2022A

2022 (1st sitting)

Question 1

Question

Outline the effects of critical illness on drug pharmacokinetics, including examples

Example answer.

Absorption

• Oral
  • Decreased CO > decreased GIT blood flow > decreased absorption PO drugs
  • Ileus + uraemia > decreased gastric emptying > decreased absorption of PO drugs
  • Diarrhoea > fast transit time > decreased absorption
  • Change in gastric pH (e.g. with PPI) alters drug absorption
  • Decreased GIT blood flow (vasoconstrictors, barbiturates) > decreased PO absorption
• Topical/IM/SC
  • Vasoconstriction > poor tissue perfusion > decreased/slow absorption
• Inhalational
  • Decreased MV / TV > decreased delivery of aerosolised medications

Distribution

• Altered Vd
  • Decreased CO (e.g. shock) > slower redistribution
  • Increased CO (e.g. hyperdynamic sepsis) > faster residistribution
  • Hypervolaemia (e.g. renal, cardiac, liver failure) > increased Vd (vice versa)
  • Critical illness > muscle wasting > alter lean mass percentage (alters Vd)
• Protein binding
  • Decreased protein synthesis (e.g. decreased albumin) > increased unbound fraction of drug > increased Vd and drug activity
  • Acid-base disturbances will alter free drug levels depending on drug pKa and the pH
• Inflammation > impairs barrier function (e.g. BBB) > increased penetration of meds (e.g. penicillins)

Metabolism

• Decreased CO > decreased hepatic/renal blood flow > decreased metabolism (e.g. propofol)
• Liver dysfunction > Impaired phase 1 and 2 reactions and reduced 1st pass effect > (e.g. labetalol, metoprolol)
• Renal dysfunction > decreased renal metabolism > prolonged drug effect (e.g. morphine)
• Hypothermia > decreased metabolism > Prolonged effect (e.g midazolam)
• Resp dysfunction > Decreased resp metabolism of drugs (e.g. opioids) > prolonged effect

Elimination

• Decreased CO (e.g. cardiogenic shock) = decreased GFR / HBF > decreased clearance (e.g. gentamicin)
• Increased CO (e.g. hyperdynamic sepsis) > increased GFR > increased clearance
• Liver dysfunction > impaired biliary excretion of drugs (e.g. vecuronium, rifampicin)
• Decreased GFR (e.g. AKI) > decreased renal elimination drugs (e.g. Gentamicin, milrinone)
• Reduced MV > decreased / slower clearance of volatile anaesthetics > prolonged effect

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Question 13, 2013 (1st sitting)

Question 2

Question

Explain the mechanisms of transport of substances across cell membranes including appropriate examples (75%). Outline the structure of the Na⁺/K⁺-ATPase pump (25%)

Example answer

Transport across cell membranes

Mode	Mechanism	Energy expenditure	Electrochemical gradient	Example	Factors affecting
Passive (simple) diffusion	Molecule passes through cell membrane	No (passive)	With/down	CO2 and pulmonary vascular endothelium	Fick's law of diffusion
Facilitated diffusion	Molecule crosses membrane via transmembrane protein	No (passive)	With/down	Glucose with the GLUT transporter	Ficks law diffusion and number of carrier proteins
Ion channels	Membrane spanning proteins (voltage, ligand or mechanical gated) > conformational change > opening of ion channel	No (passive)	With/down	nACHR (Ach is ligand) with Na/K as ions	Concentration gradient, number of channels
Primary active transport	Molecule crosses membrane via carrier proteins	Yes (active) requires ATP	Against	Na/K ATPase pump	Availability of carrier, substrate and ATP
Secondary active transport (symport or antiport)	Molecule crosses membrane via a carrier protein, with the energy being provided for the transport of another molecule	Yes (but not directly)	Against	Na / H antiporter in principle cells of renal collecting ducts	Availability of carrier, substrate and ATP
Endocytosis	Cell membrane invaginates around a large molecule > engulfs it > contained within vesicle	Yes	Usually against	Phagocytosis	Poorly understood. ATP
Exocytosis	Vesicle (containing molecule) fuses with cell membrane > release of molecule	Yes	Usually against	Exocytosis of ACh at the pre-synaptic cleft of the NMJ	Poorly understood. ATP

File:Https://derangedphysiology.com/main/sites/default/files/sites/default/files/CICM Primary/E Cellular Physiology/cell transport across membranes2.JPG

Na/K-ATPase pump

• Membrane bound protein pump
• Structure
  • Transmembrane protein, consists of two globular proteins
    • Large alpha subunit (MW = 105kDa)
    • Small beta subunit (MW 55kDa)
  • Three binding sites for Na on internal surface, two binding sites for K on external surface
  • ATPase activity at the Na binding site
• Function/Features
  • Antiport --> pumps 3 Na out and 2 K in
  • Energy dependant (requires ATP)
• Process
  • Once Na/K binding sites full, ATPase cleaves ATP > release energy > conformational change > 3na out and 2K in
• Function
  • Controls cell volume (prevents Gibbs Donnan equilibrium)
  • Electrogenic (contributes to RMP)

