GIT Drugs

1998a(12)/1996b(15): Classify and describe agents used to ↓gastric pH and

↓volume. Discuss mechanisms of action and the advantages and
disadvantages for each

Gastrin → G cells (antral muscosa) Parietal cell

↑IP3 in parietal cell
Ach → PNS, post-ganglionic fibres membrane H/K
ATPase

1° path +
↑cAMP

Gastric paracrine Parietal ↑H+, ↑vol

↑Histamine
cells cell H2R

Method MOA Adv Dis

↓Acid Production
Physicochemical: Antacids Promote ulcer Less effective than other
healing methods
Al/Mg antacid Neutralise Min systemic SoO slow
n
luminal acid by absorp (low Al: constipation
+
buffering H H2O sol), Mg: diarrhoea
long acting
NaHCO3 / Na citrate Fast SoO Short duration of action,
n
systemic absorp 2° high H2O
sol
Met alkalosis in ↑doses
Physicochemical: PG Analogue (PGE1)
n +
Misoprostil Direct inhib H Renal/hepatic ↑uterine tone, ↑risk m/c
Prophylaxis/ Rx secretion, independent Severe diarrhoea, GI upset
n
NSAID induced ↑mucous prod metabolism (FA Incomplete achlorohydria
ulcer oxidising High dose→ ↓MAP
system)
Cellular: Histamine Antagonists (H2 receptor blockers)
Cimetidine (C) Competitive ↓vol secretion C: Inhibit cytP450
+
Ranitidine (R) reversible ↓H (↓metabolism warfarin,
blockade H2R phenytoin) ↓HR, ↓BP on fast
IVI, anti-androgenic
R: Arrhythmia w fast IVI
Cellular: Proton Pump Inhibitors (PPI)
Omeprazole Non-competitive Complete Min inhibition cytP450 (nil
Pantoprazole etc irreversible block achlorohydria effect warfarin, pheny)
H/K ATPase pH<3 activates
prodrug
Cellular: ACh Blockers (Antimuscarinics)
Pirenzipine Competitive Min s/e at Less effective cf H2 blockers
blockade M1 therapeutic
mAChR → doses
↓IP3/DAG
↓Gastric Vol: Prokinetic Agents
Benzamides - Peripheral D2R Antiemetic Extrapyramidal effects

By Amanda Diaz
 GIT Drugs

n
Metaclopramide blockade; stim ↑LoS tone (central); Neurloept malignant
M1 mAChR ↓pyloric tone sydrome
Butyrophenone – Peripheral D2R Doesn’t cross IVI→ arrhythmia ↑dose
Domperidone blockade BBB → ↓central
effects
Cisapride ↑Ach release ↑QT → torsades
from mesenteric Convulsions
plexus Extrapyramidal S/E

By Amanda Diaz
 GIT Drugs

1998b(10): Describe the sites of action of antiemetic agents used for PONV
General: PONV is a common side effect of anaesthesia and analgesia
Incidence: 15-90%
Dependent on factors such as:
- surgery
o Visceral > peripheral
o laparoscopic > laparotomy
- Anaesthesia
o GA > neuraxial > regional
o Nitrous > VA > TIVA
- Opioid use
- Gender (
- Susceptibility factors
o PHx
o Motion sickness
- Smoking (↓risk
Drugs used prophylactically / in treatment
Vomiting
- Vomit centre located in medulla
o Group of neurons, nil specific centre
- Efferent neurons project to vagus, phrenic nerves and spinal
motoneurones supplying abdominal mm
o mAChR
Inputs to Vomit Centre
- Chemoreceptor trigger zone (CTZ) → v important
o Area postrema in floor of 4th ventricle → outside BBB
o Receptors: D2 and 5-HT3
- CNVIII (Vestibular N)
o Receptors: mAChR & H1
- Visceral afferents → activate vagal afferents
o Receptor: 5HT3
- Nucleus tractus solitarius (NTS) → visceral / pharyngeal inputs
o Receptors: mAChR, H1, opioidR
- Higher centres → fear, anticipation, smell → vagal afferents
o Receptors: mAChR, 5HT3
- Drugs/Endogenous toxins → direct stimulation CTZ
o D2 and 5HT3
PONV
Sites of Action for Rx PONV
D2 Receptor
- Phenothiazines (chlorpromazine, prochlorperazine)
- Butyrophenones (droperidol, domperidone)
- Benzamides (metaclopramide)
Anticholinergics
- hyoscine
- atropine

By Amanda Diaz
 GIT Drugs

5HT3 Receptor
- Ondansetron
- Tropisetron
H1 Receptors (NTS, CNVIII) → block activation of vomit centre
- Promethazine (also a phenothiazine)
Unknown MOA
Steroids
- Mode of action uncertain
- Strongest evidence in prophylactic use at beginning of surgery
Cannabis
- ?cannabinoid receptor
- 2° ↑appetite
Propofol
- ?2° GABAAR modulation
Accupuncture
High flow O2

