Physiology 15 Flashcards
Contrast physiological pain and clinical pain
Physiological:
-Nociceptive response to high-intensity stimulus
Clinical:
-Pain response to low-intensity stimuli, dependent on pain modulating mechanisms
What are the peripheral mechanisms that promote clinical pain?
- Activation of primary afferent nociceptors
- Peripheral sensitisation
- Peripheral opioid action
- Peripheral nerve injury
- Sympathetic changes
What are the types of primary afferent nociceptor fibres?
Aδ: 6-30m/s, myelinated, mechanothermal, short-lasting
C: 0.5-2m/s, unmyelinated, polymodal, dull/burning
What are the chemical mediators that sensitise peripheral nociceptors?
H+, K+ NA Histamine Kinins Eicosanoids 5-HT Nerve growth factor Neuropeptides (eg. substance P)
In what ways are peripheral nociceptors sensitised?
Direct activation / Secondary activation / Spread of hyperalgesia
Direct activation:
-Nociceptor activated by cell damage. Bradykinins, prostaglandins and K+ sensitise the terminal.
Secondary activation:
-Impulse propagated, releasing substance P, which causes nearby vasodilatation, releading more bradykinin and stimulating histamine and serotonin release.
Spread:
-Buildup of chemical mediators spreads to sensitise nearby nociceptors
What peripheral mechanism exists to reduce pain following injury?
-Production of opioid receptors in dorsal root ganglion cell bodies which are transported distally and acted on by endogenous opioid peptides
What changes occur on damage to a peripheral nerve
- Damage causes ectopic firing at nerve site or near to dorsal root ganglion
- Sympathetic nerve fibres sprout around dorsal root ganglion
- Large diameter afferent fibres sprout into superficial dorsal horn
- Ectopic firing of dorsal horn cell bodies that have lost afferent input
Which neurotransmitters and modulators are important in dorsal horn transmission?
Glutamate (major)
Substance P
Neurokinin A
CGRP
Opioid
GABA
5-HT
Adrenoceptors
Outline the mechanism of pain transmission at dorsal horn synapses
- Glutamate and SP released from primary afferent terminal
- AMPA and NK-1 receptors are activates, causing Na+ influx and second-messenger activation.
- This causes priming of NMDA receptor by removal of the MG2+ ‘plug’ and Na+ and Ca2+ influx.
- NMDA activation increases responsiveness of nociceptive system
What is the effect of central sensitisation?
- Allodynia, hyperalgesia
- ‘Wind-up’ - due to NMDA activity
- Expansion in receptive field size of peripheral neurons
- Reduction in nerve threshold and increased magnitude and duration of response
What are the ascending tracts in the pain pathway?
- Spinal
- Supraspinal (spinoreticular, spinomesencephalic, spinothalamic)
- Cortical
In which parts of the cord do pain fibres ascend?
Usually contralateral anterolateral quadrant. Some travel ipsilaterally.
Caudal fibres tend to travel laterally and rostral fibres medially
Outline which processes the supraspinal pain tracts are involved in
Spinoreticular tract:
- Descending modulation
- Arousal
- Motor and autonomic reflexes
Spinomesencephalic tract:
- Descending modulation
- Autonomic reflexes
- Intergration of responses
Spinothalamic tract:
- Lateral thalamus - Sensory discrimination of pain
- Medial thalamus - Affective and motivational aspects of pain
Outline the role of the cerebral cortex in the pain response
Parietal regions:
-Temporal and spatial features of pain
Frontal regions:
-Emotional response
How is the liver divided into lobes?
Anatomical / Physiological
Anatomical:
-Right and left lobe determined by position relative to falciform ligament
Physiological:
- Defined by blood supply and biliary drainage
- Roughly demarcated by a line from tip of gallbladder to groove of IVC (Cantlie’s line)
How is the liver divided into segments?
- Eight segments
- Defined by vascular supply and biliary drainage
Segments 1-4 in left lobe
Segments 5-8 in right lobe
What is the normal blood flow to the liver?
Where does this come from?
100ml/100g/min
25% of CO
75% of supply is from the portal vein, 25% from hepatic artery. Though this is 50:50 in terms of supplied O2 content
Outline the liver’s function as a vascular reservoir
Normal blood volume: 450ml
In context of elevated RA pressures this can double.
In the context of acute blood loss, the liver can contribute 250ml to systemic circulation
Outline the functional anatomy of the liver microcirculation
Portal tract comprises the terminal branches of portal venules, hepatic arterioles and bile ductules.
