Antiemetics and aperients Flashcards
Where is the chemoreceptor trigger zone
Area postrema on the floor of the 4th ventricle bilaterally
What receptors in particular are prominent at the chemoreceptor trigger zone
Dopamine 2 receptors
5HT3
ACh
Phenothiazines examples
Propylamine
Piperidine
Piperazine
Chlorpromazine
Thioridazine
Prochlorperazine
What class do phenothiazines come from?
Dopamine antagonists
Chlorpromazine is sometimes also known as?
Largactil
Chlorpromazine MOA
Dopamine antagonist - D2
Muscurinic recepotr antagonist
Noradrenergic alpha 1 and 2 antagonist
Histamine 1 antagonist
Seratonin antagonist
Membrane stabilising properties
Prevents noradrenaline uptake into sympathetic nerves
CNS - isolating the reticular activating system from afferent connections resulting in sedation, disregard of external stimuli and reduction in motor activity
Chorpromazine effects including side effects
CNS - EPS due to central dopamine antagonism, NMS occurs rarely, variable effects on hypothalamic function, reducing secretion of grwoth hormone while increased release of prolactin, temperature regulation altered and can result in hypothermia
CV - peripheral vasodialtion, hypotension, increased heat loss
Anticholinergic
Gut - increased appetite, weight gain
Misc - contact sensitivsation, cholestatic jaundice, agranulocytosis, leucopenia, leucocytosis, haemolytic anaemia
Chlorpromazine kinetics
Absorption - good, large hepatic first pass metabolism limits its bioavailability to 30%. IV available
Distribibution -
Large number of hepatic metabolites in the urine or bile
Variable but small fraction unchanged in the urine
Prochlorperazine vs chlorpromazine vs droperidol vs metoclopramide vs domperidone in sedation, anticholinergic effects and EPS
Prochlorperazine effects
CNS - extrapyramidal effects are seen more commonly than other dopamine antagonists, dystonias and akasthesia partcularly, children and young adults more commonly effected. When used perioperatively produces mild sedation
Cholestatic jaunice, haematological abnormalities, skin sensitisation, hyperprolactinaemia and rarely NMS
Prochloperazine kinetics
Absorption - erratic, oral bioavailability very low due to extensive first pass metabolism
IV and IM available
Droperidol belonds to which class of dopamine antagonsits?
Butyrophenone
Droperidol MOA
Antagonists D2 receptors at the CTZ
Droperidol side effects
CNS - sedation more pronounced, EPS side effects more with larger doses, may develop >12 hours post administration and up to 25% experience anxiety up to 48 hours after administration
Hyperprolactinaemia
CV - hypotension from peripheral alpha adrenoreceptor blockade
QT prolongation
Droperidol kinetics
IV alhough absorbed readily from IM
Highly plasma protein bound 90%
Extensively metabolised by the liver to products excreted in urine
Only 1% of drug excretion is as unchanged drug in urine
Domperidone different to other dropamine antagonists, how does this effect side effects
does not cross BBB
Reduced EPS
Metoclopramide belongs to which class of dopamine antagonsits?
Benzamides
Benzamide example
Metoclopramide
How effective is metoclopramide as an antiemetic?
as placebo in 50% of studies
MOA of metoclopramide
dopamine 2 receptor antagonism at the CTZ and prokinetic effects at the tstomach, also blocks 5HT3 receptor
Metoclopramide effects
CNS - crosses BBB, EPS side effects seen up to 72 hours post administration, more common in young females 1:5000, NMS possible. Agitation sometimes seen
CV - hypotension,. tachycardia or bradycardia if rapid administration
Metoclopramide pharmacokinetics
Well absorbed
First pass metabolism varies significantly with 30-90% bioavailability
IV or IM
Conjugated in liver and excreted unalong with unchanged drug in urine
What is an example of a tertiary amine anticholinergic?
Atropic
Hyoscine
Chemically atropine is?