By Amanda Diaz
 GIT Drugs

2005a(1): Classify antiemetics. Give examples and describe side effects of each class
General: PONV is a common side effect of anaesthesia and analgesia
- Incidence: 15-90%
- Dependent on factors such as:
o Surgery → Visceral > Peripheral; Laparoscopy > Laparotomy
o Anaesthesia → GA > neuraxial > regional; Nitrous > VA > TIVA
o Gender (
o Smoking (non > smokers)
o Susceptibility to vomit → PHx; motion sickness; Opioids
Antiemetic classification based on where in the vomit pathway they act.
Vomit Centre: cluster of neurons located in medulla, receive inputs from:
th
- CTZ (area postrema 4 ventricle) 5HT3 D2
- Viscera (SI, pharynx) H1, mAChR 5HT3
- Nucleus tractus solitarius (NTC) H1, mAChR opioid
- Vestibular centre (CNVIII) H1, mAChR
- Higher centres 5HT3 D2
- Vagus (CVS etc) mAChR
Outputs to:
- Vagus / phrenic nn
- Abdominal MN in spinal cord
Class Example Side Effects
D2 antagonist Phenothiazine Orthostatic hypotension ( )
Chlorpromazine Sedation (mAChR)
Prochloperazine) Extrapyramidal (D2): oculogyric crisis, dystonia,
dyskinesia (young>old)
Anticholinergic (mACh): dry mouth, ↑HR, central
cholinergic syndrome
↑appetite → ↑wt
↑gastric motility (D2)
↓shiver response to ↓T°C ( )
↑PRL release (D2)
Butyrophenones ↓BP when ↓vol ( )
Droperidol ↑QT (droperidol at high doses only) Black Box
Domperidone Warning FDA
↑PRL release (D2)
Extrapyramidal effects (D2): incidence 1%
Benzamides ↓BP, cardiac arrest
Metoclopramide ↑PRL release 2)
Sedation/dizziness (mAChR)
Neuroleptic malignant syndrome (5HT3)
Anticholinergic Hyoscine Sedation / amnesia (mAChR)
Dry mouth (mAChR)
Central cholinergic syndrome (mAChR)
5HT3 antagonist Tropisetron Minimal
Ondansetron Flushing, headache, ↓HR, constipation
H1 antagonist Phenothiazine Sedation (H1)
Promethazine Slightly antanalgesic (H1)
Unknown Steroids Adrenal suppression (minimal given small doses
Dexamethasone used)
Cannabis ?Cannabinoid receptors → ↑threshold to vomit
Propofol ?Modulation GABAAR
Amnesia / Sedation
BZ Modulation GABAAR
Amnesia / Sedation

By Amanda Diaz
 GIT Drugs

2005a(6): Briefly outline the pharmacological methods of reducing gastric acidity. Indicate
the mechanisms of action and the advantages and disadvantages of each method
General: Gastric acidity needs to be reduced in certain circumstances:
- pre-op (LSCS); GORD; Zollinger-Ellison syndrome; Eradication of H pylori
Gastric acid production
- Parietal cells produce HCl
o Stimulated by:
 H2 receptor stimulation (1° method) → ↑cAMP
 mAChR stimulation (vagal afferents) → ↑IP 3 within cell
 G cell stimulation → ↑IP3
- Acid released by activation of H/K ATPase on apical membrane of parietal cell (final
common pathway)
- Histamine released from gastric paracrine cells, stimulated by:
o Gastrin (G cells in antral mucosa)
o ACh (mAChR) parasympathetic postganglionic fibres (vagal)
Methods of ↓acid production
Method MOA Adv Dis
Physicochemical: Antacids Promote ulcer Less effective than other
healing methods
Al/Mg antacid Neutralise Min systemic SoO slow
n
luminal acid by absorp (low Al: constipation
+
buffering H H2O sol), Mg: diarrhoea
long acting
NaHCO3 / Na citrate Fast SoO Short duration of action,
n
systemic absorp 2° high H2O
sol
Met alkalosis in ↑doses
Histamine Antagonists: H2 receptor blockers
Cimetidine (C) Competitive ↓vol secretion C: Inhibit cytP450
+
Ranitidine (R) reversible ↓H (↓metabolism warfarin,
blockade H2R phenytoin) ↓HR, ↓BP on fast
IVI, anti-androgenic
R: Arrhythmia w fast IVI
Proton Pump Inhibitors: PPI
Omeprazole Non-competitive Complete Min inhibition cytP450 (nil
Pantoprazole etc irreversible block achlorohydria effect warfarin, pheny)
H/K ATPase pH<3 activates
prodrug
PG Analogue: PGE1
n +
Misoprostil Direct inhib H Renal/hepatic ↑uterine tone, ↑risk m/c
Prophylaxis/ Rx secretion, independent Severe diarrhoea, GI upset
n
NSAID induced ↑mucous prod metabolism (FA Incomplete achlorohydria
ulcer oxidising High dose→ ↓MAP
system)
ACh Blockers: Antimuscarinics
Pirenzipine Competitive Min s/e at Less effective cf H2 blockers
blockade M1 therapeutic
mAChR → doses
↓IP3/DAG
@ paracrine cell
(↓Hist release
parietal cell (↓H/
n
ATPase activ )

