtaglomerular cells of the kidney
Secretion: Pericytes
Site of action: Bloodstream
Effects: activates RAAS by converting angiotensinogen to angiotensin I
Release stimulated by: decrease in arterial BP detected by baroreceptors, decrease in Na load delivered to the distal tubule (measured by macula densa), b1 adrenergic stimulation
Release inhibited by: angiotensin II
Second Messengers
Organic molecules that are produced within a cell to initiate the response to a signal carried by an agonist that does not itself enter the cell.
- In most cases, a ligand binds to a membrane-spanning receptor protein molecule –>
- causes conformational change in the receptor –>
- activity of receptor affected –>
- production of active second messengers
3 basic types of secondary messenger molecules:
* hydrophobic molecules - water insoluble which are membrane-associated and diffuse from the plasma membrane into the intermembrane space where they can reach and regulate membrane associated effector proteins e.g. diacylglycerol (DAG)
* hydrophilic molecules - water soluble molecules that are located within the cytosol e.g. cAMP, cGMP, IP3 and Ca++
* gases - can diffuse through cytosol and across cellular membranes e.g. NO, CO, H2S
G Protein Coupled Receptors
* Gs protein –> activation of the receptor stimulates conversion of ATP to cAMP via adenyly cylase –> production of protein kinase A (secondary effector)
* Gq protein –> activation of the receptor stimulates conversion of PIP2 to IP3 and DAG via phospholipase C –> IP3 then binds to calcium pumps on the endoplasmic reticulum, transporting calcium into the cytoplasm, DAG causes production of protein kinase C
Other examples
* ANP/NO –> activation stimulates conversion of GTP to cGMP via guanyly cylase –> production of protein kinase G
Shock
- Life threatening state whereby there is globally insufficient delivery and/or utilisation of oxygen at the cellular level.
- Characteristically but not always associated with low blood pressure and impaired tissue perfusion
- Consequence of shock is cellular and tissue hypoxia, ultimately cellular death and organ dysfunction
Cardiogenic Shock
* impaired contractility
* inadequate CO as a result of cardiac failure
* myocardial ischaemia and complications, myocarditis, myocardial contusion, septic shock, poisoning or toxic exposure, end stage cardiomyopathy, dysrhythmia, valvular dysfunction, LVOT obstruction
Hypovolaemic Shock
* inadequate circulating volume secondary to fluid loss
* haemorrhage - traumatic or non-traumatic
* fluid losses - GI losses, excessive diuresis, excessive diaphoresis, burns, third spacing (pancreatitis, severe sepsis, anaphylaxis), iatrogenic (e.g. post dialysis)
Distributive Shock
* inadequate perfusion secondary to maldistribution
* neurogenic shock
* liver failure
* adrenal insufficiency
* anaphylaxis
* septic shock
* post bypass vasoplegia
* drugs and toxic exposures
Obstructive Shock
* inadequate CO as a result of mechanical obstruction
* within the circulatory system - massive PE, atrial thrombosis or myxoma, occlusive valvular lesion, other emboli (e.g. air, amniotic fluid)
* external to the circulatory system - tamponade, abdominal compartment syndrome, PTX, dynamic hyperinflation, tension pneumomediastinum, caval compression
Smoking cessation
- Quitting smoking before surgery leads to a reduced incidence of postoperative complications
- The longer the period of cessation before surgery, the greater the benefit
- RCOA advises that people who smoke should quit for at least several weeks preoperatively and may benefit from abstaining on the day of surgery
— half life of CO when breathing air is 4hrs
— half life of nicotine is 30 mins - There is no clear evidence of harm from smoking cessation within a few hours or days
- NICE recommends that patients who smoke should be identified and offered intensive support to quit
- More likely to quit if offered a combination of interventions - combined behavioural support and pharmacotherapy
- All HCPs should be trained to give brief advice on stopping smoking
— Ask and record smoking history
— Advise that the most effective way to quit is with a combination of medication and specialist support
— Act on the patient response - give information, refer and prescribe
Drugs
* Nicotine replacement therapy - patches, inhalators, vapes, chewing gum, lozenges
* Varenicline - nicotinic receptor partial agonist
* Bupropion - nicotinic receptor antagonist with dopaminergic and adrenergic actions - may work by blocking the effects of nicotine, relieving withdrawal or reducing depressed mood
Soda Lime
- Used to absorb expired CO2 from the breathing system to prevent CO2 retention.