Portal tracts are surrounded by the fluid-filled space of Mall. Vessels then pierce the surrounding parenchymal limiting plate to drain into sinusoids.
Sinusoids are a complex vascular network supplying single-cell thick plates of hepatocytes. They extend to the terminal branches of the hepatic venules, which drain the deoxygenated blood.
How is hepatic blood flow regulated?
Portal vein flow varies with factors such as exercise, eating and the respiratory cycle but there is no evidence that portal vein flow can be actively controlled by the liver.
Hepatic artery flow is regulated in 3 ways:
- Intrinsic
- Autoregulation to a MAP of 60mmHg
- Hepatic arterial buffer response (HABR). A compensatory dilatation of hepatic arterial flow if portal flow reduces and vice versa. Thought to be related to rate of clearance of adenosine from the space of Mall - Autonomic
- Para - Minor role in sinusoidal dilatation
- Symp - arteriovenous constriction due to α stimulation - Humeral
- Dilators - Secretin, CCK-PZ, glucagon, prostacyclin, low dose adrenaline. NO
- Constrictors - NA, dopamine, angiotensin, vasopressin, high dose adrenaline
What are the relevant concepts regarding the organisation of the functional liver unit?
Classic lobule / Liver acinus
Classic lobule:
- Hexagonal arrangement with central hepatic venule in the middle and portal tracts around the edges
- Cannot be regarded as a true functional unit
Liver acinus
- Portal tract in centre
- Each draining into 3 terminal hepatic venules
- Zonation of parenchyma (1, 2, 3) based on distance from afferent vessels
Zone 1:
- Nutrient-rich
- Hepatocytes contain numerous mitochondria
- Suited to oxidative metabolism and glycogen synthesis
Zone 3:
- Close to hepatic venule
- Suited to anaerobic metabolism
- Biotransformation of drugs/chemicals/toxins occurs here
- Abundant in SER and CyP450
- Most sensitive area to hypoxic injury
Explain the significance of Kupffer cells and stellate cells in the liver
Kupffer:
- Resident macrophages of the sinusoids
- 10% of liver mass
- More numerous in Z1 than Z3
Stellate:
- Store Vitamin A
- Wrap around sinusoids
- Have contractile capacity
- May regulate sinusoidal tone
What are the important unique features of the liver sinusoids?
Fenestrated capillaries with no basement membrane
Allows direct exchange between plasma and perisinusoidal space of Disse
How does cirrhosis affect the liver sinusoids?
Widespread defenestration and formation of basement tissue - precluding normal function
What are the specialised features of hepatocytes?
Microvilli on sinusoidal membrane:
-facilitated cellular transport
Biliary canaliculi:
-Gaps between lateral walls of hepatocytes, receiving actively excreted substances
RER:
-More developed in Z1
SER:
- Metabolism of xenobiotics
- CyP450
- Fat metabolism
- Cholesterol and bile acid synthesis
- More prevalent in Z3
Describe the lymphatic drainage of the liver sinusoids
Why is lymphatic drainage from the liver important?
ECF from space of Disse -> portal triads in space of Mall -> lymphatic vessels -> thoracic duct
1/3 of all lymph in the body at rest is formed in the liver
How is ascites formed?
Excess interstitial fluid in liver -> transudation across capsule -> ascites
Outline the exchange of solutes that occurs across the sinusoidal membrane
Uptake: Amino acids, glucose, bile acids, fatty acids, bilirubin, pinocytosis
Export: Albumin, lipoproteins, clotting factors
Classify and outline the functions of the liver
Metabolic / Immune
Metabolic:
- Biotransformation (drugs, xenobiotics, toxins, hormones)
- Bile formation and excretion
- Haem metabolism
- Intermediate metabolism of carbohydrates, lipids, cholesterol
- Lactate synthesis, protein synthesis, urea synthesis
Immune:
Kupffer cell function
What is a xenobiotic?
A chemical found in an organism that is not a normal component of the organism. eg. most drugs
What is the general purpose of biotransformation?
What are its possible results?
To convert lipophilic substances into hydrophilic compounds which may be excreted in urine or bile
Results:
- Detoxification
- Changes in pharmacokinetic properties
- Metabolic activation
Define first- and second-pass metabolism
First pass: metabolism of substances arriving to the liver via the portal venous circulation
Second-pass: metabolism of substances arriving via the hepatic artery
Outline Phase I metabolism
Alteration to molecular structure of lipophilic compounds (usually via oxidation, reduction or hydrolytic reactions) eg. hydroxylation, carboxylation etc.
