Withdrawal reflex is a spinal reflex intended to protect the body from damaging stimuli.
The upper centres are not involved.

Afferent

• Nociceptors detect the painful stimulus
• Conveyed to the dorsal horns of spinal cord by Aδ (fast) fibres and C (slow) fibres
  • Through the cauda equina
• Synapse at the same spinal level, or 1-2 levels above via Lissauer’s tract

Reflex arc

• (fast response to painful stimulus)
• (outside of conscious control, but can be modulated by the cerebral cortex)
• Interneurons:
  • Travel to the ipsilateral anterior horn, synapse with motor neurons
  • Cross the midline to the contralateral anterior horn
• Efferent
  • Motor neurons in the ipsilateral limb cause contraction of flexors, and relaxation of extensors
  • Contralateral limb motor neurons cause relaxation of flexors, and contraction of extensors
• Causes withdrawal of painful limb, and shift In centre of gravity to the opposite limb

Conscious pathways

(slow response to painful stimulus)

Interneurons:

• Cross the midline via the anterior white commissure
• Ascend in the spinothalamic tract to the thalamus
• Synapse in the thalamus
• Travel to the post-central gyrus of the cerebral cortex

Efferent:

• Originate in the motor cortex (pre-central gyrus)
• Project to medulla
• 90% decussate at pyramids to innervate limbs
  • Travel down the lateral corticospinal tract
• 10% continue down ipsilateral anterior corticospinal tract to innervate axial muscles
  • Decussate at the target spinal level
• Synapse at the anterior horn to lower motor neurons

Mooney / Sakurai 2016

2014A 01: 26% of candidates passed this question.
It was expected that candidates would outline both motor and sensory pathways and mention
a reflex arc and conscious pathways.

Calcium Channel Blocker Classification

• Class I – Phenylalkylamines:
  • Verapamil
  • Reduces HR, contractility and causes vasodilatation, decrease in cardiac contractility, heart rate, and both coronary and peripheral vascular tone.
• Class II – Dihydropyridines:
  • main effects are on vasodilatation
  • 1st gen = nifedipine
  • 2nd gen = felodipine, nimodipine
  • 3rd gen = amlodipine
• Class III – Benzothiazepines:
  • diltiazem
  • some reduction in HR and contractility, also causes vasodilatation, mild to moderate decrease in myocardial contraction, and decreases heart rate by decreasing both the automaticity of the SA node and the rate of conduction in the AV node.

Calcium Channel Blocker Pharmacology
(Include as per the question)

Click here to Open CICMWrecks Table: Calcium Channel Blockers

Class Effects:

• Heart
  • V-W Class 4 antiarrhythmic
  • Decr SA node automaticity
  • Decr AV node conductivity
  • Vasodilation
  • Negative inotropy
  • reflex tachycardia
• 2) Vasculature
  • Decr SVR and BP
  • Decr Hypoxic pulmonary vasoconstriction
  • Incr coronary and cerebral blood flow
• 3) Other
  • Tocolytic
  • NDMR potentiation.

Gladwin / JC 2021

2014A 02: 61% of candidates passed this question.
Most candidates managed to provide a classification of calcium anatagonists. The pharmacology of verapamil was less well understood. The structure for answering a pharmacology question was often poor and there was commonly a lack of precision in pharmacokinetics. We suggest that candidates look at a general pharmacokinetic structure when answering these questions. One approach would be a structure that covers drug name and description, pharmaceutics (chemistry/ ampoule contents), Pharmacokinetics, Pharmacodynamics (Think CNS/CVS/Resp/GIT etc. if relevant), Dose and Side effects then Indications and Contraindications can help organize the information.

Physiology of Vomiting

Vomiting

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

Triggers

• Excessive GI tract distension
• Stimulation of CTZ
  • Directly by certain drugs eg apomorphine, morphin
  • Rhythmic motion of the body stimulating the vestibular labyrinth of the inner ear
• Cerebral excitation secondary to odours, pain, stress

Central control of vomiting

• Vomiting center (5HT₃, NK1, Muscarinic and Histamine), near NTS
  • Inputs
    • Chemoreceptor trigger zone (NK1, 5HT₃, Dopamine), area postrema outside BBB
    • Vestibular system (Histamine and Muscarinic) via CNVIII
    • GI Tract (5HT₃, stretch and chemoreceptors) via vagal
    • Higher centres
  • Efferent arc
    • via CN V,VII,IX,X,XII and spinal nerves to abdominal wall musles and diaphragm

Vomiting act

• Antiperistalsis as the prelude to vomiting
• At the onset of vomiting, strong intrinsic contractions occur in both the duodenum and the stomach
• Partial relaxation of the lower oesophageal sphincter (LOS)
• Deep inspiration
• Raising of the hyoid bone and larynx to open the upper oesophageal sphincter
• Glottic closure
• Lifting of the soft palate to close the posterior nares
• Strong down ward contraction of diaphragm and simultaneous contraction of all the abdominal wall muscles
• Complete relaxation of the LOS

Gladwin / Sakurai 2016

Pharmacology of Ondansetron

2014A 03: 58% of candidates passed this question.
Candidates who failed the question did not answer the actual question. They did not discuss the neural integration but instead listed various inputs into the CTZ and vomiting centre. It was expected candidates could detail the pathways involved (afferent and efferent limbs) and describe the relationship with the coordinating centres. For example, afferent pathways to the vomiting centre include stretch and chemoreceptors located throughout the GIT via vagal and sympathetic nerves, pharyngeal touch receptors via glossopharyngeal nerves etc. Again structuring pharmacology answers was often poor.

Respiratory Changes In Pregnancy

Anatomical

• Diaphragm ascends ~4cm due to foetus
• AP and lateral diameters of thorax increase 2~3cm due to relaxin effect on chest
  wall
• Thoracic circumference increases 5~7cm (AP and lateral diameters increased 2~3cm)
• Airway dilatation → decreased resistance (35%) and increased deadspace (45%)
• Increased cardiac output, intravascular volume, and decreased oncotic pressure
  • Increased plasma volume → increased pulmonary blood volume → decreased compliance
  • Venous engorgement → Upper airway oedema

Mechanical

• Lung volume changes occur from 20 weeks
• TLV decreases 5% from baseline
• FRC decreased 20% due to both ERV and RV
• Significant postural change in FRC of 70%
• Progesterone → increased sensitivity to CO2 → Minute ventilation increases 50%
  • TV increases (25%)
  • RR increases
  • Results in hypocarbia and compensated respiratory alkalosis
    • pCO2 ~ 26-32mmHg
    • HCO3 ~ 18-20mmol/l
  • Further increase in MV during contractions
• Inspiratory capacity increased by 10%
• Closing capacity unchanged
• Increased O2 consumption during labour (60%)

After birth

• FRC and RV return to normal within 48 hours
• TV returns to normal within 5 days

Sakurai 2016

2014A 04: 26% of candidates passed this question.
This question was variably answered, with a wide range of marks. Candidates often mentioned central regulation, anatomy, respiratory mechanics, static lung volumes or gas transfer, but did not provide comprehensive cover of all areas. Very few clearly described the extent of any change (either as a percentage or actual amount relative to the non-pregnant state). A number of candidates presented information well in diagrammatic form (e.g. static lung volumes) however then repeated this same information in text, which was unnecessary.