Tertiary amine - esters formed by combination of tropic acid and organic base (tropine) and are abel to cross BBB
How is glycopyrrolate different in structure and therefore action to atropine?
Synthetic quaternary amine as opposed to tertiary amine - this means it is charged and unable to cross the BBB with no central effects
Hyoscine comes in what combination?
Raecaemic - only hyoscine I is active
Hyoscines effects
Central - anticholinergic syndrome (excitement, ataxia, hallucinations, behavioural abnormalities
Compare hyoscine, atropine and glycopyrlolate in terms of their
- Antiemetic potency
- Sedation/amnesia
- Anti-sialogogue
- Mydriasis
- Placental transfer
- Bornchodilation
- heart rate
Hyoscine pharmacokinetics
variable absorptiopn, oral bioavailability between 10-50%
Transdermal administration effective despite low plasma levels
Extensively metabolised by liver esterases and only small fraction excreted unchanged in urine
Duration of action shorter than atropine
Atropine preparation includes
Raecemic mixture
Only 1 - atropine is active
Atropine effects
CNS - sedative, can cause central cholinergic crisis
CV - initial bradycardia due to central effects on vagal nucleus, or reflecting partial agonist effect at cardiac muscurinic receptors
Respiratory - bronchodilation, increased dead space, reduced secretions
GIT - less effective antisialogogue than hysocine, tone of lower oesophageal sphincter decreased, small decrease in GIT secretion
Misc - sweating inhibited, may provoke pyrexia in paediatric patients, increase intra ocular pressure
Atropine pharmacokinetics
Intestinal absorption rapid, unpredictable levels
50% plasma protein bound
Extensively metabolised by liver esterases
Excreted in urine (tiny fraction unchanged)
Glycopyrolate pharmacokinetics
Intestinal absorption negligibale
Oral bioavailability <5%
Does not cross BBB
Minimally metabolised and 80% excreted unchanged in urnie
Cyclizine MOA
histamine 1 antagonist with anticholinergic properties that may contribute to its antiemetic actions
Cyclizine chemically
piperazine derivative
Cyclizine IV beware
Prepared with lactic acid at pH 3.2 and can be painful, particulaly intramuscular dosing
Cycliznie effects
Gut - increases lower oesophegeal sphincter tone
Anticholinergic - mild
EPS rarely
Cyclizine kinetis
Well absorbed orally and high oral bioavailability 75%
Little is known regarding the rest fo the kinetics
Ondansetron belongs to what class and subclass
5HT3 antagonists
Carbazole
Ondansetron available in what preparations?
Tablets, SL, suppository, clear solution for slow IV injection
MOA of ondansetron
Peripehral 5HT3 and central 5HT3 antagonism
Side effects of ondansetron
headache, flushing, constipation, bradycardia
Pharmacokinetics of ondansetron
Well absorbed with oral bioavailability 60%
75% protein bound
Signficiant heptatic metbaolism by hydroxylation and subsequent glucoronide conjugationto inactive metabolites
Half life 3 hours
Dose should be reduced in hepatic imapirment
Aprepitant belongs to which class
NK1 receptor antagonists
Name a neurokinin 1 receptor antagonist
Aprepitant, fosaprepitant
NK1 receptor antagonist MOA
Block the actions of substance P in the brain stem nuclei of the dorsal vagal complex central to the regulation of vomiting
Aprepitant is adminsitered how?
oral
Fosaprepitant is adminsitered how?
IV prodrug
Pharmacokinetics of aprepitant
Bioavbailability 60%
97% plasma protein bound
Metabolised by CYP3A4 to weakly active metbaolites excreted in urine and faeces
Dexamethasone antiemetic actions potentiated most when?
Prevention of post operative vomiting
Not effective in established vomiting
How much dexamethasone is effective for vomiting?
4mg as effective as higher doses
MOA of dexamethasone as an antiemetic
Not well understood
May involve prostalganding antagnoism
Releas eof endorphins - appetitie stimulation and release of endorphis
Antiinflammatory effect reducing gut seratonin release
Nabilone is what type of antiemetic
cannabinoid
Which benzodiazepine has some action as an antiemetic
Lorazepam
Mode of action uncertain
Metoclopramide is from what class of dopamine antagonsits?