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Question 10, 2012 (2nd sitting)

Question 3

Question

Define respiratory compliance, include its components and their normal values (25% marks). Explain the factors that affect respiratory compliance (75% of marks)

Example answer

Respiratory compliance

• <math display="inline">Compliance \; = \; \frac{\Delta \;volume}{\Delta \; pressure}</math>
• Compliance in the respiratory system (C_RS) is a function of lung (C_lung) and chest wall (C_CW) compliance
  • <math display="inline">\frac {1}{C_{RS}}\; = \; \frac {1}{C_{Lung}} \; + \; \frac {1}{C_{CW}}</math>
  • Chest wall and lung compliance are roughly equal in healthy individual (~200mls.cmH2O)
  • Thus normal compliance of the respiratory system is ~100mls.cmH2O
• Static compliance
  • Compliance of the respiratory system at a given volume when there is no flow
• Dynamic compliance
  • Compliance of the system when there is flow (respiration)
  • Will always be less than static compliance due to airway resistance
  • At a normal RR is approximately equal to static compliance
• Specific compliance
  • The compliance of the system divided by the FRC
  • Allows comparisons between patients which are independent of lung volumes

Factors effecting compliance

Chest wall

• Increased
  • Collagen disorders (e.g. Ehlers-Danlos syndrome)
  • Cachexia
  • Rib resection, open chest
• Decreased
  • Obesity
  • Kyphosis / scoliosis / Pectus excavatum
  • Circumferential burns
  • Prone positioning

Lung compliance

• Increased

  • Normal ageing

  • Emphysema

  • Upright posture

  • Lung volume (highest compliance at FRC)

• Decreased

  • Loss of surfactant (E.g. ARDS, hyaline membrane disease)

  • Loss of functional lung volume (e.g. pneumonia, lobectomy, pneumonectomy, atelectasis)

  • Pulmonary venous congestion (pHTN) and interstitial oedema (APO)

  • Reduced long elasticity (e.g. Pulmonary fibrosis)

  • Positioning (e.g. supine positioning)

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Question 17, 2019 (2nd sitting)
• Question 14, 2017 (1st sitting)
• Question 15, 2014 (1st sitting)
• Question 7, 2011 (2nd sitting)
• Question 13, 2007 (1st sitting)

Question 4

Question

Describe the mechanisms of action and potential adverse effects of inhaled nitric oxide and prostacyclin

Example answer

Nitric oxide MOA (inhaled)

• Pulmonary vasodilator
• Diffuses into smooth muscle cell > activates guanyl cyclase > increased conversion of GTP to cGMP > decreased intracellular calcium > relaxation of smooth muscle > vasodilation
• As it is inhaled it selectively vasodilates well ventilated alveoli, which leads to improved V/Q matching > decreased work of breathing and increased oxygenation

Prostacyclin MOA (inhaled)

• Pulmonary vasodilator
• Binds to prostacyclin receptor (IP receptor) > active GPCR > increased conversion of ATP to cAMP > decreased intracellular calcium > relaxation of smooth muscle > vasodilation
• Improves V/Q matching by the same mechanism of NO

Adverse effects (NO)

• May exacerbate left ventricle heart failure
  • Decreased pulmonary pressures > increased RV SV > increased LV preload
  • Can overwhelm an impaired LV > pulmonary oedema / worsening HF
• Vasodilatory effects
  • Leads to flushing, headache, hypotension
  • Less pronounced with inhaled therapy
• Rebound pulmonary hypertension and hypoxia
  • Occurs following abrupt cessation
  • Build up of vasoconstrictive molecules during therapy which are unopposed following cessation
• Thrombocytopaenia (up to 10%)
• Methaemaglobinaemia
  • Relatively rare
  • NO reacts with OxyHb to produce MetHb and nitrates
  • Significant amounts >5% only occurs at high doses e.g. > 20ppm
• Tachyphylaxis (over days)
• AKI
  • Usually with high doses > 20ppm
  • Relatively rare

Adverse effects (Prostacyclin)

• Inhibits platelet aggregation > increased risk of bleeding
• Rebound pulmonary hypertension and hypoxia (same mechanism as above)
• Exacerbate LV heart failure (same mechanism as above)
• Vasodilatory effects > flushing , headache, hypotension (less pronounced with inhaled)

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Question 17, 2020 (2nd sitting)
• Question 14, 2011 (1st sitting)

Question 5

Question

Write short notes on the pharmacology of labetalol and esmolol, highlighting their differences