- 100g of soda lime can absorb >15L of carbon dioxide.
- Contains 75% calcium hydroxide Ca(OH)2, 20% water and 5% NaOH/KOH
- Granules are 4-8 mesh (mesh with 4 holes per square inch) size - balance between surface area (speec/efficacy of reaction) and resistance to flow
Reactions
* Carbon dioxide reacts with water in the soda lime to form carbonic acid:
* H2O + CO2 –> H2CO3
- Carbonic acid reacts with sodium hydroxide to form sodium carbonate and water:
- H2CO3 + 2NaOH –> Na2CO3 + 2H2O + heat
- Carbonic acid reacts with slaked lime (calcium hydroxide) to form calcium carbonate and water:
- H2CO3 + Ca(OH)2 –> CaCO3 + 2H2O
- Sodium carbonate reacts with the calcium hydroxide to form calcium carbonate and sodium hydroxide:
- Na2CO3 + Ca(OH)2 –> CaCO3 + 2NaOH
Sodium
- Most abundant cation in the Extracellular fluid compartment
- Requires 1.0-2.0mmol/kg/day
- Normal plasma sodium concentration is 135-145mmol/L
- Intracellular fluid concentration is approximately 10-12mmol/L
- Maintenance of this transmembrane concentration gradient is necessary for generating the resting membrane potential and for action potential propagation
- Also the main osmotic solute in the ECF - water travels in the direction of increasing Na concentration via osmosis
- Essential in regulating intravascular volume and is highly linked to fluid balance and BP
Hyponatraemia
* speed of onset more important than level
* most patients won’t be symptomatic until Na+ <125mmol/L
* nausea + vomiting
* neuropsychiatric symptoms
* headache, lethargy
* seizures, coma
* if hypovolaemic - treat cause, give isotonic saline
* if euvolaemic (SIADH) - fluid restrict, frusemide, NaCL tables, demeclocycline
* if hypervolaemic - fluid restrict, frusemide
* if chronic symptomatic - max 10mmol/L/day correction
* if acute symptomatic - raise by 1-5mmol/hr until symptoms resolve or Na+ 125-130mmol/L (hypertonic saline 3% 1-2ml/kg/hr)
Hypernatraemia
* excessive thirst
* CNS dysfunction - lethargy weakness, confusion, irritability, myoclonic jerks, seizures
* evidence of dehydration - dry mouth, abnormal skin turgor, oliguria, tachycardia, orthostatic hypotension
* treat cause
* rehydrate
* central DI - DDAVP + 5% dex to correct H2O deficit
* nephrogenic DI - Na+ restriction, thiazide diuretics, DDAVP
Somatostatin
Polypeptide hormone
AKA growth hormone inhibiting hormone
Production: ventromedial nucleus of the hypothalamus
Secretion: delta cells at several locations in the digestive system
Site of action: parietal cells, anterior pituitary
Effects: inhibits secretion of pancreatic polypeptides including insulin and glucagon, inhibits release of GH, TSH and PRL, decreases gastric emptying and motility of GI tract
Release stimulated by: Glucose, amino acids, ketone bodies, CCK, gastrin, secretin, insulin (at high glucose concentration)
Release inhibited by: Splanchnic nerve stimulation, noradrenaline
Metabolism: Peptidase enzymes in plasma and tissues
Hypersecretion: somatostatinoma
Storage of Blood Products
RBCs
- collected into bag containing CPD
—> C = citrate - chelates calcium, anticoagulant
—> P = phosphate - prevents decrease in pH
—> D = dextrose - supports ATP generation
- store at 2-6 degrees C
- added preservatives - SAGM - shelf life 35 days
—> S = saline
—> A = adenine - synthesises ATP
—> G = glucose - supports ATP generation
—> M = mannitol - prevention of haemolysis
- stored RBCs —> decrease in % of viable RBCs, decrease in pH, decrease in 2,3-DPG, decrease in O2 affinity, decrease in Na+, increase in K+
Platelets
- stored at room temperature (20-24 degrees C)
- gentle agitation
- platelet additive solution (NaCl, citrate, acetate, phosphate, K, Mg)
- shelf life 5-7 days
FFP
- stored in freezer (<25 degrees C)