Benzamide
Antemetic activity of metoclopramide
D2 receptor antagonist - CTZ - primary action
5HT3 antagonist at high doses
Decrease in sensitivity of visceral aferrants for supply of information to the vomiting centre
Metoclopramide has additional actions beyond its antiemetic activity through? Describe its MOA for this effect
Prokenitic
Selective stimulation fo gastric muscurinic receptors causing prokinetic activity
peripheral D2 receptor antagonist causing prokinetic activity
5HT4 AGONIST causing prokinetic activity
Direct action on smooth muscle to icnrease tone
What effect on gastric motility does metoclopramide have”
inreased gastric emptying - a,plitude of gastric contractions increases, accelerates small intestinal transit time, variable effects on large bowel motility
Increased lower oesophageal spincter tone
No effec ton gastric secretions
Major side effects of metoclorpamide
EPS - up to 72 hours after adminsitration
Akasthesia - inner restlessness
Sedation
Oculogyric crises
NMS
Hyperprolactinaemia
CVS - tachycardia or bradycardia, hypetnesion or hypotension
Contraindications to metoclopramide
Porphyria
Oral bioavailability of metoclopramide
30-90%
Variable first pass metabolism - first pass metabolism with sulfate conjugation
Rapidly absorbed
Ondansetron comes from what class
Synthetic carbazole
Ondansetron acts where?
selective antagonsit of 5HT3 at CTZ and gut
What interactions does ondansetron have
reverses soe analgesic effects of tramadol
Side effects of ondansetron?
Headache
FLushing
Constipation - large bowel transit time
Uncommon
- LFTs increase
- Hypotension, bradycardia
- Hypersensitivity
- prolonged QT
Ondansetron pharmacokinetics
Absorption - passively and completely
Oral bioavailability - 60%
Peak plasma concentrations 1.5 hours orally
Protein binding - 75%
Vd 2L/kg
Significant hepatic metabolism by CYP 450 (3A4, 2D6, 1A2) by hydroxylation or demethylation followed by conjugation with glucoronide or sulfate . No dose adjustment for interactions due to multiple enzymatic routes of emtabolism
Inactive metabolites
Renal excretion - <5% unchanged
Half life 3 hours
Granisetron MOA
Selective antagonsit at 5HT3 CTZ and gut
Granisetron SE
Headache
FLushing
Constipation
Uncommon
- LFTs increase
- Hypotension, bradycardia
- Hypersensitivity
- prolonged QT
Pharmacokinetics of granisetron
demethylation by CYP450
Excreted in urine and facecs
Half life 9 hours
Ondansetron presentation
Clear colourless aqueous solution in ampoules of 4ml, tablets and SL
ONdansetron vs critical illness
Renal failure - no change required, despite delayed clearance has inactive metbaolites
Hepatic failure - near 100% oral bioavailability, signfiicantly reduced clearance and dose reduction to 8mg per day advised
Chemical structure of metoclopramide
Chlorinated procainamide derivatve
Presentations of metaclopramide
10mg tablets, syrup, clear colourless solution
Metaclopramide pharmacokinetics
Absorption - rapid, near complete. Oral bioavailability however is 30-90% due ot sulfate conjugation
Distribution 20% pritein bound, Vd 2.5L/kg
Metbaolism - liver - sulfate derivative metbaolite
Excretion - 80% of oral dose excreted in urine within 24 hours., 20% unchanged, remainder appears as non metabolised drug conjugated to sulfate or glucoronide
Elimination half life 3-5 hours
Not removed by haemodialysis
Droperidol is chemically derived from?