Example answer

Name	Labetalol	Esmolol
Class	Alpha and beta blocker	Beta blocker
Indications	Hypertension	Short term management of tachycardia/hypertension in hospital settings (e.g. OT)
Pharmaceutics	100/200mg tablets Clear solution (5mg.ml, 10ml ampoules) Mixture of stereoisomers	Clear/slight yellow colourless solution 100mg/10ml
Routes	IV, PO	IV only
Dose	IV: 5-20mg boluses, infusion 1-2mg.min PO: 100-800mg BD	10mg boluses / infusion titrated to effect
Pharmacodynamics
MOA	a1 adrenergic antagonist Nonspecific Beta antagonist	B1 selective antagonist
Effects	CVS: decreased chronotropy, inotropy, dromotropy (beta effects), decreased SVR and afterload (alpha effects) > decreased myocardial oxygen consumption + decreased BP RENAL: B1 blockage at JG cells > decreased renin release > decreased BP	Same as labetalol (except no alpha mediated vasodilation)
Side effects	CVS: bradycardia, hypotension (esp orthostatic), heart block RESP: dyspnoea, bronchospasm CNS: dizziness GIT: nausea, raised LFTs	CVS: hypotension, bradycardia, heart block (B1 effects) RESP: NO bronchospasm or dyspnoea (no B2 effects) CNS: dizziness GIT: Nausea
Pharmacokinetics
Onset	1-2 hours (PO), <5 mins (IV)	Immediate (seconds-mins)
Absorption	PO bioavailability 25% (extensive 1st pass metabolism)	0% oral bioavailability
Distribution	50% protein bound VOD = 8L/kg	60% protein bound VOD 3.5L/kg
Metabolism	Hepatic (extensive) Glucuronide conjugation Inactive metabolites	Rapid metabolism - Hydrolysis by RBC esterases Inactive metabolites
Elimination	Renal (50%) / faecal (50%) elimination Inactive metabolites T 1/2 - 6 hours	Renal Inactive metabolites T 1/2 = 10 mins (parent)

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Question 9, 2021 (2nd sitting)
• Question 14, 2019 (2nd sitting)

Question 6

Question

Describe the cardiovascular changes seen throughout pregnancy

Example answer

Factor	Response during pregnancy	Comments
HR	Increases	by up to 25% Peaks in 3rd trimester
SV	Increases	by up to 25% Predominately in 1st trimester
CO	Increases	- Up to 50% - Due to increased blood volume, increased HR/SV, increased VR and decreased SVR - Majority > placenta (nutrient/gas to foetus), kidneys (80% increase, waste excretion), skin (regulates temp)
BP	Decreases	- By about 10% - Due to decreased SVR
Systemic vascular resistance	Decreases	- By up to 30% - Due to increased progesterone, PGs and downregulation of alpha receptors - Occurs predominately in 1st trimester
Blood volume	Increases	- By up to 40% - Due to stimulation of RAAS (oestrogen) and increased erythropoiesis (increased renal EPO) - Plasma volume increased > RBC volume increase > decreased HCT (dilutional anaemia)
CVP	Unchanged
Oxygen delivery	Increased	Due to increased CO
Aorto-caval compression	Increased	Due to weight of the gravid uterus > decreased VR
Colloid osmotic pressure	Decreases	Predisposes to oedema
Factor	Response during delivery	Comments
BP/VR/CO	Uterine contraction	By up to 50% Squeezes blood back into maternal circulation > increases VR > increased CO > increased BP
Factor	Response post partum	Comments
CO	Increased (immediately post)	By up to 80% Due to autotransfusion of blood normally directed toward placenta/foetus
CO/ BP	Decrease	Return to normal ~2 weeks post delivery

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Question 7, 2016 (first sitting)

• Question 19, 2013 (second sitting)

• Question 4, 2010 (second sitting)

Question 7

Question

Write notes comparing the use of serum creatinine and creatinine clearance in the assessment of renal function in the critically ill

Example answer

• Creatinine

  • Product of muscle metabolism

  • Freely filtered and not reabsorbed (but is partially secreted)

    • Given this, it can be used to approximate GFR (decreased GFR is indicative of worsening renal function)

Creatinine clearance (CrCl)

• CrCl = the volume of plasma cleared of creatinine per unit time

• Measuring CrCl

  • 1. Measure the plasma creatinine concentration

  • 1. 24 hour urine collection

  • 1. Use the fick principle to calculate the CrCl

    • CrCl = urine volume x urine concentration / plasma concentration

• Estimating CrCl

  • Measuring urine concentrations is cumbersome

  • Can be estimated using various formula

    • e.g. the Cockcroft-Gault equation and MDRD formulas

    • Uses Age, weight, gender and height to calculate CrCl from serum Cr

    • Not as accurate and makes several assumptions

Creatinine concentration

• Decreased renal function > decreased CrCl > increased Cr
• Therefore increased Cr is indicative of worsening renal function
• However
  • The relationship is non linear
  • Plasma creatinine concentration only begins to rise when ~50% of the renal function (GFR) is lost
  • Thus there is a significant decrease in GFR before a noticeable rise in Cr

Normal serum creatinine measurements do not exclude serious loss of...