- shelf life 36 months
- can keep for 24hrs at 4 degrees C after thawing
- A/AB is universal donor
- RhD matching not required
Structure/Function Relationships
Barbituric acid
* addition of phenyl group —> anticonvulsant
* addition of alkyl group —> hypnotic
* increase in number of side chains —> increased hypnotic potency
* more than 6 carbon side chains —> convulsant properties
* addition of sulphur at C2 —> increases solubility and increases speed of onset as it allows the molecule to cross the blood brain barrier more easily
* addition of methyl group at N1 —> increases excitatory/convulsant side effects
Volatiles
* Cl/Br —> increases potency
* F —> increases stability and SVP, minimises flammability, decreases toxicity and potency
* Ether —> increases stability
* large number of hydrogen atoms increases flammability and potency
* CF2H moiety can liberate CO in reaction with dry soda-lime
Local Anaesthetics
* composed of lipophilic aromatic group, intermediary link and hydrophilic amine group
* intermediary group categorises LA into esters (cocaine, chlorpromazine, prilocaine) or amides (bupivacaine, lidocaine, Ropivacaine)
* increased bulk of amine side chain groups added to aromatic portion leads to increased lipid solubility and protein binding leading to increased potency and prolonged duration of action
* replacement of the tertiary amine by a pipe riding ring increases lipid solubility and duration of action
* addition of butyl group in place of the amine on the benzene ring of procaine —> amethocaine/tetracaine
* addition of propyl group to the amine end of mepivacaine —> ropivacaine (lower lipid solubility that allows more selective sensory block than bupivacaine)
* addition of butyl group to the amine end of mepivacaine —> bupivacaine (longer duration of action)
Summary of Pituitary Hormones
Anterior Pituitary (production and secretion)
* ACTH - stimulates adrenal gland to produce cortisol in response to CRH
* TSH - stimulates thyroid to secrete thyroxine in response to TRH
* LH/FSH - controls reproductive function and sexual characteristics, stimulates ovaries to produce oetrogen/progesterone and tests to produce testosterone in response to GnRH
* Prolactin - stimulates breasts to produce milk in response to PRLH
* GH - stimulates growth and repair in response to GHRH
* MSH - exact role in humans unknown
Posterior Pituitary (secretion)
* ADH - affects water retention by kidneys to control body fluid and electrolytes in response to changes in plasma osmolality/tonicity and baroreceptor detection of reduced circulating volume
* Oxytocin - affects uterine contractions and release of breast milk in response to suckling
The Cell Cycle
G1 - cell growth. The cell is metabolically active and protein synthesis occures. No DNA replication occurs.
S - synthesis stage where DNA replication occurs. DNA helicase unwinds the DNA strands and DNA polymerase extends the DNA chain. Topoisomerase prevents the supercoiling of DNA during the cell replication process
G2 - cell growth and protein synthesis in preparation for mitosis
M - mitosis (cell division)
G0 - resting phase
Mitosis:
* prophase - condensation of chromosomes and the beginning of the formation of microtubules. Centromeres migrate to the poles of the cell to form mitotic spindles.
* prometaphase - nuclear membrane breakdown and attachment of microtubules to the chromosomal kinetochores
* metaphase - chromosomes migrate to the equatorial centre of the cells with centromeres at the poles of the cells
* anaphase - separation of daughter chromatids by depolymerisation of microtubules
* telophase - reassembly of the nuclear membrane with the disassembly of microtubule complexes. Decondensation of chromosomes occurs.