Pharmacological effects of Paracetamol

• Arachidonic acid ——(COX)—–>
  • Prostaglandins   → inflammation, sensitise spinal nerves to pain
  • Prostacycline  → vasodilation
  • Thromboxane   → platelet aggregation and activation
• Paracetamol: Weak COX-1 and COX-2 inhibitor in peripheral tissues
• Relatively selective for COX-2 → less inhibition of thromboxane production
• Possible cause for antipyretic effect:
  • Inhibition of COX-3 (variant of COX-1), leading to central effects

Toxic Effects and Management

Toxicity

• Occurs in doses >4g/day
  • Overdose dose lower in chronic alcoholics, elderly and children
• Paracetamol
  • → glucuronidation
  • → sulphation
  • → N-hydroxylation to NAPQI
• In overdose, glucuronidation and sulphation pathways saturated → increased production of toxic NAPQI
• NAPQI usually conjugated with hepatic glutathione
  • In overdose, glutathione exhausted → accumulation of NAPQI
• NAPQI bonds with hepatocyte sulfhydryl groups → cell death and necrosis

Therapy

• Decision to treat based on paracetamol overdose nomogram
  • Serum paracetamol level, time since dose
• If within 4 hours → activated charcoal
• Hepatic failure, GI upset, renal failure (less common)
• N-acetyl-cysteine should be given
  • Replenishes glutathione stores
  • Directly conjugates NAPQI
• Monitoring and supportive care:
  • Bilirubin
  • Transaminases
  • Creatinine (dialysis)
  • Liver synthetic function (albumin, INR) (vitamin K, maybe FFP, but discuss with liver unit first)
  • Blood sugar (glucose infusion) 
  • Conscious level (hepatic encephalopathy) (lactulose, intubation)

Mooney 2016

2014A 05: 63% of candidates passed this question.
This question was generally well answered with narrow variance; very few candidates discussed factors predisposing to hepato-toxicity or renal toxicity. Discussion of pharmacokinetics only gained marks when relevant to toxicity.

Principles

Beer-Lambert Law

• Incidence of light is inversely proportional to the path distance and concentration of light absorbing particles within the path.

Hb absorbance at 660nm and 940nm utilized

• 660nm maximally absorbed by deoxyhaemoglobin
  • Ratio of absorbance at 660nm and 940nm utilized to calculate SpO₂

using healthy volunteers derived R values
Sats 100% R = 0.4
Sats 85% R = 1.0
Sats 50% R = 2
Sats 0% R = 3.4

Pulse oximeter

• Light emitter
  • Produces infra-red light at 660nm and 950nm
• Light detector
  • Detects light at 660nm and 950nm
• Processor
  • Calculates SpO₂ using the ratio of absorbance at 660nm and 950nm
  • Light detected (incidence) represents light passing through both pulsatile (arterial) blood and non-pulsatile elements (venous blood and other tissues)
  • Processor differentiates light incidence during maxima and minima of pulse wave and calculates SpO₂ from pulsatile blood only giving SaO₂

Limitations

Absorption spectra confounded by:

• Carboxyhaemoglobin
  • Absorbs 660nm, not at 940nm
  • R closer to 0.4
  • causes the pulse oximeter to read artificially high
• Methemoglobin
  • though it absorbs 660nm light, it also absorbs 940nm light to a greater degree
  • R closer to 1
  • causes the SpO2 to trend towards 85%

Sakurai 2016

2014A 07: 34% of candidates passed this question.
Explanation of several crucial principles was expected for a good answer. These would include that Haemoglobin can be measured and quantified with a light absorbance technique; based on the Beer Lambert law (a description of this was required). In addition, oxygenated haemoglobin must be distinguished from reduced haemoglobin (the 2 dominant species of Hb) and that the oximeter determines pulsatile from non pulsatile blood. The oximeter accounts for ambient light and that “R”, a ratio of absorbances during pulsatile and non pulsatile flow is calculated and compared within a computer algorithm to standardised values of SaO2 to deliver a final value.
Mention of limitations was not required except to answer the second part of question. Common omissions included failure to describe accurately the Beer Lambert Law, and no explanation of how pulsatile component was detected, or ambient light accounted for. Many candidates understood the clinical inaccuracy associated with CO and Met HB, but failed to identify the spectrophotometric reason and application of the R value for this discrepancy.

Sarcomere

“Sarcomere” → basic unit of muscle contraction within myofibril

Components of the sarcomere:

• Myosin
  • Large protein that consists of:
    • 1x long tail – 2 interwound α-helices with a flexible hinge (S2 segment)
    • 2x globular heads (S1 segment) – Connected to long tail via S2 segment. Each head has 1x heavy chain that binds 1x G-actin, and 2x short chains that bind ATP
  • 2x myosins fuse together at M-line via their long tails → forms “thick filament”
• Actin (thin filament)
  • Consists of 2x chains of F-actin (≈ double-strand cord) formed from the polymerisation of G-actin
• Tropomyosin
  • 2x α-helical chains that lie between 2x chains of actin polymers → under the influence of Troponin, it can acts to inhibit or permit myosin-actin interaction
• Troponin
  • Present with tropomyosin on thin filament at regular intervals (every 7 actin monomers)
  • Consists of 3 subunits – (a) T (binds tropomyosin), (b) I (inhibits myosin ATPase) and (c) C (binds Ca2+)
  • Binding to Ca2+ causes a conformation change in troponin-tropomyosin complex → allows actin to interact with myosin
• Titin
  • Large elastic molecule that attaches myosin to Z-line → acts to return muscle to
    resting length

Process of Muscle Contraction and Relaxation:

(1) Excitation-contraction coupling:

• Motor neuron depolarisation
• ACh vesicular release
• Multiple MEPs → End plate potential
• Muscle AP propagates via T-tubles
• Opens L-type Ca channels
• Calcium induced calcium release from SR
• Ca-troponin C interaction
• Alteration and movement of Trop-tropomyocin complex
• Exposure of Actin
• Removal of Troponin I inhibition of myosin ATPase
• Cross bridge cycling

2) Contraction (Sliding filament cross bridge cycling):

• “Flexed” Myosin without ATP binds to Actin.
• Binding of ATP to Myosin causes release of Actin/Myosin complex and extension of the head
• In the presence of Ca, Actin binding sites are open and binding of myosin/Actin/ATP complex is formed
• Hydrolysis of ATP to ADP + P in myosin head causes a conformational change “initial flexing” the myosin head and releasing phosphate
• Release of ADP further flexes Myosin head
• In presence of Ca return to step 2