Download Scientific Diagram

Limitations of serum creatinine as biomarker of renal function

• Creatinine is partially secreted > overestimates GFR
• Creatinine fluctuates
  • Increased with: increased protein consumption, muscle injury, steroid use
  • Decreased in: fasting, patients with low muscle mass, increased plasma volume (dilutional)
• Creatinine takes time to accumulate / only rises significantly following >50% of loss of renal function
• Therefore
  • Fluid resus or oedema > falsely low creatinine > falsely improving kidney injury
  • Patients with low muscle mass may have low Cr > masked kidney injury
  • Extremes of age / weight / muscle mass > unreliable results
  • Cr and CrCl detect kidney injury late
• The level of inaccuracy increases with extremes of renal function

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Question 11, 2013 (second sitting)

Question 8

Question

Describe the regulation of body water

Example answer

Overview

• Water intake
  • Approximately 25-30ml/kg of water is needed to be ingested for fluid/body homeostasis
    • ~2-2.5L per day for an average person
  • Approximately half comes from drinking fluids, half from food and metabolic processes
• Water is lost through numerous ways
  • Urine
    • ~1 - 1.5L / day
    • Obligatory loss is ~500mls to cover solute/waste clearance
  • Insensible losses (skin, lungs etc)
    • ~900mls / day
  • Faeces
    • ~100mls / day
• The body tightly regulates water balance to preserve plasma osmolality and intravascular volume status, but also allow waste clearance
  • Note: Preservation of blood volume takes precedence over plasma osmolality

REGULATION

• Sensor
  1. Osmoreceptors in hypothalamus detect increased (>290mosm/L) osmolality with dehydration (major)
  2. Low pressure baroreceptors (RA, great vessels) detect reduced pressure (stretch) with dehydration
  3. High pressure baroreceptors (carotid sinus, aortic arch) detect reduced pressure (stretch) with dehydration
  4. Macula densa (kidneys) detect reduced GFR (Na/Cl delivery) with dehydration
• Integrator
  • Hypothalamus (anterior and lateral regions, predominately)
• Effector/effects
  1. Release of ADH
     • Synthesised in hypothalamus, transported to posterior pituitary for release
     • ADH acts on collecting ducts in the kidney in to increase aquaporins on luminal wall --> increased water reabsorption
     • Released in response to increase osmolality and activation of RAAS
  2. ANP/BNP
     • Decreased stretch > decreased ANP/BNP secretion --> increased water reabsorption
  3. RAAS
     • Decreased baroreceptor activation --> increased renin release
     • Decreased GFR sensed by macula sensa > increased renin release
     • Renin > activation of RAAS > increased water reabsorption
  4. Thirst centre (hypothalamus)
     • Activation of thirst centre in the lateral hypothalamus (due to increased osmolality) > behavioural change to increase water intake
• Feedback
  • The above systems work predominately on a negative feedback system

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Question 1, 2021 (2nd sitting)
• Question 8, 2008 (1st sitting)
• Question 4, 2015 (1st sitting)
• Question 9, 2018 (2nd sitting)

Question 9

Question

Describe the pharmacology of 4% albumin

Example answer

Name	Albumin
Class	Colloid (human plasma protein suspended in crytaloid sollution)
Indications	Intravascular volume replacement Hypoalbuminaemia Plasma exchange Hepatorenal syndrome, pancreatitis, burns
Pharmaceutics	4% Albumin = 40g/L Contains Na 140mmols, Cl 128mmols, Octanoate 6.4mmols Hypotonic (260mOsm) -Albumin collected by blood donation (Whole blood > plasmpheresis > fractionated > pasteurised > partitioned > stored) Stored at room temp (<30 degrees)
Routes of administration	IV
Pharmacodynamics
MOA	Related to volume of fluid (i.e. volume expansion) Increase albumin concentration > increase oncotic pressure / restores transport/drug binding function
Side effects	No risk of bacteria/parasite infections (destroyed during processing), but risk of blood borne viruses (HIV, HepB, HCV) remains. Allergy, fluid overload, pulmonary oedema.
Pharmacokinetics
Absorption	IV only (0% oral bioavailability)
Distribution	Rapid distribution within intravascular space. Small Vd - about 5% leaves per hour
Metabolism	Cellular proteolysis by cysteine protease
Elimination	Degradation by liver and reticuloendothelial system Half life of ~20 days
Special points	- Likely worsens outcomes in TBI - No need for blood cross matching

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Question 12, 2020 (2nd sitting)
• Question 1, 2015 (2nd sitting)
• Question 1, 2009 (2nd sitting)

Question 10

Question

Describe the determinants of intracranial pressure (80% marks) and outline how it can be measured (20% marks)

Example answer

Intracranial pressure (ICP)

• ICP = The pressure within the cranium, relative to atmospheric pressure
• Normal ICP is 5- 15 mmHg
• Governed by the Monro-Kellie doctrine (below)
• There is rhythmic variation in ICP due to variations in respiration and blood pressure

Monro-Kellie doctrine

• The skull is a rigid container of fixed volume

• The skull contents include: brain (~85%), CSF (~5-8%), blood (~5-8%)