The Ideal Inhaled Anaesthetic Agent
Physiochemical properties
- liquid at room temperature
- high SVP (vaporisable at room temperature)
- low specific heat capacity
- long shelf-life
- light stable
- heat stable
- does not react with the components in the breathing circuit - rubber, metal, plastic, soda lime
- not flammable/explosive
- smells nice
- preservative free
- environmentally friendly
- cheap
- easy to manufacture
Pharmacokinetic properties
- high oil:gas partition coefficient - low MAC (high potency)
- low blood:gas partition coefficient - rapid onset and offset
- not metabolised/minimal metabolism to non toxic metabolites
- non toxic
Pharmacodynamic
- does not cause laryngospasm or airway hyperreactivity
- bronchodilation
- no effect on haemodynamic parameters
- analgesic
- hypnotic
- amnestic
- anti-epileptic
- no increase in ICP
- skeletal muscle relaxation
- anti-emetic
- no tocolytic effects
- not teratogenic or otherwise toxic
- no drug interactions
- not a trigger for MH
The Nephron
Glomerulus
* loop of capillaries, surrounded by Bowman’s capsule
* filtration under pressure (generated by afferent and efferent arterioles) of 7L/hr
* small molecules are freely filtered, larger molecules barely cross the barrier
* negatively charged molecules filter less easily than positively charged
Proximal Convoluted Tubule
* Reabsorption of many ions - 70% Na/H2O/K/Cl, 100% glucose/amino acids, 85-90% HCO3
* Sodium glucose linked transporters - then facilitated diffusion of glucose
* Na+/H+ antiporter
* Na+/amino acid symporter
* Na+/HCO3- symporter
* Na+/K+ antiporter
* H2O reabsoprtion via osmosis
* H+ + HCO3~ –> H2CO3 via carbonic anhydrase
* Secretion of organic acids and bases e.g. bile salts, oxalate, catecholamines, H+ ions and drugs/toxins (via H+/OC+ exchanger) into tubular lumen
Thin descending limb of Loop of Henle
* Passive reabsorption of water via AQP1 channels
* Small amounts of urea, Na and other ions are reabsorbed
* Active reabsorption of sodium in the thick ascending limb drives the counter-current multiplier system
Thin ascending limb
* Impermeable to water
* Passive sodium reabsorption via epithelial Na+ channels (eNaC)
* Cl- ion reabsorption through chloride channels
Thick ascending limb
* Impermeable to water
* Active sodium reabsorption via Na+/K+/ATPase - low intracellular concentration of sodium creates an electrochemical gradient
* NKCC2 transporter - 1x Na, 1x K, 2x Cl taken up from tubular lumen
* K+ transported back tinto tubule by renal outer medullary potassium (ROMK) channels
* Some paracellular reabsorption of Mg, Ca, Na, K
Early Distal Convoluted Tubule
* Absorption of ions including Na, Cl, Ca
* Impermeable to water
* Macula densa in 1st segment - involved in tubuloglomerular feedback
* Na/K-ATPase transporter
* Sodium-chloride cotransporter
* Chloride ion uniporter moves chloride into the extracellular fluid
* Sodium-calcium antiporter
* PTH inserts calcium channels to increase calcium reabsorption
Late Distal Convoluted Tubule
* Principle cells - involved in uptake of sodium and extrusion of potassium
* Na+/K+-ARPase
* Sets up gradient for sodium to enter through ENaC channels
* Intercalacted cells assist in acid base control by controlling levels of H+ and HCO3-
* Type A intercalated cells - actively secrete H+ whilst reabsorbing HCO3-
* Type B intercalated cells - net effect is secretion of HCO3- and reabsorption of H+
Collecting Duct
* Determines final urine concentration via H2O excretion
* ADH from hypothalamus inputs AQP2 channels, increasing ability to reabsorb water from the filtrate
* UO 100ml/hr
Thromboxane
Eicosanoid hormone
Production: Platelets from arachidonic acid
Secretion: Platelets
Site of action: Thromboxane receptor (Gq) in lung, spleen, uterus + placenta, aorta, heart, intestin, liver, eye, thymus, kidney, spinal cord and brain
Effects: vasoconstrictor, potent hypertensive agent, facilitates platelet aggregation
Release stimulated by: vascular damage
Release inhibited by: aspirin, dipyridamole, naproxen (high dose)
Metabolism: degraded to weaker form
Thyrotropin-releasing hormone