(3) Muscle relaxation:

1. AChE metabolises ACh in the NMJ → ↓ nAChR activation at MEP → ↓ EPP and muscle AP generation
2. SR actively sequesters Ca2+ (via Ca2+-Mg2+ ATPase) → ↓ IC [Ca2+] → Ca2+ removed from troponin C → tropomyosin mediated inhibition of actin-myosin interaction returns
3. Elastic components of the sarcomere causing the muscle to return to its normal length

Energy Source for Muscle Contraction

• Energy (in the form of ATP) is needed for muscle contraction AND relaxation
• The method of ATP generation depends on the level of activity present:
  • Creatinine phosphate store
    • ATP generated from Creatine phosphate during intense exercise
    • ADP + Creatine phosphate → ATP + creatinine (enzyme: Creatine Phosphokinase)
    • Replenished at rest by reversing the above reaction by aerobic/anaerobic generation of ATP
  • Aerobic generation of ATP:
    • Glucose (and Glycogen stores) – ATP is produced during exercise/activity by substrate phosphorylation (via glycolysis) and oxidative phosphorylation (via Kreb’s cycle and the ETC)
    • Fat – β-oxidation of fat produces ATP during light exercise and at rest
  • Anaerobic generation of ATP:
    • When O2 supplies are insufficient, ATP is produced in smaller amounts from the anaerobic glycolysis of glucose → produces lactic acid

JC / Gladwin 2020

2014A 08: 34% of candidates passed this question.
This question required a description of excitation- contraction coupling. Marks were gained for a brief outline of the structure of a sarcomere and how it facilitates shortening. An explanation of membrane processes, receptor interactions and the contraction processes was required. Mention of the role of ATP was also required and marks were gained for commenting on the mechanism of return to the relaxed state.
Most candidates wrote extensively on the nerve action potential and neuromuscular junction transmission, with minimal reference to events occurring within the skeletal muscle cell membrane. They could not gain marks for this. Few candidates demonstrated knowledge of the ATP dependent walk along processes of myosin heads during contraction.

Drug Factors

• Dose: Higher dose (eg. multiples of ED95) = faster onset.
• Plasma clearance: Postulated that drugs with faster clearance (eg. sux) have faster onset.
• Potency:
  • Inverse log relationship between potency and speed of onset (non-depolarisers).
  • Low potency = bigger dose needed (more molecules), so higher conc gradient between plasma and site of action = more rapid onset.
• Depolarisers vs non-depolarisers.

Patient Factors

• Rate of injection: faster rate = faster onset.
• Site of injection: Central vein (more rapid distribution)> peripheral vein > IM
• Cardiac output and muscle blood ­flow: Higher CO and muscle ­flow = faster delivery to site of action.
• Priming: small dose of non-depolariser as a premed can partially block NMJ, followed by intubating dose. This decreases time from intubating dose to intubation conditions.
• Disease states: eg. myasthenia gravis (fewer ACh receptors, so needs more sux, but about 10% dose of non-depolariser).

Other factors

• Muscle group: Fastest affected = small, rapidly moving muscle groups (eye, digits), with trunk/abdo muscles last affected.
• Recovery is in reverse order: diaphragm/intercostals recover first.
• Onset more rapid in muscle groups relevant to intubation: laryngeal, masseters. Slower in monitored muscles (eg.adductor pollicus).
• Probably due to muscle blood fl­ow.
• Smaller volume of distribution due to blood loss can augment potency ie: speed of onset(Stoelting)

Drugs:

eg. ephedrine can increase speed of rocuronium onset. Inhalationals/aminoglycosides.

JC 2019

2014A 09: 16% of candidates passed this question.
Speed of onset is related to how quickly an effective dose reaches the neuromuscular junction, the type of interaction with the receptor and the margin of safety of the receptors. Examples of parameters that increase speed of onset include a high drug rate of delivery (high CO, high muscle
group blood flow, and fast injection rate), high drug concentration (higher dose, low potency, higher ED 95, lower protein binding) or a depolarising block. A good answer would include a list of these factors, with a brief explanation. Mention of other factors such as electrolyte disturbances gained additional marks. It was expected that the direction of an effect would be clearly indicated (e.g. “potency” would not score a mark unless the candidate wrote – “low potency increases speed of onset”, etc.). These drugs are charged molecules which do not cross cell membranes and have a low volume of distribution. Absorption from GIT, Lipid solubility, pKa, metabolism and clearance have minimal relevance to speed of onset.

Gram Stain

Method of differentiated bacteria according to their cell wall characteristics, using
staining with crystal violet dye

• Gram positive bacteria have a thick outer cell wall composed of peptidoglycan,
  which stains positive with crystal violet dye
• Gram negative bacteria have an outer cell membrane enclosing a thinner
  peptidoglycan cell wall, which has decreased affinity to the crystal violet dye

Classification of bacteria

Gladwin / Sakurai / JC 2020

MECHANISMS OF ANTIBIOTIC RESISTANCE

• Mechanisms of Antibiotic Resistance can be classified broadly:
  • Efflux Pumps
  • Blocked Penetration / Alteration in access to target site
  • Target Modification
  • Modification of Drug or pathways
• There might be multiple resistance mechanisms at play in the same organism

Spread of Bacterial Resistance

• Selective pressure selects for favourable mutations of resistance
• mosaic genes (from other bacteria eg strep pneumo from strep mitus) or uptake of DNA from environment
• transfer of resistant bacteria from person to person
• horizontal gene transfer;
• transduction – acquisition of bacterial DNA from a phage (a virus that propagates in bacteria);
• transformation – uptake and incorporation of free DNA released into the environment by other bacterial cells;
• conjugation – gene transfer (usually on plasmids), by direct cell-to-cell contact through a bridge.

Sources:
Microbiology Lippincott Williams & Wilkins
https://courses.lumenlearning.com/microbiology/chapter/drug-resistance/
https://www.encyclopedie-environnement.org/en/health/antibiotics-antibiotic-resistance-and-environment/

Gladwin / Sakurai / JC 2019

2014A 10: 63% of candidates passed this question.
Generally candidates provided an accurate classification of bacteria based upon Gram staining and shape. None or poorly staining organisms were often overlooked. Mechanism of resistance was also well covered, with examples. Areas of weakness were a lack of descriptive detail and/or omission of an example for each mechanism. Mechanisms such as metabolic blockade of essential pathways for antibacterial action and active removal of intracellular antibiotic were more commonly omitted.

RED BLOOD CELL

Formation

Simplified – main steps.