• Therefore any increase in volume of one substance must be met by a decrease in volume of another, or else there will be rise in the ICP

image-20211012142839178

image-20211012142839178

Determinants of ICP

• Brain tissue
  • No capacity to alter volume under physiologically normal circumstances
  • Increased volume in pathology: e.g. tumours, cerebral oedema > increased ICP
• CSF
  • Constantly produced (24mls/hr) and reabsorbed (24mls/hr), thus volume remains the same
  • With increased ICP
    • CSF can be displaced from the cranium into the spinal subarachnoid space (as the spinal meninges have better compliance) > decrease ICP
    • Increased ICP > increased driving pressure for CSF reabsorption
  • However if there is obstruction to CSF flow then there can be accumulation (e.g. hydrocephalus) > increased ICP
• Blood
  • Increased blood in cranium (e.g. cerbral vasodilation or haemorrhage) > increased ICP
  • With increased ICP > Compression of the dural venous sinuses > displace venous blood from the cranium > lower ICP
  • Blood flow is extensively autoregulated and effected by
    • MAP
    • PCO2
    • PO2
    • CMRO2

Measurement of ICP

• Clinical

  • Cannot be directly measured clinically

  • Though increased ICP may result in

    • Headaches, nausea, vomiting

    • Papilledema

    • Decreased LOC

    • Cushing's reflex (critically high ICPs, very late)

  • Optic nerve sheath diameter

    • on US

  • Lumbar puncture opening pressure

    • Can approximate but not directly measure ICP

    • high CSF opening pressure may indicate high ICP

    • Numerous reasons why there would be a discrepancy in patients with pathology

• Devices

  • EVD (gold standard)

    • Catheter which sits in the lateral ventricle

    • Pressure transmitted to wheatstone bridge via fluid filled tubing

    • Zeroed to atmospheric pressure

  • Codmans / Intraparenchymal pressure monitor

    • Sits in brain parenchyma (~2cm deep)

    • Pisoelectric strain gauge pressure sensor connected to a monitor via a fibreoptic cable

    • Only measures local ICP and cannot be re-zeroed

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Question 7, 2020 (2nd sitting)
• Question 15, 2018 (1st sitting)
• Question 18, 2016 (2nd sitting)
• Question 14, 2016 (1st sitting)
• Question 18, 2010 (1st sitting)

Question 11

Question

Outline the structure and function of the NMDA receptor (25% marks). Discuss the pharmacology of ketamine (75% marks)

Example answer

NMDA receptor

• Structure
  • Tetrameric (4 subunits), ligand gated, transmembrane receptor
• Location
  • Abundant in the CNS (brain, spinal cord)
• Ion permeability
  • Ca, Na, K
• Activated by
  • Glutamate (excitatory neurotransmitter) and glycine
  • Activation leads to removal of central Mg plug > Na/Ca in, K out > EPSP
• Blocked by
  • Ketamine, Mg, memantidine

Name	Ketamine
Class	Anaesthetic (phencyclidine derivative)
Indications	induction GA, conscious sedation, analgesia,
Pharmaceutics	10/50/100mg/ml. Clear colourless solution. Racemic mixture of S and R enantiomers, or S+ enantiomer alone. Water soluble.
Routes of administration	IV/IM/PO/SC/PR
Dose	0-0.25mg/kg/hr (analgesia), 1-2mg/kg (GA), 0.5mg/kg (sedation)
pKa	7.5
Pharmacodynamics
MOA	NMDA antagonism, weak opioid receptor agonism, weak Ca ch inhibition
Effects	CNS: dissociative anaesthesia and analgesia. CVS: increased HR/BPN (SNS stimulation), decreased pulmonary and systemic vascular resistance, Resp: bronchodilation
Side effects	CNS: emergence reactions including hallucinations, unpleasant dreams. may increase ICP in non ventilated patients CVS: may increase HR/BP, increased myocardial O2 req. GIT: Nausea, vomiting, increased salivation RESP: apnoea
Pharmacokinetics
Onset	30s IV, duration of effect 10-20mins
Absorption	Lipid soluble > readily absorbed. But poor OBA (16%) due to 1st pass metabolism
Distribution	Large (~3L/kg) VOD Small protein binding (~30%). Crosses placenta.
Metabolism	Hepatic (CYP450) Demethylation > norketamine (30% potent) and inactive metabolites
Elimination	Elimination T1/2 = 2 hours. Kidneys (95%), faeces (5%)
Special points

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Direct copy of Question 15, 2019 (1st sitting)
• Ketamine
  • Question 4, 2018 (2nd sitting)
  • Question 22, 2015 (1st sitting)
  • Question 16, 2011 (2nd sitting)
  • Question 7, 2010 (2nd sitting)

Question 12

Question

Describe the process of excitation-contraction coupling and relaxation in smooth muscle

Example answer

Excitation contraction coupling

• The process linking depolarisation (generated by an action potential) and initiation of muscle contraction

