Gastric Physiology (Emesis, Histamine, Acid) Flashcards
Define nausea
the sensation of needing to vomit
define vomiting
the involuntary, forceful expulsion of gastric contents via the mouth
Describe the physiology of vomiting
Complex action with multiple afferent and efferent pathways but all interact with the vomiting centre in the medulla.
- CTZ in the floor of the fourth ventricle - outside the BBB. Contains D2, 5 HT3 (serotonin) receptors. Provides efferent input to the vomiting centre in the medulla.
- Vestibular system
- Pain pathways
- Intestinal chemoreceptors.
- Cerebral cortex
Describe the process of vomiting
- PRE-EJECTION PHASE
- nausea
- sympathetic stimulation (tachycardia, sweating)
- parasympathetic stimulation (lower oesophageal sphincter relaxation, salivation, retrograde contraction of small bowels) - EJECTION PHASE
- cease respiration
- glottis closes
- soft palate elevates to close nasopharynx
- diaphragm and abdo muscles contract - rise in intragastric pressure
- gastro-oesophageal sphincter opens
- ejection gastric contents
What the potential complications of vomiting?
Aspiration
Wound dehiscence
electrolyte imbalance
dehydration
elevated intra-ocular and intracranial pressure
What are the main risk factors for PONV?
Three categories:
PATIENT - female, smoker, previous PONV, motion sickness
ANAESTHETIC - N2O, opiates, etomidate, neostigmine, hypotension
SURGICAL - middle ear surgery, ophthalmic surgery (esp squint correction), gynaecology
Which receptors are involved in the stimulation of nausea and vomiting?
Histamine (H1)
Muscarinic (mAchR)
Serotonergic
Dopaminergic
Opioid
a1 and a2 adrenoreceptors
Stimulation of any of these receptors can lead to activation of vomiting centre.
What measures can you take to reduce PONV?
PRE OPERATIVE - pre-asssessment, use of benzodiazepine for anxiety, pre-hydration, limiting starvation time.
INTRAOPERATIVE - maintain hydration and BP, avoid nitrous oxide, TIVA. Analgaesia (using regional techniques reduce opioid requirement/ volatile requirements), pre-emptive anti-emetics
POST OPERATIVE - prescribe antiemetics for use acutely, continue to control analgaesia
What are the main receptor sites of action for anti-emetics?
RECEPTOR ANTAGONISTS:
1. HISTAMINE:
- antihistamines target H1 in CNS. ie. Cyclizine
2. MUSCARINIC/ anticholinergic:
- hysocine and atropine. Act on mAchR in the GIT. Antispasmodic, decrease salivation/ gastric secretions. Effective for opioid induced PONV.
3. DOPAMINERGIC:
- ie metoclopramide, domperidone, phenothiazines
- CTZ and GIT targeted
- *4. 5-HT3:**
- ie. ondansetron, granisetron
- 5-ht3 abundant in CTZ and GIT
- effective in PONV and chemotherapy induced vomiting.
Others: Steroids, Propofol, Benzodiazepine, Neurokinin-1-receptor antagonist, cannabinoids, acupuncture.
Which drugs increase gastric motility?
Metoclopramide
Erythromycin
Domperidone
Neostigmine
Which drugs inhibit gastric motility?
Antimuscarinic drugs - decrease parasympathetic tone in GIT, by antagonising M3 receptor
Opioids - agonist at MOP receptors in myenteric plexus. Stimulation causes hyperpolarisation of cells, reducing stomach emptying/ gut motility, increases intestinal transit time.
Discuss Cyclizine
Class: Antihistamine
Form: Tablet and solution, PO or IV
Dose: 50mg 8 hourly
MOA: Competitive antagonist at H1 and muscarinic receptors.