Takes 7 days

• Proerythroblast propagates
• From proerythroblast to reticulocyte
  • Concentration of haemoglobin increases
  • Nucleus disappears
  • Endoplasmic reticulum disappears
• Reticulocyte
  • Ribosomes
  • Mitochondria
• Reticulocyte released into circulation
• Matures to RBC in 1-2 days

EPO increases rate of differentiation
Produced in the kidney (in response to low PO₂)

Structure

• Are 7.5μm in diameter
• Are 2um thick
• biconcave disc, contains haemoglobin A (Hb F in-utero), has a central Fe moiety and demonstrates positive cooperativity in binding oxygen
• Have a lifespan of 120 days
• make up 40-50% of the blood volume, usual value 4-5 x 10¹²/L
• Carry ~29pg of haemoglobin

JC / Mooney 2019

2014A 11: 19% of candidates passed this question.
Candidates generally provided detailed description of the cell lineage that led up to the production of the mature red blood cell (RBC), but often omitted to mention those aspects unique to the RBC that were essential to its functions (e.g. biconcave shape gives the RBC a greater surface area and shorter distance to central regions, thus optimising diffusion of gases; the RBC enhanced ability to change shape and travel through narrow capillaries; lack of organelles maximises space for Hb, etc.). Mention of RBC function often lacked detail (e.g. restricted to just mentioning “O2 carriage”) or failed to mention, and describe, the RBC’s role in acid base buffering and HCO3- production.

• Autoregulation: “intrinsic ability of an organ to maintain a constant blood flow despite changes in perfusion pressure“
• if perfusion pressure is decreased to an organ, blood flow initially falls, then returns toward normal levels over the next few minutes
• This autoregulatory response occurs in the absence of neural and hormonal influences and therefore is intrinsic to the organ, although these influences can modify the response

Mechanisms of Autoregulation

Local

• Myogenic
  • Stretch of vessel walls causes constriction due to stretch mediated Ca²⁺ release
    • Prominent in small arterioles throughout body
    • Prevents excessive increases in blood flow in response to pressure
  • Sheer stress on vessels due to increased flow causes release of Endothelial Derived Relaxing Factors such as Nitric Oxide which dilates the vessel, increasing vessel diameter and reducing sheer stress
• Metabolic
  • Increased concentration of metabolic byproducts such as CO₂, lactate, adenosine and H⁺, K⁺, cause upstream vasodilation
    • This diffuse through the interstitium to upstream pre-capillary sphincters, arterioles and meta-arterioles
    • Due to alteration of vessel radius, flow increases, according to the Poisuille-Hagen Equation
  • Conversely, presence of excess nutrients (and O₂) leads to vasoconstriction and decreased flow
• Reactive hyperaemia
  • During occlusion to blood flow to a tissue, metabolic products build-up
    • On restoration of flow to the tissue, flow can increase 4~7 fold due to buildup of metabolites and autoregulatory mechanisms
• Active hyperaemia
  • During periods of increased metabolic work, due to the consumption of nutrients and production of metabolites, blood flow increases due to autoregulation

Regional Circulations

Other Influences which modify Autoregulation

Neural factors

• Sympathetic
  • Sympathetic α adrenergic stimulation causes vasoconstriction (integral in baroreceptor response)
    • Resting sympathetic tone contributes significantly to peripheral vascular resistance
    • Most tissues except coronary and cerebral circulations
  • Sympathetic cholinergic vasodilator supply under cortical control to skeletal muscle

Hormonal factors

• β₂ mediated vasodilation in response to adrenaline in skeletal muscle
• α₁ mediated vasocontriction in response to circulating adrenaline

Long term

• Arterioles and vessels increase in size and number due to increased metabolic requirements of a tissue and chronic hypoxia
  • Important factors
    • VEGF
    • Angiogenin

Sakurai 2016

2014A 12: 8% of candidates passed this question.
Most candidates failed to fully comprehend the question. Candidates displayed some difficulty in differentiating regulation at a local level (which is what the question asked for) from that of central regulation (e.g. sympathetic nervous system activity, cardiac output, etc.), which was not what the question asked for. Other omissions were a failure to define and explain autoregulation. Most candidates mentioned the myogenic and the metabolic theories, but failed to provide sufficient details as to their mechanisms. It was expected candidates would provide some detail as to locally acting factors. Adenosine and nitric oxide were mentioned on occasions but others such as endothelin and prostacyclin were often omitted.

Afferent

• In response to chemical, mechanical or noxious stimuli in larynx, trachea, carina or bronchi
• Signal transduced via internal laryngeal nerve (vagus nerve)

Central processor

• Medullary respiratory centre
  • No single “cough centre” isolated

Efferent

Co-ordinated action of inspiratory muscles, pharyngeal muscles, and expiratory muscles

1. Inspiratory phase
   • Inhalation of a volume of air sufficient for cough generation (phrenic nerve and intercostal nerves)
2. Compressive phase
   • Closure of the glottis (recurrent laryngeal nerve)
   • Activation of expiratory muscle against closed glottis
   • Generation of transient increase in pressure of 300mmHg in thorax arterial blood and CSF
3. Expulsive phase
   • Opening of glottis due to posterio-cricoarytenoid muscle activation
   • High velocity flow generated in bronchi, trachea and larynx
     • “Choke point” – high velocity flow causes turbulant flow → increased shear stress between gas and airway lining → drag and expulsion of irritant

Intrinsic muscles of the larynx

• Cricothyroid
  • Upper lip of cricoid cartilage → Inferior aspect of thyroid cartilage
  • Innervated by superior laryngeal nerve
  • Tenses vocal cords – elevates vocal tone
• Thyroarytenoid
  • Anterior inner surface of thyroid à arytenoid cartilage
  • Innervated by inferior laryngeal nerve
  • Relaxes vocal cords – depresses vocal tone
• Posterior cricoarytenoid
  • Posterior aspect of cricoid cartilage → arytenoid cartilage
  • Innervated by inferior laryngeal nerve
  • Abducts vocal cords
• Lateral cricoarytenoid
  • Lateral aspect of cricoid cartilage → arytenoid cartilage
  • Innervated by inferior laryngeal nerve
  • Adducts vocal cords
• Transverse and Oblique arytenoids
  • Spans the arytenoid cartilages
  • Innervated by the inferior laryngeal nerve
  • Adducts vocal cords

Sakurai 2016

2014A 13: 26% of candidates passed this question.
Many candidates struggled with this question. A good answer included a brief description of the role of the cough reflex, an outline of the sensory pathways, central integration and motor pathways of the reflex, and a description of the components of the cough reflex. Most candidates failed to accurately describe the sequence of events involved in the cough reflex. Very few gave sufficient detail on the nerve supply of the larynx

Cerebral Blood Flow

• CBF = CPP / CVR (Cerebral Perfusion Pressure / Cerebral Vascular Resistance)
• CBF 15% resting CO → ~750ml/min or 50ml/100g brain tissue/min
  • CBF<50ml/100g/min → cellular acidosis
  • CBF<40ml/100g/min → impaired protein synthesis
  • CBF <30ml/100g/min → cellular oedema
  • CBF <20ml/100g/min → failure of cell membrane ion pumps, loss of transmembrane electrochemical gradients
  • CBF <10ml/100g/min → cell death