Production: Hypothalamus (parvocellular neurons of the paraventricular nucleus)
Secretion: Hypothalamo-hypophyseal portal circulation
Site of action: Anterior pituitary
Effects: Stimulates release of TSH and prolactin
Release stimulated by: cold, stress, exercise, low T3/T4
Release inhibited by: ghrelin, increased T3/T4, dopamine
Thyroxine (T4)
Amine hormone
Production: Follicular cells of the thyroid gland, from tyrosine
Secretion: From thyroid
Site of action: Thyroid hormone receptors (nuclear receptors) on nearly every cell in the body. Metabolised to more active T3 form
Effects: Increased metabolism - increased MV due to increased CO2 production, increased HR, increased inotropy, increased CO, decreased SVR and DBP, increased CNS excitability, increased osteoblastic activity, impotence/oligomenorrhoea, increased GIT motility, increased BMR
Release stimulated by: TSH from the anterior pituitary gland
Release inhibited by: Negative feedback loop, elevated T3/T4 inhibit production of TSH
Metabolism: as sulphate and glucuronide form in the bile, urinary excretion
Hypersecretion: Hyperthyroidism
Hyposecretion: Hypothyroidism
Tri-iodothyronine (T3)
Amine hormone
Production: Thyroid follicular cells, liver, kidney, CNS, pituitary, brown adipose tissue, heart vessel, synthesised from thyroxine
Secretion: From site of production
Site of action: Thyroid hormone receptors (nuclear receptors) on nearly every cell in the body
Effects: Increased metabolism - increased MV due to increased CO2 production, increased HR, increased inotropy, increased CO, decreased SVR and DBP, increased CNS excitability, increased osteoblastic activity, impotence/oligomenorrhoea, increased GIT motility, increased BMR
Release stimulated by: TSH from the anterior pituitary gland
Release inhibited by: Negative feedback loop, elevated T3/T4 inhibit production of TSH
Metabolism: as sulphate form in bile, glucuronide form in bile or urinary exretion
Hypersecretion: Hyperthyroidism
Hyposecretion: Hypothyroidism
TSH (Thyroid Stimulating Hormone)
Glycoprotein hormone
Production: Anterior pituitary
Secretion: Anterior pituitary
Site of action: Thyroid
Effects: Stimulates follicular activity and the synthesis and release of thyroid hormones (T3 and T4).
Release stimulated by: TRH
Release inhibited by: Somatostatin, thyroid hormones
Hypersecretion: Secondary hyperthyroidism
Hyposecretion: Secondary hypothyroidism
Types of Hormones
- Polypeptides e.g. ADH, oxytocin, ACTH, PTH, FSH-RH, LH-RH, ACTH-RH, TRH, calcitonin, insulin, glucagon, somatostatin
- Glycoproteins e.g. FSH, LH, TSH
- Steroids e.g. aldosterone, corticosteroids, androgens
- Amines e.g. dopamine, adrenaline, noradrenaline, thyroxine, tri-iodothyronine
- Fatty acid derivatives e.g. prostaglandins, vitamin D
Types of Hypersensitivity Reaction
- Type I - Immediate/Anaphylctic
— IgE mediated
— mast cells, basophils - Type II - antibody dependent
— cytotoxic
— IgM, IgG + surface antigen
— e.g. transfusion reactions, HIT-2 - Type III - immune-complex mediated
— antigen + IgM/IgG form complex —> activate complement pathway
— e.g. RA/SLE - Type IV - delayed
— antigen + T cell —> macrophage activation
— e.g. contact dermatitis, Tuberculin test
Types of Hypoxia
- Hypoxic hypoxia —> low PaO2 and PvO2
— decreased FiO2
— decreased MV
— diffusion defect
— VQ mismatch - Anaemic hypoxia —> normal PaO2, low PvO2
— low Hb
— decreased ability of Hb to carry O2 (eg. CO) - Stagnant hypoxia —> normal PaO2 and PvO2
— decreased tissue or organ perfusion - Histotoxic hypoxia —> normal PaO2, increased PvO2
— tissues unable to utilise O2
Types of Muscle
- Skeletal muscle - striated, sarcoplasmic reticulum present, t-tubules
— Type I - slow oxidative
— Type IIa - fast oxidative
— Type IIb - fast glycolytic
Troponin binds to calcium.
Nerve impulse initiates contraction.
No gap junctions. - Cardiac - striated, moderately developed SR present, t-tubules
Troponin binds to calcium.
Pacemaker cels initiate contraction.
Gap junctions present - intercalated discs. - Smooth muscle - not striated, poorly developed SR, no t-tubules
Calcium binds to calmodulin
Pacemaker potential.
Gap junctions.