Process

• Calcium influx
  • Voltage (from action potential) or ligands (e.g hormone, neurotransmitter) can open Ca channels > calcium enters the cell
  • The initial increase in calcium > further release of Ca from the SR (calcium induced calcium release)
  • Hormones/Neurotransmitters can also directly release calcium from the SR via IP3-DAG 2nd messenger pathway
• Calcium-calmodulin complex
  • Calcium binds to calmodulin forming a complex
  • The complex then activates myosin light chain kinase (MLCK)
• Activation of MLCK
  • MLCK phosphorylates (activates) the myosin heads (requires ATP)
  • Allows cross bridge formation between actin/myosin
• Relaxation
  • Decrease in Ca (taken up in the SR by SERCA) leads to relaxation (no further MLCK activation)
  • Myosin phosphatase dephosphorylates already active MLCK

image-20220531131819978

image-20220531131819978

Smooth muscle ECC vs skeletal/cardiac muscle ECC

• There are no t-tubules
  • The AP propagates through gap junctions (unlike cardiac/skeletal muscle)
• There is no troponin
  • They facilitate cross bridge formation via calmodulin instead (unlike cardiac/skeletal muscle)
• Smooth muscle cells have poorly developed sarcoplasmic reticulum
  • Calcium influx is mainly from ECF and not from the SR (unlike cardiac/skeletal muscle)
• There is DHPR/ ryanodine receptor
  • Calcium induced calcium release from the SR (unlike cardiac/skeletal muscle)
• 10x slower, lasts 30x longer

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Question 13

Question

Compare and contrast the pharmacology of suxamethonium and rocuronium

Example answer

Name	Suxamethonium (succinylcholine)	Rocuronium
Class	Depolarising NMB	Aminosteroid NMB / Non depolarising NMB
Indications	Facilitate endotracheal intubation during anaesthesia (i.e. RSI)	NMB (e.g. intubation, assist with difficult mechanical ventilation)
Pharmaceutics	Clear colourless solution (50mg/ml) Refrigeration (4°C) - 2/52 at room temp Precipitates with thiopentone	Clear colourless solution (10mg/ml, 5ml vial) Refrigeration (4°C) - 3/12 at room temp
Routes of administration	IV, IM	IV
Dose (RSI)	1-2 mg/kg (IV), 2-3 mg/kg (IM) Cant be given as infusion due to phase 2 block	0.6 - 1.2mg/kg Can be given as an infusion but variable offset
ED95	0.3mg/kg	0.3 mg/kg
Pharmacodynamics
MOA	Binds to the nACh receptor on motor end plate > depolarisation. Cannot be hydrolysed by Acetylcholinesterase in NMJ > sustained depolarisation (i.e. Na channels remain in open-inactive state) > muscle relaxation	Inhibit the action of ACh at the NMJ by competitively binding to alpha subunit of nAChR on post junctional membrane
Effects	NMB - paralysis.	NMB - paralysis
Side effects	Major: anaphylaxis, suxamethonium apnoea, malignant hyperthermia Minor: hyperkalaemia, myalgia, bradycardia/arrhythmia Pressure: increased IOP, ICP, intragastric pressure.	CVS: tachycardia (in high doses, rare otherwise) IMMUNE: anaphylaxis (<0.1%)
Pharmacokinetics
Onset/Duration	Onset: 30s - 60s Duration <10 mins	Onset: 45-90s Duration: ~30-45 mins
Absorption	-	-
Distribution	Protein binding = 30% Vd = 0.02 L/Kg	Protein binding = 10% VOD = 0.2 L /kg
Metabolism	Rapid hydrolysis by plasma and liver pseudocholinesterase's (~20% reaches NMJ)	Minimal hepatic metabolism (<5%)
Elimination	Minimal renal elimination (due to rapid metabolism) T 1/2 = 2 mins	Bile 70%, Renal 30% Excreted unchanged T 1/2 - 1 - 1.5hrs
Special points	May have prolonged duration of action with congenital or acquired (e.g. liver, renal, thyroid disease) pseudocholinesterase deficiency Treatment of malignant hyperthermia is with dantrolene (+ cooling + supportive care)	Reversible with sugammadex and anticholinesterases (e.g. neostigmine)

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Rocuronium
  • Question 13, 2018 (2nd sitting)
• Suxamethonium
  • Question 6, 2011 (1st sitting)
  • Question 2, 2012 (2nd sitting)
  • Question 1, 2013 (2nd sitting)
  • Question 10, 2018 (1st sitting)
  • Question 10, 2020 (2nd sitting)
• Various other questions relating to properties of NMB more broadly

Question 14

Question

Describe the neural integration of vomiting, highlighting the site and mechanism of action of antiemetics

Example answer

Vomiting

• Involuntary, forceful and rapid expulsion of gastric contents via the mouth

Stages of vomiting

• Deep inspiration
• Closure of the nasopharynx and glottis
• Large retrograde contraction of intestines > forces content into stomach
• Relaxation of the oesophagus, lower oesophageal sphincter and body of stomach
• Contraction of abdominal and thoracic muscles (including diaphragm)
• Increased intrabdominal pressure > forces gastric contents into oesophagus and through the mouth