Determinants of CBF

• CPP
  • Net pressure gradient driving blood flow through the cerebral circulation
  • CPP = MAP – ICP
    • MAP = CO x SVR; CO = HR x SV; SVR = MAP / CO
    • ICP dependent on: brain, blood, CSF
• CVR

Regulated by 4 primary factors:

• Cerebral metabolism
  • flow-metabolism coupling: ­
    ↑ metabolic demand → ↑ CBF + substrate delivery
  • Controlled by vasoactive metabolic mediators:
    H+ ions, K, CO2, adenosine, glycolytic intermediates, NO
• CO₂ and O₂
  • CO₂
    • At normotension: relationship between PaCO₂ and CBF = almost linear
    • ↑ ­PaCO₂ → cerebral arteriolar vasodilation → ↓ CVR + ­↑ CBF
      • 2~4% increase for every 1mmHg increase in CO2
    • ↓ PaCO₂ → cerebral arteriolar vasoconstriction → ­↑ CVR + ↓ CBF
    • Initial stimulus = ↓ brain ECF pH
    • Effects regulated by: NO, prostanoids, K channels, intracellular [Ca²⁺]
  • PaO2
    • little effect at normal PaO₂
    • PaO₂ <60mmHg → cerebral arteriolar vasodilation → ­­↑ CBF
    • Mechanism: hypoxia acts on →
      • cerebral tissue to promote release of adenosine → cerebal vasodilation
      • cerebrovascular smooth muscle → hyperpolarisation → ↓ Ca²⁺ uptake → vasodilation
• Autoregulation
  • Constant across CPP 50-150mmHg
    • CPP >150mmHg: CBF µ CPP
    • CPP <50mmHg: CBF <50ml/100g brain tissue/min → ischaemia
  • Stimulus to autoregulation = CPP (not MAP)
  • autoregulation curve R shifted in HTN; L in neonates
  • Mechanism:
    • Myogenic mechanism: arterioles vasoconstrict in response to ↑ ­wall tension + vasodilate in response to ↓ wall tension → ↓ or ↑­ CVR
    • May involve adenosine
    • Can be impaired in SAH, tumour, stroke, head injury
• Neurohumeral factors
  • Relative lack of humoral + autonomic control on normal cerebrovascular tone
  • Main action of SY nerves = vasoconstriction
• Other factors
  • Blood viscosity: directly related to HCt; ↓ viscosity → ↑ ­CBF as per Hagen-Poiseuille law
  • Temperature: ↓ CMRO₂ by 7% for each ↓ 1°C in temp
  • Drugs
    • E.g. barbiturates ↓ cerebral metabolism
    • Volatile agents → ↓ tension cerebral vascular smooth muscle → vasodilation + ­CBF

Effect of Propofol and Ketamine

Kerr 2018

2014A 14: 74% of candidates passed this question.
This question was well answered. It is a structured question that guides candidates through exactly what is required. Well drawn graphs were a particularly effective means of scoring marks.

Lung compliance

• Change in lung volume per unit change in transmural pressure
• Normal lung compliance ~200ml/cmH2O
• Static compliance (Cs)
  • ” Compliance of lung measured when lung held at constant lung volume”
  • no pressure componet due to resistance
  • is a function of: Elastic recoil of the lung, Surface tension of alveoli
• Dynamic compliance (Cd)
  • ” Compliance of lung measured during cycles of inspiration and expiration”
  • includes the pressure required to generate flow by overcoming resistance forces
  • is a function of: respiratory rate
• Dynamic Compliance usually < Static Compliance due to the degree of time dependence in the elastic behaviour of a particular lung
• Specific compliance
  • Compliance per unit volume lung
  • Used to compare different lungs

• Hysteresis
  • any process where the future state of a system is dependent on its current and previous state
  • Compliance of the lung is different in inspiration and expiration
  • In dynamic compliance curves:
    • Airways resistance is a function of flow rate. Flow rate (therefore resistance) is maximal at the beginning of inspiration and end-expiration.
  • In static compliance curves:
    • There is no resistive component. Hysteresis is due to viscous resistance of surfactant and the lung.

Factors Affecting Compliance

Lung Compliance

• Surfactant
  • increases lung compliance
  • decreases surface tension at alveolar air – water interface
  • prevents small alveoli from collapsing
  • accounts for most of hysteresis in intact lungs
• Lung volume
  • Lung Compliance decreases at higher lung volumes
  • Specific compliance (Compliance/FRC) remains constant
    • Elephants have greater lung compliance than mice!
• Pulmonary blood volume
  • Increased PBV decreases lung compliance
  • Pulmonary venous congestion from L heart failure or mitral regurgitation
    decreases lung compliance
• Bronchial smooth muscle tone
  • Increased bronchial smooth muscle tone decreases compliance
  • Decreased dynamic lung compliance by 50% in animal models of methacoline
    challenge
• Disease
  • ARDS, pneumonia decreases lung compliance
  • pulmonary fibrosis → Impraired elasticity → decreases lung compliance
  • Asthma, Emphysema increases lung compliance

Chest Wall Compliance

• Chest wall restriction – reduced chest wall compliance
  • Obesity
  • Spastic paralysis of chest wall musculature
  • Ossification of costal cartilages
  • Kyphosis/scoliosis
  • Scarring/constriction (e.g. circumferential burns)
• Position: Prone (60% reduced compliance)
• Collagen Disorders: Increased Chest Wall Compliance

Measurement of Compliance

Dynamic Compliance

• ” Compliance of lung measured during cycles of inspiration and expiration”
• Measure:
  • Measure with spirometer
  • Using Volume/Pressure curve during normal rhythmic breathing at points of no flow
  • Equation above then gives dynamic compliance

Static Compliance

• ” Compliance of lung measured when lung held at constant lung volume”
• Volume vs Pressure loops during inspiration and expiration demonstrate Hysteresis
• Measure:
  • @ no flow in or out of the lung, AND time for pressure to equlibrate across the lung (>10sec).
  • Patient exhales in steps holding the volume with open glottis
  • Intrapleural pressure measured as oesophageal pressure
  • Measured compliance secondary to viscoelastic properties and accounts for both short and long time-constant alveoli.