Butyrophenone
Droperidol main actions and MOA
Antiemetic and neuroleptic
Central dopamine D2 blockade at CTZ
Post synaptic GABA antagonism
Methods of droperidol adminsitration
Oral
IM
IV
Droperidol effects
- CVS
- Respiratory
- CNS
- Abdominal
- Metabolic
CVS - minimal, some antagonistic effects at alpha adrenergic receptors leading to hypotension if hypovolaemia coexistent
Resp - decreased minute volume and FRC and airway resistance decreases
CNS - neurolepsis, diminished motor activity, anxiolysis, indifference. Seizure threshold raised
Abdominal - antiemetic
Metabolic -= hyperprolactinaemia
Reduces total body oxygen consumption
Droperidol SE
EPS - 1%
LFT abnormalities
Allergic rare
NMS
Droperidol kinetics
Absorption - well absorbed IM, oral absorption not elucidated
Distribution 90% protein bound, Vd 2L/kg
Metabolism - extensively metabolised in the liver, oxidative dealkylation
Excretion - 75% excreted in urine, 1% unchanged, 22% in faeces
Clearance 10-18 ml/min/kg
Elimination half life 2 hours
Prochlorperazine is otherwise known as?
Stemetil
Prochlorperazine chemically derived from
phenothiazine of the piperazine subclass
Preparations of prochloperazine
tablets
Sippositories
Clear colourless IV injection
Prochlorperazine MOA
Dopamine antagonsim centrally
Effects of prochlorperazine
- CVS
- Respiratory
- CNS
- Abdominal
- Metabolic
CVS - orthostatic hypotension secondary to alpha adrenergic blockade, ECG changes including prolonged QTc
Respiratory - mild respiratory depression
CNS 0 neuroleoptic
Abdominal - lower oesophageal tone increased
Metabolic - antiadrenergic, antiinflammatory, antipruritic, anticholinergic, anti histaminergic
Prochlorperazine side effects
EPS
Jaundice
Leucopenia
Rashes
NMS
NMS side effects would appear as?
Catatonia
CV lability
Hyperthermia
Myoglobulinaemia
Prochloperazine pharmacokinetics
Absorption - slow, 0-16% bioavailability
Distribution - highly protein bound 90%, Vd 20L/kg
Metabolism - first pass metabolism ++, CYP3A4 and CYP2D6 S oxidation to a sulfoxide
Half life 6-8hours
Promethazine chemically
Phenothiazine
Promethazine main actions
Antihistaminergic
Sedative
Antiemetic
Reversible competitive antagonsit at H1 histaminergic receptors
Anticholinergic
Anti serotonergic
Anti dopaminaergic
Effects of promethazone
CVS
Resp
CNS
Abdominal
CVS - rapid intravenous adminsitration causing hypotension
Resp - bronchodilation, reduces respiratory tract secretions, antitussive
CNS - sedative, anxiolytic, slight antanalgesic, reduces motion sickness by vestibular end organ recepotr and inhibitor actions at CTZ.
Abdominal - decreases tone of lower oesophageal sphincter
Promethazine side effects?
Anticholinergic
EPS
Jaundice
Photosensitivity
Excitatory phenomena
Promethazine kinetics
Absorption - well absorbed, extensive first pass metabolism
Distribution 90% protein bound, Vd 2.5L/kg
Metabolism - sulfoxidation and N dealklylation in the liver
Excretion - urine, 2% unchanged
Clearance 1L/min
Eliomination half life 10 hours
Dopamine antagonists which act as antiemetics include what classes
- Phenothiazines (Chlorpromazine/prochlorperazine - Stemetil), which also have potent activity against muscarinic, H1, 5-HT3 and dopamine receptors
- Butyrophenones (droperidol), which have slightly less potent anticholinergic, 5HT3 blockade and antihistamine effects - haloperidol faster antiemetic than droperidol IM, similar IV
- Benzamides (metoclopramide), which have a prokinetic effect related to indirect cholinergic activity, cleanest dopamine blockade D2
◦ Mild action at H1 receptors, strong D2 blockade, mod 5HT3 blockade
What characteritises phenothiazines as antiemetics
- Phenothiazines (Chlorpromazine/prochlorperazine - Stemetil), which also have potent activity against muscarinic, H1, 5-HT3 and dopamine receptors
What MOA characteristics do you find of butyrophenones as antiemetics? e.g.