Types of Nerve Fibres
SENSORY and MOTOR
* A - alpha: motor - large, heavily myelinated, fast
* A - beta: touch/pressure - medium, heavily myelinated, moderately fast
* A - gamma: intrafusal fibres - medium, heavily myelinated, moderately fast
* A - delta: touch/pressure/temperature/fast pain - small, heavily myelinated, moderately fast
* B: preganglionic autonomic nerves, small, lightly myelinated, moderately fast
* C: slow pain, postganglionic autonomic nerves, olfaction - small, unmyelinated, slow
SENSORY ONLY
* Ia: muscle spindle afferents - large myelinated, fast
* Ib: Golgi tendon organ afferents - large myelinated, fast
* II: secondary afferents of muscle spindles: touch/pressure - medium, myelinated, moderate
* III: touch/pressure/fast pain/temperature - small, myelinated, moderate
* IV: pain/temperature/olfaction - small, unmyelinated, slow
Types of Receptors
- Ligand gated ion channel receptor - integral membrane proteins that contain a pore which allows the regulated flow of selected ions across the plasma membrane - bind neurotransmitters and open in response to ligand binding
- G-protein coupled receptor - integral membrane proteins that are activated, creating a conformational change in the receptor leading to activation of a G protein
- Tyrosine kinase linked receptor - cell surface receptors that when bound, phosphorylate and propogate a signal through the plasma membrane.
- Intracellular nuclear receptors - once bound, undergo conformational change which triggers a cascade of events that direct the receptor to DNA transcription regulation sites, resulting in up or down regulation of gene expression
Urinary Indices in AKI
Pre-Renal
— urine osmolality >500mOsm/kg (normal)
—— high = serum osmolality = 100
— low urinary sodium
— high urine/plasma urea and creatinine
— high specific gravity
— hyaline casts
Renal
— low urine osmolality <350
— high urinary sodium
— low urine/plasma urea and creatinine
— fixed/normal specific gravity
— brown sediment, granular casts
Post-renal (late)
— low urine osmolality <350
— high urinary sodium
— low urine/plasma urea and creatinine
— low specific gravity
— bland sediment
Variability of Drug Response
There are four mechanisms which result in variable response to a drug:
* Alteration in drug that reaches the receptor - typically due to pharmacokinetic factors
* Relative difference in presence of exogenous and endogenous ligands
* Variation in receptor function and number
* Alteration in function distal to the receptor
Physiological
* age - liver function, GFR, Vd
* gender
* pregnancy
* tobacco
* ETOH
Pharmacological
* idiosyncratic - individual patient response to a drug - typically mediated by a reactive metabolite rather than the drug itself
* pharmacogenetic
* tachyphylaxis - rapid decrease in response to repeated dosing over a short time period, usually due to depletion of transmitter
* up/down regulation of receptors
* Densistisation - loss of response over a long period of time, usually due to change in receptor morphology or loss in receptor numbers
* tolerance - requirement for a larger dose to achieve the same effect - due to altered sensitivity of the receptors to the stimulant
– pharmacokinetic - altered drug metabolism (increased or decreased)
– pharmacodynamic - change in receptor morphology, receptor down-regulation, receptor up-regulation, exhaustion of mediators, physiological adaptation, active removal of the drug from the cell
* drug interactions
– synergistic
– additive
– antagonistic
Pharmacokinetic
* factors affecting absorption
– food, PPIs altering gastric pH, gut microbiome, CO and blood flow to site of injection (central vs peripheral, SC vs IV), rate of administration
* factors affecting distribution
– protein metabolism, fluid balance
* factors affecting metabolism
– metabolising organ function, metabolising organ blood flow, factors affecting chemical reaction rate (e.g. body temperature, pH)
* factors affecting clearance
– clearance organ function, clearance organ blood flow
Pathological
* liver function
* renal impairment
* cardiac disease - CO
* obesity
* neurological e.g. myaesthenia, myopathy, autonomic neuropathy
Vocal Cord Palsies
- Causes of laryngeal nerve damage
– malignant - thyroid, lung
– vascular - aortic aneurysm
– cervical lymphadenopathy/infective
– iatrogenic - surgery, ETT
– traumatic - neck or chest