Specific Compliance

• Measure of the average compliance across all lung units
• Children = Adults ~ 0.05 cmH₂O^-1

Gladwin / Sakurai / JC 2020

2014A 15: 34% of candidates passed this question.
There was a good understanding of the definitions of compliance but many candidates failed to clearly demonstrate an understanding of the difference between static and dynamic compliance. Many candidates had little knowledge of how compliance is measured. It was expected that descriptions of methods to measure static and dynamic compliance would be provided. There were frequent errors in descriptions that were provided

Structure of Cell Membrane

Cell Membrane

• Made of
  • Phospholipids
  • Proteins
  • Cholesterol – Found in eukarocytes ie cells with nuclei
• Cell membrane = 7.5nm thick semi permeable structure

Lipid Bilayer

• Fluid rather than solid
• Phospholipids have:
  • eg phosphatidyl-choline & phosphatidyl-ethanol-amine
  • Hydrophilic head
    • Water soluble
    • Exposed to aqueous exterior & interior
  • Glycerol backbone
  • Fatty acid tails –
    • Hydrophobic
    • Meet in middle of cell membrane
• Proteins can be either:
  • Integral – ie pass through bilayer eg ion channels
  • Peripheral = straddling
    • make up 50% of cell membranes mass

Function of CM Proteins

• Structural
• Carriers for facilitated diffusion (i.e. down electrochemical gradient)
• Pumps for ion active transport
• Ion channels (diffusion down electro- or chemical gradient or both; e.g. K-“leak” channels)
• Receptors for chemical messengers (i.e. hormones , neurotransmitters , autacoids…)
• Enzymes
• Glycoproteins involved in AB processing or anticoagulation (e.g. the mucopolysaccharide glycocalyx of the endothelium which repels clotting factors + PLT’s → helps prevent blood from clotting in intact blood vessels)

Transmembrane Transport Processes

Mooney / JC 2019

2014A 16: 60% of candidates passed this question.

The structure of the cell membrane was generally well covered by most candidates. Many had difficulties structuring an answer for the transmembrane transport processes. Dividing this section into proteins (some receptors, channels etc.) and carbohydrates (some receptors, immune reactions etc) followed by a very brief discussion of each type of process would have aided candidates towards providing a good answer.

Local Anaesthetics

• Local anaesthetic agents act via inhibition of voltage gated Na+ channels, by binding to the intracellular portion of the channel
  • → Decreased Na influx
  • → Inhibition of depolarization
  • → Inhibition of action potential formation and propagation
• Local anaesthetics are formed by a hydrophobic and hydrophillic component, and are classified according to the linkage between the two, either amide or ester
• Amide Local Anaesthetics
  • e.g. Lignocaine, ropivacaine, bupivacaine
  • Metabolized by hepatic dealkylation by P450 enzymes
  • Longer duration of action
• Ester Local Anaesthetics
  • e.g. Procainamide, cocaine
  • Metabolized by plasma esterases
  • Shorter duration of action

Mooney / JC 2019

Pharmacology of Lignocaine

2014A 17: 71% of candidates passed this question.
The first part of this question was answered well by most candidates.
Generally, the second part of the question was poorly organised by many candidates, the consequence being that many opportunities for picking up marks were lost. A brief statement as to what lignocaine is, its presentations and dose, some facts about PD and PK followed by a few lines on toxicity (CC/CNS ratio) was mostly what was required. Only a few candidates mentioned lignocaine toxicity

Origin / Course / Termination

• Originates at the jugular foramen where it continues the sigmoid sinus
• Exits the foramen accompanies by the glossopharyngeal (IX), vagus (X) and accessory (XI) nerves
• runs caudally down the neck – The vein lies most superficially in the upper part of the neck
• The vein lies lateral, first, to the internal carotid artery, separated by the hypoglossal (XII) nerve, and then to the common carotid artery, with the vagus nerve between and posterior to the artery and vein.
• These three structures lie in a common fascial compartment (the carotid sheath) with the cervical sympathetic chain lying posterior to the sheath.
• These four structures, two vessels and two nerves, form a quartet throughout the neck.
• The deep cervical chain of lymph nodes lies close against the carotid sheath
• The vein is initially posterior to, then lateral and then anterolateral to the carotid artery during its descent in the neck
• Terminates behind the sternoclavicular joint, where it joins the subclavian vein to form the brachiocephalic vein 

Relations of the IJV

• Anterior –
  • Internal carotid artery and vagus nerve
  • Superficially, the internal jugular vein is overlapped above and then lower down covered by the sternocleidomastoid muscle and is crossed above by the posterior belly of the digastric and lower down by the inferior belly of the omohyoid
• Posterior –
  • C1, sympathetic chain, dome of the pleura. On the left side, the IJV lies anterior to the thoracic duct
  • Posteriorly, the vein rests on (from above downwards) the rectus capitis lateralis, the transverse process of the atlas, the scalenus medius, and the scalenus anterior, with the phrenic nerve crossing it; and all are covered by the precervical fascia
• Medial – Carotid arteries, cranial nerves IX-XII

Surface Anatomy for Venepuncture

• Lies lateral to the carotid artery within triangle formed by: Two heads of Sternocleidomastoid muscle and clavicle
• On Ultrasound: Non-pulsatile, thin walled, compressible vessel lateral to the carotid artery

Anatomical Variations

• The right IJV (80.5%) was more often larger than the left IJV.
• With reference to the CCA, 85.2% of the IJV were found in the lateral position, 12.5% anteriorly, 1.1% medially and 1.1% posteriorly.
• IJV were sometimes found to be hypoplastic, and in rare cases this was seen bilaterally in both the right and left IJV.
• 5.5% have an IJV that does not correspond to the site predicted by external markings
• Other variations:
  • IJV bifurcation
  • IJV duplication
  • IJV fenestration
  • IJV trifurcation
  • Posterior tributary

Sources:
Ellis H. The clinical anatomy of the great veins of the neck. Br J Hosp Med (Lond). 2010 Feb;71(2):M20-1. doi: 10.12968/hmed.2010.71.Sup2.46501. PMID: 20220708.
Asari AIA, Barros RAV, Borges MAP. Anatomic variant of the internal jugular vein and its importance in vascular access for hemodialysis. J Vasc Bras. 2019 Oct 23;18:e20190014. doi: 10.1590/1677-5449.190014. PMID: 31692937; PMCID: PMC6822959.

Gladwin / JC 2020

Doppler effect

• Change in apparent frequency of sound for an observer moving relative to its source
• Use in ultrasound
  • Sound waves reflected off objects moving toward or away from transducer
    (usually blood)
    • If object moving toward transducer, frequency appears increased – displayed as red (however this is not standardized across machines)
    • If object moving away from transducer, frequency appears decreased –
      displayed as blue
  • Can be used to measure velocity of flow, as well as direction
    

Sakurai 2016

2014A 18: 40% of candidates passed this question.
An overview of the Internal Jugular vein stating where it is formed and terminates would be a good start. The important surface anatomy of the vein (left and right) followed by mention of the important anatomical relationships was then required. Few candidates mentioned anatomical variations.
Many answers had no identifiable structure and went back and forth around the topic as information came to mind. A number of answers contained very rough diagrams that did not contain mark worthy information but took time to draw.
The second part of the question was generally well answered by those attempting it. Many candidates ignored or forgot about this part of the question. Some candidates wrote 2 or more pages of significant detail in stark contrast to what they had written for the first part of the question. The percentage of marks allocated is a good guide as to the level of detail required in the answer.