Use: Antiemetic/ Menieres Disease
Effects:
GI - lowers oesophageal sphincter tone
CVS - tachycardia
Other - pain on injection because pH 3.2, mild sedation
Absorbtion/Distrib. : PO Bioavailability 75%, t½ - 10 hours
Metabolism: Hepatic metab, decrease does in liver failure, renal excretion
Discuss Ondansetron
CLASS: Carbazole
FORM: tablet/ solution
DOSE: 4-8mg 8 hourly, 0.1mg/kg 8 hourly children
MOA: Antagonises peripheral 5-HT3 receptors
USES: antiemetic motion sickness, PONV, chemo
EFFECTS:
GI - constipation
CNS - headache
CVS - bradycardia, flushing, caution in prolonged QT. Dose dependent prolongation of QT intervals, cardiac arrhythmias including TDP
ABSORB/DISTRIB: PO bioavailability 60%, t½ - 3 hours
METAB/ EXCRET: hepatic metab, reduce in hepatic failure, renal excretion.
Discuss metaclopramide
CLASS - Benzamine
FORM - Tablet/ slow release capsules/ syrup/ solution
DOSE - 10mg 8 hourly
MOA: Antagonises D2 receptor at CTZ + muscarinic receptor GIT
USES: antiemetic, prokinetic
EFFECTS:
GI - increased tone LOS, decrease pyloric tone, prokinetic
CNS - cross BBB, extrapyramidal effects, oculogyric crisis, neuroleptic malignant syndrome, sedation, agitation
CVS - hypotension, tachycardia
ENDOCRINE - increase prolactin causing gynaecomastia, galactorrheoa, percipitates porphyria
ABSORB/ DISTRIB: PO bioavailability, significant first pass metabolism
METAB/ EXCRETION: hepatic metab, excreted in urine.
Discuss prochloperazine
CLASS: phenothiazine
FORM: tablets, syrup, suppositories, solution
DOSE: 5-20mg 8-12 hourly
MOA: antagonises D2 receptors
USES: N+V, vertigo and motion sickness, psychosis, pre-medication
EFFECTS:
CNS - extrapyramidal, acute dystonias and akathesia (in young), sedating
GI - cholestatic jaundice
OTHER - haematological abnormalities, neuroleptic malignant syndrome, pruritis, increase prolactin
ABSORB/ DISTRIB: low oral bioavailability, significant first pass metabolism
METAB/ EXCRETION: hepatic metabolism, bile + urine excretion
How is stomach acid produced?
By parietal cells in the stomach body and fundus.
water (H2O) and carbon dioxide (CO2) combine within the parietal cell cytoplasm to produce carbonic acid (H2CO3), which is catalysed by carbonic anhydrase. Carbonic acid then spontaneously dissociates into a hydrogen ion (H+) and a bicarbonate ion (HCO3–).
The hydrogen ion that is formed is transported into the stomach lumen via the H+– K+ ATPase ion pump.
The bicarbonate ion is transported out of the cell into the blood via a transporter protein called anion exchanger which transports the bicarbonate ion out the cell in exchange for a chloride ion (Cl–).
This chloride ion is then transported into the stomach lumen via a chloride channel.
This results in both hydrogen and chloride ions being present within the stomach lumen. Their opposing charges leads to them associating with each other to form hydrochloric acid (HCl).
What stimulate stomach acid production?
Gastrin
ACh
Vagal stimulation
Distension of body of stomach (vagal reflex)
Histamine (H2 receptors)
What inhibits HCl production in stomach?
Acidity
Anti-muscarinics
Vagotomy
Somatostatin
Prostaglandin E2
H2 receptor antagonists
PPIs
What is the purpose of the acidic stomach environment?
Facilitates breakdown of protein
Activates pepsinogens and provides optimal conditions for pepsin activity
Improves solubility and hence absorption of calcium and iron
Kills pathogenic micro-organisms
PPI Mechanism of action?
Proton pump inhibitors (PPIs) effectively block gastric acid secretion by irreversibly binding to and inhibiting the hydrogen-potassium ATPase pump that resides on the luminal surface of the parietal cell membrane.