By Amanda Diaz
 GIT Drugs

2005b(6): Describe the therapeutic and unwanted effects of dexamethasone

General: Dexamethasone → synthetic glucocorticoid
- Nil mineralocorticoid activity
- 25 – 30 x potency of hydrocortisone
- In general, corticosteroids produce their effect by activation of intracellular steroid
receptors
o Activation leads to modification of gene transcription within the nucleus of a cell
Therapeutic Effects of Dexamethasone
Unknown Action
- PONV prophylaxis
o MOA: Unknown
o Evidence: IV Dex (4-8mg) 1-2hrs prior to the end of anaesthesia → ~24hrs ↓risk
PONV and ↓rescue therapy req (droperidol/tropisetron)
- Requires single dose only
Anti-inflammatory / Immunosuppressive Actions
- Prevent inflammatory response (redness, swelling, tenderness)
o ↓vascular permeability / proliferation
 ↓oedema (cerebral, pulmonary)
o ↓inflammatory cell activity (leukocytes, mononuclear cells)
o ↓hypersensitivity responses after antigen-antibody reactions
o ↓immune mediators (cytokine production, PAF, complement components)
Regulatory Action:
- HPA axis
o Negative feedback and suppression of endogenous corticosteroid production
o Useful for suppression of ACTH production
- Treatment Addison’s disease
Unwanted Effects: in general only after prolonged exposure
↓wound healing/ ↑risk infection
- Requires early antibiotic intervention
- ↑risk of thrush
- Breakdown of bowel anastomoses
Suppression of Endogenous corticosteroid production
- Suppression of HPA axis occurs gradually and is clinically significant ~10days with dose
1mg/kg → may last up to 2 yrs after stopping according to PI!
o Requires tapering of dose in order to avoid Addisonian Crisis
o Suppresses ACTH production rapidly
Metabolic Action
- CHO: ↑gluconeogenesis, glycogenesis, ↑BSL, ↓cell uptake glucose
- Proteins: ↑catabolism, ↓anabolism
- Fats (occurs after prolonged use): ↑Lipolysis; Redistribution of fat (Cushing’s)
Other:
- Osteoporosis
- ↑IOP, glaucoma
- Peptic ulceration
- Mental disturbance
- Na/H2O retention (min with dex)

By Amanda Diaz
 GIT Drugs

2005b(7): Briefly outline the pharmacology of droperidol, emphasising its

mechanism of action, perioperative use and side effects
Physicochemical
Chemical Butyrophenone derivative
Presentation Tablet 10mg Dose: IV 0.25 – 0.5mg (antiemetic)
Syrup 1mg/ml 5-10mg (antipsychotic)
n
Sol 2.5mg/ml Onset: 3 – 20min
Duration: up to 12hrs
Incompatible STP / methohexitone Precipitation
Pharmacodynamic
Use Antiemetic(1° prophylaxis / Antiemetic effect take 3-20min,
rescue therapy) Effect to 12hrs → useful PONV
Control hiccupping

Neuroleptanalgesia (in combo ↓requirement other CNS depressants

w fentanyl) NOT ANYMORE ↑duration of action of fentanyl
↑risk dysphoria cf fent alone
Historical neurolept Antipsychotic agent
n th
MOA D2 antagonist Blocks activ of CTZ (area postrema 4
ventricle outside BBB), therefore ↓afferents
to vomit centre / ↑threshold to vomit
As effective as ondansetron for prophylaxis
CNS Neurolepsis: sedation, ↓motor Dose dependent effect
n
activity, ↓awareness of “locked in” → limits use in premed
surroundings Not amnestic
↑time to wake post-op
Extrapyramidal S/E Incidence 1%, dose dependent
Neurolept malignant syndrome Rare
CVS 1 block: ↓BP esp with ↓vol Min at low dose
Dose dependent effect
BLACK BOX WARNING Long D-D, ↑risk in inherited / aquired ↑QT (↓Mg,
QT Class 1a, 3 anti-arrhythmics, TCA)
GIT GIT disturbance Diarrhoea, N&V in high doses, ↑secretions
Abnormal LFT
Allergy Reported Rare
Pharmacokinetic
Absorption Unknown oral bioavail IMI effective
Distribution ~90% protein bound
Vd ~2L/kg
Metabolism Hepatic (extensive) Oxidative N-dealkylation
Excretion Urinary / bile 1% unchanged
CL 9 – 18ml/min/kg
t ~2hrs

By Amanda Diaz