– neurological - MG, CMT, MS
– congenital - hydrocephalus, TOF
Partial RLN damage:
Cords are held in midline position as abductors are more affected than adductors
* Unilateral palsy - hoarse voice
* Bilateral palsy - complete airway obstruction
Complete RLN damage:
Cords are held midway between midline and abducted position
* Unilateral - stridor
* Bilateral - loss of voice and aspiration
Superior laryngeal nerve damage
* weak voice because of slack vocal cords
Vomiting Reflex
Afferents
* GI tract - mechano and chemoreceptors vis the vagus nerve to the NTS in the brain stem (involving cholinergic, 5HT3, dopamine and NK1 receptors)
* CTZ - area postrema in the floor of the 4th ventricle, outside BBB - responsible for detecting toxins in blood and CSF (5HT3), also the nausea associated with sleep deprivation
* Vestibular system - especially motion sickness (H1 and H2)
* CVS - afferents mainly from the baroreceptors
* Higher centres - sights, sounds, smells, unpleasant thoughts
* Pharyngeal afferents
* Auricular branch of the vagus nerve
* Visceral pain
Vomiting Centre
* not an anatomical entity
* several nuclei in the brain stem responsible for coordinating the efferent limb of the vomiting reflex
— nucleus tractus solitaries
— dorsal vagal nuclei
— reticular formation
— respiratory neural networks
* receives input from the afferent limbs of the reflex
What affects volume of distribution?
Drug properties
- % plasma protein binding
- % tissue protein binding
- molecule size
- molecule charge
- pKa
- lipid/water partition coefficient (aka lipid solubility)
Patient factors
- blood flow to the various tissues
- age
- gender
- body muscle/fat proportion
- level of hydration
- water distribution (oedema, effusions, ascites, pregnancy)
- extracorporeal sites of distribution (circuit, filters, oxygenator etc)
What influences basal metabolic rate?
- age (increased in children)
- gender (higher in men than men)
- body surface area
- stress
- catecholamines
- increased temperature
- hyperthyroidism
- muscle activity
- pregnancy/breast feeding
What is Hypoxic Pulmonary Vasoconstriction
- Reflex contraction of vascular smooth muscle in the pulmonary circulation in response to a low partial pressure of oxygen
- Aims to divert blood flow away from hypoxic areas of the lungs to areas with better ventilation and oxygenation
- Increases PVR and PAP - can precipitate right heart failure
Stimulus = tissue partial pressure of oxygent in the region of the pulmonary arteriole (determined by ppO2 in alveolus or in mixed venous blood
Biological oxygen sensing theories
- direct modulation of K channels
- changes to cytoplasmic redox state
- mitochrondria reactive oxygen species production
- cellular energy state e.g. concentrations of high-energy compounds
- alteration of membrane-bound protein function
- activation of transcription enzymes via hypoxia inducible factor
- alterations of cyclo-oxygenase or lipoxygenase systems
Site of action = pulmonary arterial smooth muscle cells (PASMCs)
PASMC contraction –> narrowing of vessels –> reduced blood flow
- membrane depolarization after sodium ion influx
- leads to increase in cytosolic calcium ion concentration
- increase in Ca ions binding to calmodulin, activiating myosin light chain kinase
- alteration in shape of myosin results in contraction of the smooth muscle
Modulation = localised mediators produced by pulmonary endothelial cells in the presence of hypoxia
- NO - smooth muscle relaxation caused by reducing intracellular calcium
- prostacyclin - vasodilator - stimulates cyclic adneylate cyclase and increases cAMP
- endothelin-1 - small peptide paracrine mediator with potent vasoconstrictor properties - acts via G protein receptors
Whipples Triad
Signs suggestive of insulinoma
1. Signs and symptoms of hypoglycaemia
2. Low plasma glucose level
3. Resolution of symptoms once glucose level raised
Yellow Flags
Psychosocial risk factors for chronicity and disability
* Belief that pain is potentially severely disabling
* Fear avoidance behaviour
* Low mood and social withdrawal
* Expectation of passive treatment rather than belief that active participation can help
STARTback tool –> risk of developing chronic pain
* Attitudes
* Beliefs e.g. catastrophising
* Compensation
* Diagnosis
* Emotions e.g. depression/anxiety
* Family e.g. overbearing/undersupportive
* Work (relationship with)