Mechanism of action of H2 Receptor antagonists? Example drugs
H2RAs decrease gastric acid secretion by reversibly binding to histamine H2 receptors located on gastric parietal cells, thereby inhibiting the binding and activity of the endogenous ligand histamine. H2 blockers thus function as competitive antagonists.
Ie. Ranitidine
Discuss histamine receptors
FOUR TYPES - H1, H2, H3, H4
H1 mediates allergic reactions, present in blood vessels, skin, heart and airway. Competitive antagonists at histamine H1 receptors may be divided into first (sedating) and second (non-sedating) generation agents. Both types of compound are useful in the treatment of allergic reactions such as hay fever. Some of the first generation compounds are used as sedative/hypnotic agents and those that also block muscarinic acetylcholine receptors are used as anti-emetic agents. Ie. Chloraphenamine, Cyclizine
H2 - GIT - Competitive antagonists at H2 receptors are useful for the control of gastric acid secretion. Ie. Ranitidine
H1 receptors couple to Gq which regulates Ca++ mobilization, H2 receptors couple to Gs to stimulate cyclic AMP,
What is the portal triad?
In the liver this consists of the portal vein, hepatic artery and bile duct. Located on the periphery of the lobule. Blood drains from the portal triad via sinusoids to the central vein (branch of hepatic vein) at the centre of the lobule.
What are hepatic zones?
The liver acinus is divided into Zones 1-3. Blood supply becomes progressively poorer from Zone 1 to 3.
ZONE 1 - portal triad + hepatocytes close by. Mitochondria rich cells, suited to oxidative metabolism and glycogen synthesis.
ZONE 3 - Hepatocytes are periphery of acinus - blood that already has nutrients and O2 taken up by Zones 1 and 2. Rich in SER, CYP450, key region for drug and toxin biotransformation. Most at risk of cellular damage.
Describe blood supply to the liver.
Receives 100ml/ kg/ min.
Dual blood supply: 70% portal vein (Sats 70%, therefore 40% of livers O2 supply), 30% hepatic artery (60% O2 supply).
Portal vein (splenic and mesenteric vein - straight from GI tract)
Hepatic artery from coeliac plexus.
Hepatic extraction ratio 0.5, can be increased.
What factors affect blood flow to the liver?
HEPATIC ARTERY: Autoregulated down to MAP 60.
- Intrinsic Control - Myogenic response, Hepatic artery buffer response (contricts/ dilates as portal flow changes to main constant over all flow)
- Extrinsic Control - Sympathetic stimulation (constriction), Drugs (volatiles/ norad reduce flow), GA/ Spinal (reduce flow), Surgical handling (reduces flow)
Classify and discuss the functions of the liver.
- BIOTRANSFORMATION - Phase 1 and Phase 2 reactions
- SYNTHETIC FUNCTIONS (albumin, immunoglob, clotting, CRP, antithrombin.
- METABOLIC FUNCTIONS (glucogenesis, glucogenesis, glycogenolysis, protein synthesis, deamination, cholesterol and triglyceride synthesis, activates vitamin D)
- DIGESTION (bile production - lipid emulsification, absorption fat soluble vitamins)
- STORAGE - 100g glycogen, Vitamins ADEK, copper, iron (ferritin)
- CAPACITANCE - can hold 15% circulating blood volume, half return to circulation with sympathetic stimulation.
- IMMUNOLOGICAL - Kupffer cells remove old erythrocytes, bacteria and antigens via phagocytosis.
What factors determine hepatic clearance?
- Portion of drug bound to protein
- Rate of drug presentation to liver (flow limited)
- Rate of enzymatic breakdown (capacity limited)
- Interference by inducers or inhibitors
- Health of hepatic function
Name 3 enzyme inducers
Carbamazepine
Phenytoin
Phenobarbitone
Rifampicin
Smoking
Name 3 enzyme inhibitors
Ciprofloxacin
Sodium valproate
Fluoxetine
Isoniazid