- Butyrophenones (droperidol), which have slightly less potent anticholinergic, 5HT3 blockade and antihistamine effects - haloperidol faster antiemetic than droperidol IM, similar IV
Metoclorpramide belongs to which class of dopamine antiemetics? What characterises this class? What actions does it have
- Benzamides (metoclopramide), which have a prokinetic effect related to indirect cholinergic activity, cleanest dopamine blockade D2
◦ Mild action at H1 receptors, strong D2 blockade, mod 5HT3 blockade
Anticholinergic antiemetics include? 3 side effects
- Hyoscine, atropine (purely antimuscarinic)
- Phenothiazines and butyrophenones also have strong antimuscarinic effect
- Side effects
◦ Hallucinations
◦ Drying of secretions - dry mouth, dry eyes, constipation
◦ Central - anticholinergic syndrome (excitement, ataxia, hallucinations, behavioural abnormalities
5HT3 antagonists as a class include? What other agents are potent at this receptor
General side effects of this class
5-HT3 antagonists:
* ondansetron and granisetron are pure, high-affinity 5-HT3 antagonists
* Phenothiazines and butyrophenones also have strong 5-HT3 antagonist effects
* SE - constipation, headache, LFT
Antihistamine antiemetics include?
Side effects
MOA
- Promethazine, Cyclizine and prochlorperazine have mainly anti-H1 effects
◦ promethazine - Phenergen - dominant histamine and dopamine blockade with some muscurinic action also. Could be in the phenothiazine group - Most centrally acting H1 antagonists also have potent antimuscarinic activity
- Side effects
- drowsiness
What is aprepitant
NK1 antagonist
Miscellaneous antiemetics include
Propofol
Dexametjasone
Cannabindois
Benzos
Metoclopramide pharmacodynamics 4
◦ Selective stimulation of gastric muscurinic receptors causing prokinetic activity
◦ peripheral D2 receptor antagonist causing prokinetic activity
◦ 5HT4 AGONIST causing prokinetic activity
◦ Direct action on smooth muscle to increase tone
oeosphageal effects of metoclopramide
◦ Increased amplitude of oesophageal perstaltic contractions (though not every study is able to demonstrate this effect)
◦ Increased resting tone of the lower gastro-oesophageal sphincter (a short-term effect, lasting approximately one hour)
gastric effects of metoclorpamide
- Gastric effects:
◦ Accelerates gastric emptying, including the scenarios of diabetic and post-operative gastroparesis - this is described by the college as “appears to depend on intramural cholinergic neuron”. In actual fact it appears to be an indirect effect, where metoclopramide enhances the acetylcholine release from suitable nerve endings (Sanger, 1985)
◦ Increased antral contractions
◦ Improved “antroduodenal coordination” (Lee & Kuo, 2010)
◦ No effect on gastric secretion - Intestinal effects
◦ Increases the peristaltic activity of the upper small intestine - speeding intestinal transit time
Antiemetic general rules
- Formulations
- Bioavailability
- Vd
- Protein binding
- Metabolised
- Half lives
- Qt
- Oral formulations are available for all of them, even though it makes no sense to force a vomiting nauseous person to ingest a tablet.
- Most of them have good oral bioavailability, the exceptions being prochlorperazine and domperidone
- They all have modest volumes of distribution, except domperidone which behaves a bit like amiodarone
- They are all highly protein-bound, except for metoclopramide and hyoscine.
- They are all metabolised by the liver. Of these, the only exception is metoclopramide, of which 20-50% is renally eliminated.
- Their half-lives do not usually reflect the duration of their effect (for example, the effects of aprepitant last for 48 hours, but its half-life is 9-13 hours).