Neural integration

image-20220610194545783

image-20220610194545783

Anti-emetics

Class	Example	MOA
Serotonin antagonists	Ondansetron	Central and peripheral 5-HT3 receptor antagonism > reduced afferent input to vomiting centre in medulla
Corticosteroids	Dexamethasone	MOA unclear. May involve: decreased peripheral 5HT release, PG antagonism
Dopamine antagonists	Metoclopramide, Droperidol	Central D2 antagonism at chemoreceptor trigger zone > reduced afferent input to vomiting centre in medulla
Antihistamine	Cyclizine	Competitive H1 antagonism. Also has
NK1 antagonist	Aprepitant	Blocks action of substance P in brainstem vagal complexes involved in regulation of vomiting
Others	Canabinoids	Thought to act within the vomiting centre

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Question 3, 2014 (1st sitting)

Question 15

Question

Describe the sequence of haemostatic events following injury to a blood vessel wall until clot stabilisation

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Question 10, 2019 (1st sitting)

Question 16

Question

Outline the impact of sedative agents on thermoregulation (40% marks) and describe the physiological effects of a low body temperature (60% marks)

Example answer

Core body temperature

• 37 degrees +/- 0.4 degrees

Effects of anaesthesia

• The interthreshold range

  • The range of core temps at which no autonomic thermoregulatory responses occurs

  • Normally 37 +/- 0.2 degrees

  • With general anaesthesia this is widened to 37 +/- 2 degrees

• Responses to general anaesthetic

  • Behavioural responses completely abolished (seek warmth, clothing etc)

  • Volatile anaesthetics, opioids (e.g. morphine), IV sedatives (e.g. propofol) > vasodilation > increased heat loss.

  • Decreased responsiveness to temperature change (widened interthreshold range)

  • Opioids also decrease sympathetic outflow > impaired vasoconstriction

  • If adjunct muscle relaxant used -> shivering also prevented (decreased heat generation)

  • Therefore the only thermoregulatory responses available to anaesthetised/paralysed patient with hypothermia are vasoconstriction and non shivering thermogenesis. Hence body temperature changes passively in proportion to the difference in heat production and heat loss

Mild hypothermia

• 34-36.5
• Common during anaesthesia

Effects of hypothermia

• METABOLIC

  • BMR drops 6% for every 1 degree in core temp --> Decreased VO2

  • Hyperglycaemia (decreased cell uptake)

• CVS

  • Decrease inotropy and chronotropy > decreased CO

  • Arrhythmias (AF, VF)

  • QT prolongation, J wave

  • Resistance to DCCV

  • Peripheral vasoconstriction and blood redistribution

  • Increased risk of myocardial ischaemia

• CNS

  • Confusion and decreasing LOC

  • Shivering

  • Seizures (increased seizure threshold)

• RESP

  • Decreased RR

  • Left shift of O2 dissociation curve

• GIT

  • Ileus

  • Decreased hepatic drug metabolism and clearance (slows enzymatic reactions, decreased blood flow)

• HAEM

  • Increased HCT and blood viscosity

  • Coagulopathy,

  • Platelet dysfunction and sequestration

• RENAL

  • Cold diuresis (decreased vasopressin synthesis)

• ENDO

  • Decreased ACTH, TSH, vasopressin

• ACID-BASE

  • Increased pH

Examiner comments

33% of candidates passed this question.

Sedation reduces body temperature by interfering with heat production and increasing heat loss, along with widening of hypothalamic inter-threshold range. This portion of the question was generally well answered. The question asked to "outline" the answer. Many candidates actually "described" the thermoregulation process in general but were unable to relate those with the impact of sedation. The second part of the question (physiological effect of low body temperature) was answered by most of the candidates with the structure of organ-system wise description. A few candidates scored extra marks by relating these effects with degree of hypothermia and by describing how thermogenesis responses (including shivering) can influence those effects. Some candidates restricted their answers to the effect of thermogenesis in response hypothermia and did not include the overall physiological consequences of low body temperature. Better answers displayed an understanding of core temperature regulation, inter-threshold range and the effects of sedatives on thresholds for thermogenic responses, although only a few mentioned gain and maximal response. Better answers included specific detail (mentioned bradyarrhythmia, slow AF, VF, prolonged PR/QRS / J waves rather than just stating arrhythmia) across several organ systems. Marks were not awarded for generic statements such as 'decreased liver function' without some additional detail. Inadequate depth of knowledge was main reason behind overall poor scores.

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Question 9, 2021 (1st sitting)

Question 17

Question

Write notes on:

• The principles of ultrasound
• Transducer properties and image resolution
• The doppler effect

Example answer

Ultrasound = sound waves at higher frequencies then can be heard by humans (>20kHz)

Sound wave generation

• Produced by piezoelectric effect
  • Electrical voltage applied to quartz (piezoelectric) crystal > vibrates > sound emitted (Converts electrical energy to sound energy)
• Frequency of sound wave
  • Different probes emit different frequencies of sound waves:
    • Liner = 15-6 MHz
    • Curved = 8-3 MHz
    • Cardiac = 5-1 MHz
  • Effects
    • Higher frequency = shallower depth, better resolution
    • Lower frequency = better depth, less resolution

Sound wave effected by tissue and may be

• Absorbed
  • Sound is absorbed, lost as heat
• Reflected
  • Sound reflected off objected back to probe sensor
  • Reflection occurs at interfaces of tissues with different densities (impedance)
• Refracted
  • Change in direction (bending) of sound wave
• Scattered
  • Sound reflected from tissue but not received by probe sensor