Predominantly undertaken by CyP450 enzymes
Outcome:
- Water solubility -> excretion
- Suitability for phase II metabolism
- Bioactivation
- Toxic transformation, requiring further metabolism
Give an overview of cytochrome P450
- Group of haem-containing enzymes
- Fe moiety is the active part
- Comprise a gene superfamily with 57 members. Fifteen belong to CyP1, 2 and 3 families which are responsible for 70-80% of phase I metabolism of drugs
- In the liver, they exist as a complex embedded in lipid bilayer of SER in hepatocytes
- Complex comprises P450, NADP-oxidase and glucuronyl transferase (involved in phase II metabolism)
- Also occur in small bowel, kidney, lung and brain
Give an overview of Phase II metabolism
- Synthetic reaction involving conjugation of polar compound (phase I metabolite or unmetabolised) to a hydrophilic endogenous substrate.
- Substrates derived from metabolism of carbohydrates (glucuronic acid) and amino acids (glutathione, methionine)
- Enzymes are transferases eg. glucuronyl transferase
- Conjugates are water soluble and very rarely toxic
- Larger compounds excreted in bile, smaller in urine
Outline glutathione’s metabolism role in phase II metabolism
- Thiol containing tripeptide
- Binds toxic and highlty reactive intermediates to form mercapturic acid conjugates
- Central to paracetamol detoxification, where glutathione stores may become depleted, leading to hepatic necrosis. Glutathione stores are replenished by cysteine-containing drugs eg. NAC
How much bile is secreted by the liver per day?
500-1200ml
What are the constituents of bile?
Water Inorganic electrolytes Bile acids (in salt form) Phospholipids Cholesterol Bilirubin/biliverdin
What are the functions of bile?
Elimination of cholesterol, phospholipids and bilirubin
Facilitation of fat digestion and absorption
Absorption of fat soluble vitamins
How are bile acids produced?
Formed in hepatocytes by steroid metabolism
Conjugated with glycine or taurine when released into canaliculus
Form micelles in the canaliculus due to amphiphaticity
What are the chemical properties of bile acids?
Water soluble, acidic
Powerful detergent properties
Amphiphatic anions (cholesterol part is hydrophobic and amino acid conjugate is highly hydrophilic)
What are the types of bile acid in humans?
Primary / Secondary
Primary (produced in liver)
- Cholic acid
- Chenodeoxycholic acid
Secondary (above metabolised in bowel)
- Deoxycholic acid
- Lithocholic acid
How is bile concentrated in the gallbladder?
Active transport of Na+ through gallbladder wall, followed by secondary chloride and water movement.
This enables 5-20fold concentration
What is the capacity of the gallbladder?
30-60ml
Outline the release and processing of bile in the gut
Food in duodenum stimulates CCK release -> gallbladder contraction
Due to conjugation, bile acids are not absorbed in the proximal intestine
90% reabsorbed actively in terminal ileum
10% travels to colon where bile acids are deconjugated to secondary bile acids. Some of these are absorbed and some lost in faeces.
What is the first-pass extraction rate for bile acids in the enterohepatic circulation?
70-90%
What are the consequences of loss of terminal ileum on bile acid circulation?
Cannot be reabsorbed, leading to malabsorption of fats and fat-soluble vitamins
How is haem metabolised?
Haem -> oxidised to Biliverdin + CO + Fe3+
Biliverdin -> reduced to bilirubin
What proportion of bilirubin is produced from RBC degradation?
What are the other sources?
70-80%
Other haemoproteins include myoglobin, cytochrome and peroxidase
What is normal daily production of bilirubin?
250-400 mg
How is bilirubin transported?
Unconjugated - bound to albumin (toxic)
Conjugated - free
Unconjugated bilirubin can be displaced from albumin by sulphonamides, coumarins and radiographic dyes
How is bilirubin conjugated?
Enters hepatocyte by facilitated diffusion
Binds to glutathione S transferase
Mostly diglucuronidated (some monoglucuronidation) at the SER by uridine diphosphoglucuronate glucuronosyl transferase (UGT)
Active transport into canaliculus
How is conjugated bilirubin further changed following release into the gut?
Degraded by bacteria -> urobilinogen -> urobilin (brown)