- The vast majority of them prolong the QT interval. It would actually be easier to list the ones that don’t do it: hyoscine, dexamethasone, benzodiazepines, cannabinoids, palonosetron (alone among the 5-HT3 antagonists), aprepitant, cyclizine and prochlorperazine (alone among the phenothiazines).
Describe the 8 classes of aperients
Clue
- 2 major subclasses of which each has 4 agents
4 Aperients
4 laxatives
Aperients
- Bulk
- Soften
- Lubricate
- Osmotic
Laxatives
- Prostaglanding
- Macrolides
- Cholinergic stimulant
- Opioid
Bulk forming laxatives include what agents? MOA
Side effects
Bulk-forming laxatives
* e.g. Psyllium, Methylcelulose, Polycarbophil
* Large polymers which trap water in a gel matrix, increasing the mass and water content of stool and thus encouraging peristalsis
* Side effects - Abdominal distension (metabolised by gas producing gut bacteria), Bowel obstruction, Delayed absorption of nutrients, Delayed absorption of drugs
Osmotic laxatives e/.g/
Work how? Side effects
Osmotic laxatives
* e.g. ionic salts (Mg), sugar alcohols (mannitol), saccharides (lactulose), magcogols (polyethylene glycol - macrogol just refers to larger molecular mass PEG 3350)
* Osmotic gradient counteracting colon absorption of water - smaller molecules than large starchy molecules of bulk forming group
* SE - abdominal distension (metabolic substrate for gut bacteria), malabsorption, electrolyte and volume depletion
Lubricant laxatives includes? MOA? SE
- Mineral oil - microlax, paraffin
- Emulsify the stool, increased slipperiness and reduced resistance to passage
- SE - decreased fat soluble vitamin absorption, pruritis ani, lipid pneumonitis if inhaled
Stool softeners include? Action? SE
Stool softeners
* Docusate, bisocodyl
* Surfactant effect - increase access of existing water to stool particles increasing its water content reducing its viscocity without causing fluid transit from gut to lumen
* SE - increased absorption of lipids and lipid soluble molecules, more rapid absorption of fat soluble drugs
Bowel stimulants include? MOA? SE
Bowel stimulants
* Sodium picosulfate, senna
* Increase peristalsis and gut secretory activity by a number of mechanism, including PGE2- mediated increase in chloride secretion and inhibition of enterocyte Na+/K+ ATPase
* SE - enteric neuropathy
Macrolide MOA for bowel stimulation? SE?
Macrolides
* Act as motilin receptor agonists, which stimulates contraction by activation of smooth muscle L-type calcium channels from gastric antrum through the SB until the ileum, producing increased antral activity, increased gastric emptying, and more high-amplitude propulsive contractions
* Interstingly all macrolides just as effective - so if on azithromycn no need to add erythromycin. Erythromycin however now has little clinical use as an antibiotic with increasing resistance hence utilising it here. It is also used in doses smaller than bacterioinhibitory doses to avoid resistance as there is no selection pressure on bacteria.
* SE
◦ QT interval prolongation
◦ Potential antimicrobial resistance
◦ Increased risk of C. difficile infection
◦ Tachyphylaxis
Cholinergic prokinetics action how? SE
- Neostigmine
- By acting directly or indirectly at muscarinic receptors in the gut (M2 and M3 GPCR) –> DAG and IP3 –>, increase the availability of intracellular calcium and increase the contractility of the intestinal smooth muscle
- SE
◦ Miosis
◦ Secretions
‣ Salivation
‣ Increased bronchial secretions
◦ Bradycardia
◦ Urinary and faecal incontinence
Opioid anatagonsits as bowel stimulants do what?
- Naloxone
- Reverse peripehral effects of opioids by antagonsim of intestina delta and kappa opioid receptors
- Theoretically, counter-analgesic effects with systemic absorption
- May produce peripheral features of opioid withdrawal
Lactulose
- Class
- Presentation
- Pharmaceutics
- Mechanism
- Adverse effects
- Duration of action
- Absorption
- Metabolism