Cardiac Output

Cardiac output = Volume of blood ejected by the heart per unit time (minute)

HR determined by autonomic input

• Resting HR approx 60
  • Sympathetic blockade causes HR to slow to 50
    • Sympathetic output to heart governed by the medullary vasomotor area
  • Parasympathetic blockade causes HR to hasten to 110
  • Both sympathetic and parasympathetic blockade causes HR to hasten to 100
  • Electrolytes
  • Drugs

SV = Amount of blood ejected by the heart per contraction

Governed by:

• Preload
  • Tension applied to myocyte immediately prior to contraction
    • Starling relationship
      • Optimal sarcomere length ~2.2um
      • Over-stretch inhibited by fibrous pericardium
    • Preload governed by
      • Blood volume and MSFP (increases preload)
      • RAP (decreases preload)
      • Resistance to venous return (decreases preload)
      • Negative intrathoracic pressure (aids in venous return)
      • Musculovenous pumps (aids in venous return)
      • One-way venous valves (aids in venous return)
• Afterload
  • Load against which the ventricle must exert its contractile force
  • According to Laplace law
    • Afterload ∝ (Aortic pressure x ventricular radius) / thickness of ventricular wall
  • Other factors affecting afterload
    • Resistance
      • Viscosity inversely proportional to flow
        • As viscosity decreases (e.g. Hb decrease), output increases
      • Flow is proportional to vessel radius to the 4^th power
• Contractility
  • Intrinsic ability of myocardium to contract at given preload and afterload
  • Governed
    • Sympathetic increases contractility
    • Parasympathetic decreases contractility
    • Other hormones
    • Electrolytes

Measurement

Cardiac output measurement can be performed:

• Invasively
  • Pulmonary Artery Catheter
    • Thermodilution
    • Fick Principle
  • Indicator Dilution Technique
  • TOE
  • Arterial waveform analysis
    • PiCCO
    • FloTrak/Vigileo
    • Acumen/Hemosphere
• Non-invasively
  • TTE
  • MRI
  • Thoracic impedance

Sakurai / JC 2019

2014A 19: 58% of candidates passed this question.
This is a core question. It was expected candidates could provide a definition (heart rate x stroke volume) and then move on to outline factors that affect it (afterload, preload, contractility). Additional marks were awarded for descriptions of the relationship to mean systemic filling pressure and other influences beyond this. Most candidates described a thermodilution cardiac output curve but almost all described the technique as based on the “Fick equation or method” (which is used to estimate cardiac output from oxygen consumption). Very few candidates correctly identified the Stewart Hamilton equation as the integration method used to relate cardiac output (flow) to temperature change as an example of indicator dye dilution. Candidates seemed to lack depth and understanding on this topic.

Drug Factors

1. Lipid solubility
   ◦ ↑ lipid sol → ↑ absorption
   ◦ Must still have some water soluble component
2. Molecular size
   ◦ ↓ size → ↑ rate of absorption
   ◦ Larger molecules require processes other than simple diffusion
3. Degree of ionisation
   ◦ pH-pKa gives the degree of ionisation
   ◦ ↓’d ionisation favours absorption
4. Physical forms
   ◦ Gases faster than liquids faster than solids
5. Dosage forms
   ◦ Capsules more rapidly absorbed than tablets
6. Formulation
   ◦ The addition of Na to the formulation for stability can reduce the bioabalability via the oral route
7. Concentration
   ◦ From Fick

Patient factors

1. Area of absorptive surface
   ◦ intestinal resection or coeliac → ↓ absorptive surface → ↓ absorption from Fic
2. Vascularity
   ◦ Shock → ↓ absorption
3. pH
   ◦ effect degree of ionisation
   ▪ ↓ pH favours absorption of acidic drugs
   ▪ ↑ pH favours absorption of basic drugs
4. Presence of other substances
   ◦ Statins should be taken with food
   ◦ Milk ↓’s and Vit C ↑’s absorption of iron
5. GI motility
   ◦ ↑ motility → ↓ absorption
6. Functional Integrity of the absorptive surface
   ◦ Coeliac disease → flattened mucosa → ↓ absorption
7. Coexisting disease state
   ◦ diarrhoea → ↓ absorption

Gladwin 2016

45% of candidates passed this question.

This is a very broad and open question. While a structured approach was useful, a sound knowledge of first principles or even being able to “think on the fly” would have provided candidates with enough opportunities to generate a pass.

2014A 21: 29% of candidates passed this question.
Most candidates were able to provide some details about warfarin however dabigatran was less well known. The syllabus provides a guide to depth of knowledge required for listed drugs and so more detail was expected for Warfarin as a class “A” drug than was expected for dabigatran (a class “C” drug). It was however expected that candidates would provide more than just generalisations regarding “hepatic metabolism and renal excretion” when applied to both agents that actually have different modes of elimination.

Buffer

• Weakly ionised acid or base in equilibrium with its full ionised salt
• A buffer can “resist” change in pH by absorbing or releasing H+ ions
• Works best when pKa is closest to the target pH (7.4)
• Isohydric Principle
  • All buffer systems which participate in defence of acid-base changes are in equilibrium with each other. There is after all only one value for [H⁺] at any moment. This is known as the Isohydric Principle.

Effectiveness:

• buffer pKa (most effective if pKa = pH of carrying solution)
• pH of carrying solution
• amount of buffer present
• open (physiological) vs closed (chemical) system

Buffer Systems by site

Buffer Systems

Protein (Intracellular)

• pKa of imidazole group is 6.0
• pKa of the histadine residues themselves = 6.8
• Protein buffer ability is proportional to Histadine residue content.

Haemoglobin (Blood)

• Protein buffering system
• Important intracellular buffer in RBC
  • Exists as weak acid – HHb and potassium salt KHb.
  • Hb a pK_a of 8.2 in deoxy form and 6.6 in oxyHb
  • Buffering capacity due to imidazole residues on 38 histidine residues on Hb molecule
    • pKa of residues 6.8 à close to physiological pH

• Also important in extracellular buffering (following bicarbonate buffer system)
  • Due to fast equilibration of HCO₃^– (Hamburger Shift)
  • Band3 Transporter (HCO₃^–/Cl^– antiporter)
  • Allows carbonic anhydrase reaction to take place by limiting build-up of HCO₃^– (la chatelier principle)

• Formed in erythrocytes as a tetramer of 4 subunits
• Hb ~ 6 times the number of histadine (38) residues compared with albumin. (3-6x buffering capacity)
• Hb is in much greater concentrations than any other protein (15 g/dL vs 7 g/dL)
• For each mmol OxyHb, 0.7mmol H⁺ is buffered and 0.7mmol of CO₂ can enter circulation without a change in pH
• Available at high concentrations in RBC
• Isohydric exchange
  • the buffer system (HHbO₂-HbO₂-) is converted to another more effective buffer (HHb-Hb-) exactly at the site where an increased buffering capacity is required
  • Deoxyhaemoblobin is a much more effective buffer
  • oxygen unloading increases the amount of deoxyhaemoglobin and this better buffer is produced at exactly the place where additional H⁺ are being produced because of bicarbonate production for CO₂ transport in the red cells.