Detection of sound

• The probe spends 1% time emitting sound, 99% time listening for sound
• The crystals are vibrated by returning sound waves (echos) and generates a voltage (converse piezoelectric effect)

Processing

• Amplitude of the wave determines echogenicity
• Time taken for echo's to return determines depth
• Output mode
  • B mode (brightness mode)
    • 2D crossection through tissue
    • Largest amplitude = brightest, smallest amplitude = darkest
  • M mode (motion mode)
    • Movement of structures over time
• Resolution
  • Spatial resolution
    • Dependant on axial (parallel to beam) and lateral (perpendicular to beam) resolution
    • Enhances by pulse wave and focusing
  • Contrast resolution
    • Distinguish between two regions of similar echogenicitiy
  • Temporal resolution
    • Distinguish change over time
    • Improved by framerate

Doppler effect

• The change in frequency of a wave in relation to an observer that is moving relative to the wave source.
• In medical ultrasound
  • The change in frequency of sound waves reflected from moving tissue (e.g. erythrocytes)
    • Away from probe (lower frequency = blue colour)
    • Towards probe (higher frequency = red colour)

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Question 18

Question

Describe the anatomy of the left subclavian vein

Example answer

Course

• Continuation of the axillary vein (commences at the lateral border of the 1st rib)
• Travels medially, first arching cephalad before heading caudally toward the sternal notch
• Terminates by joining the internal jugular vein (IJV) and forming the brachiocephalic (innominate) vein behind the sternoclavicular joint

Tributaries

• External jugular vein
  • Drains into the subclavian at the lateral border of anterior scalene muscle
• Thoracic duct
  • Drains into either subclavian or innominate vein behind the sternoclavicular joint

Relationships

• Cephalad
  • Skin, subcutaneous tissue, platysma
• Anterior
  • Skin, clavicle, subclavius muscle
• Posterior
  • Anterior scalene muscle which separates from the subclavian artery
• Posterior-inferiorly
  • 1st rib, pleura, phrenic nerve
• Medial
  • Brachiocephalic vein, mediastinal structures (vagus, trachea, aorta)
• Lateral
  • Axillary vein, brachial plexus

Surface anatomy (infraclavicular approach)

• Needle is placed in the deltopectoral groove, inferior and lateral to the middle third of the clavicle.
• The needle is inserted at a shallow angle, passing under the middle third of the clavicle aiming at the sternal notch.

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Question 19

Question

Describe the physiological factors that affect PaCO₂

Example answer

Overview

• PaCO₂ is normally 40mmHg +/- 3mmHg
• PaCO₂ is a balance between production and elimination

CO₂ production

• Metabolism
  • CO₂ is the by-product of mitochondrial respiration via TCA cycle
  • Increased metabolism > increased CO₂ production
    • Metabolic rate is increased with
      • Exercise
      • Increased temp (e.g. infection)
      • Youth
      • Male sex
      • Pregnancy
      • Eating
• Energy source
  • RQ = Ratio of Co2 produced: O2 consumed
    • Effected by the energy source utilised
    • Normally
      • Fats 0.7
      • Ketones/alcohols 0.7
      • Proteins 0.8
      • Carbohydrates 1.0
  • Hence carbohydrates Increase CO2 production compared to lipids/proteins (though hot chips are delicious)

CO2 elimination

• Alveolar ventilaiton
  • CO2 is a ventilation limited gas
  • Increase minute ventilation (RR, TV) > increase CO2 elimination via respiration > decreased PaCO2
  • Physiological factors that increase RR: Pain, anxiety, pregnancy, Hypoxia
• Tightly regulated
  • Minute ventilation is increased by increased PaCo2
    • MV linearly increases 2L/min for every 1mmmHg increase in PaCo2
    • Due to the chemoreceptor responses
      • Central chemoreceptors
        • Located: Ventral medulla
        • CO2 diffuses across BBB > increased H+ > decreased pH > detected by chemoreceptor > stimulate dorsal resp group > Increase MV
      • Peripheral chemoreceptors
        • Located: Carotid bodies, aortic bodies
        • Increased PaCo2 or decreased PaO2 > stimulate the respiratory centre > increased MV

Examiner comments

33% of candidates passed this question.

Candidates who scored well generally defined PaCO2 and proceeded to describe factors in terms of those related to production and elimination. Good answers described the key production factor as being rate of production through aerobic metabolism which is in turn influenced by substrate and BMR. Those who scored well described elimination as being dependent upon minute ventilation, which in turn is influenced by CO2 detection by chemoreceptors, specifically detailing the difference between peripheral and central. Many candidates detailed pathophysiological factors which unfortunately did not gain any marks.

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Question 20

Question

Describe the physiological control of systemic vascular resistance (SVR)

Online resources for this question

• Jenny's Jam Jar
• CICM Wrecks
• Deranged physiology

Similar questions

• Question 7, 2020 (1st sitting)