Bicarb (Plasma, Interstitium, Urine (minimal))

• Catalysed by carbonic anhydrase (slow where CA is absent (plasma))
• Open at both ends
• Bicarb regulation at kidneys
• CO₂ regulation at lungs

Ammonia (Urine)

Equlibrium between ammonia and ammonium

Steps:

• Glutamine enters PCT cells
  • 20% from filtrate
  • 80% from peritubular capillaries
• Ammonia (NH3) produced from glutamine in PCT by glutaminase secreted into lumen
• Reabsorbed in TAL of LoH
• Diffuses into peritubular cells of CD down conc Grad
• H+ secreted into lumen of CD
• Combines with ammonia to form ammonium
• Ammonium positive charge prevents reabsorption
• Thus “excess hydrogen can be secreted with ammonium”

Phosphate (Urine, Bone)

Effect in urine is limited due to:

• Minimal urinary pH is 4.5 → equation B is >99% ionised → of little use.
• Requires filtered PO4 → Normally low levels.
• Depends on Diet and PTH.
• Where H is secreted in distal tubules, there is minimal PO4 excretion

CaCO3 (Bone)

• Important in chronic metabolic acidosis
• Release of calcium carbonate from bone is the most important buffering mechanism involved in chronic metabolic acidosis.

Please Note: This answer is viewed from the Traditional approach to Acid-Base theory. Alternative (physicochemical approaches) deemphasise bicarb due to its equilibrium with water and relatively low concentration compared with the strong ions.

Gladwin / Sakurai / JC 2020

2014A: 37% of candidates passed this question.
Candidates who described an overall view of the body’s buffer systems scored well.
Most candidates could define buffer and could discuss the bicarbonate buffer system;
however this was not sufficient to pass the question. To pass there had to also be a discussion of the other buffer systems including phosphate, protein (haemoglobin, plasma proteins and intracellular proteins), ammonia and bone.
Best answers included discussion of open versus closed systems and the relative contribution of the differing buffer systems in blood, intracellular fluid, extracellular fluid and urine.

GFR

GFR:

• “The amount of glomerular ultrafiltrate formed divided by the time of filtration”
• Normal value is approx 125 mL/min or 180 L/day
• Renal blood flow 1.25l/min in 70kg male → Filtration fraction 0.2

Functional anatomy:
3 Distinct Layers:

• glomerular capillary endothelium
  • highly specialised endothelium with fenestrations to ↓ filter thickness
  • prevents cellular components of blood from coming into contact with BM
• glomerular BM
  • made of CT; -vely charged
  • acts as filter
• bowmans epithelial cells (podocytes)
  • epithelial cells with foot processes → large SA
  • negatively charged
  • maintain BM + phagocytic functions

Direct GFR Determinants

The GFR (Net flux across the membrane) is the balance of hydrostatic pressure and oncotic pressure, as defined by the Classic Starling Equation.

where
K_f = Filtration coefficient
P = hydrostatic pressure
π = oncotic pressure
σ = Staverman’s reflection coefficient ie. Permeability of membrane to protein

• Normally NFP = 17mmHg
• Tubular oncotic pressure = zero throughout
• GC oncotic pressure varies from 21 to 33 mmHg as filtrate is removed.
• Thus less GFR produced at distal end of tubule.

Factors influencing GFR

Circulating Factors

• Prostaglandins
  • PGI₂ and PGE₂ → vasodilates → ↑ renal blood flow → ↑ GFR
  • ↓ PGE2, PGI2 and NO levels → inhibits afferent arteriolar vasodilation → ↓ GFR
• Long term → ↓ renin release → ↓ ATII-induced efferent arteriolar vasoconstriction → ↓ GFR
• Noradrenaline / Adrenaline
  • constrict renal afferent and efferent arterioles → ↓ renal blood flow and reducing filtration → ↓GFR
  • Constrict mesangial cells to → ↓ GFR.
• Mesangial cell tone:
  • Angiotensin 2, Endothelin, vasopressin → ↓ glomerular surface area and GFR
  • ANP, PGE2, Dopamine and cAMP → all increase GFR

Solute factors

• Size
  • < 7 kDa (Eg. glucose, ions, urea, H2O) filtered freely,
  • > 70 kDa (Eg. albumin) are not filtered;
  • neutral particles < 4 mm diameter filtered freely, > 8 mm are excluded
• Charge
  • Negatively charge (Anionic) particles repulsed
  • Cationic substances filtered more readily
• Protein binding
  • Albumin excluded

Disease Factors

• Filtration decreases
  • Shock → decreased glomerular pressure
  • Obstruction → increased bowman’s capsule hydrostatic pressure
  • Hypoproteinaemia → hepatic failure, nephrotic syndrome

JC / Gladwin / Sakurai / Kerr 2020

2014A 23: 40% of candidates passed this question.
Generally this question was well answered. Almost all answers gave the correct value for GFR and the correct formula for Starling’s forces across the glomerular membrane. Better answers discussed the physiological factors affecting each force (hydrostatic and osmotic) across the membrane in a stepwise logical manner. Some answers discussed the control of renal blood flow; this was not expected and therefore was not rewarded

Mechanism of Action and Effects

• Opiates act on MOP, DOP, KOP and NOP receptors
• MOP are distributed widely:
  • Cortex
  • Basal ganglia
  • Spinal cord – dorsal horn
  • Periaqueductal grey – descending inhibition
• DOP, KOP and NOP less affected by commonly used opiates
  • Produce analgesia, with different levels of other opiate effects
• Opioid receptors are G_iPCR
  • Inhibit Ca²⁺ channels
    • Prevent neurotransmitter release at pre-synaptic nerve terminals
  • Open K⁺ channels
    • Hyperpolarise post-synaptic nerves, preventing signal transmission

Analgesia

• Analgesia induced by inhibition of ascending pain transmission
• Sites of action
  • Primary afferents
  • Dorsal horn interneurons
  • Descending modulatory neurons
    • Inhibition of GABA-releasing inhibitory neurons
  • Supraspinally
• Analgesia enhanced by centrally mediated euphoria and sedation

Respiratory depression

• MOP-mediated
• Action on medullary chemoreceptors
  • Blunted increase in respiratory drive with increasing CO₂
• Effect is antagonised by painful stimulus

Constipation

• Mediated by MOP, KOP and DOP receptors
  • Expressed in high density throughout GIT nerve plexus
• Increased GIT tone, with subsequent loss of rhythmic peristaltic movements

Mooney 2016

2014A 24: 11% of candidates passed this question.
This question was poorly answered with a low pass rate; which was unexpected for this core topic. In general, completed answers demonstrated good understanding of the analgesic mechanisms of opiates, but only superficial understanding of respiratory depression and constipation. Better answers explained the decreased responsiveness of the respiratory centre to CO2, and the effects of opiates on the enteric nervous system and peristalsis.