2. Antibiotics - Metronidazole Flashcards
What class of drug is metronidazole?
synthetic nitroimidazole
pro-drug - needs to undergo metabolic process to reach its ultimate active form
What is the mechanism of action of metronidazole?
- enzymatic reduction (oxidoreductase)
- following reduction the drug forms a covalent bond to DNA which produces metabolites which damage the DNA to eventually induce cell death
Which cells are affected by metronidazole?
- penetrates all cells equally HOWEVER
- main effect primarily on bacteria, anaerobes and protozoa which contain reductase enzymes which convert it to its active antibacterial derivative i.e. does not affect human cells or aerobes
Summarise the action of metronidazole (what it is selective for and why)
metronidazole is selective for anaerobic bacteria due to their ability to intracellularly reduce the drug to its active form
What concerns have been expressed about metronidazole?
- potential mutagenic, teratogenic, or carcinogenic effects
- however studies have suggested there has been no increased risk of congenital abnormalities or adverse fatal outcomes following exposure, however there is no controlled data in human pregnancy
Why might metronidazole be a suitable alternative to penicillin?
similar spectrum of activity
What is the spectrum of activity of metronidazole (what bacterias is metronidazole active against)?
- obligate anaerobes
- gram -ve pathogens (anaerobe)
- bacteriodes (e.g. melaninogenicus in abscesses)
- clortidium (C. Diff)
- fusobacterium spp
- prevotella
- peptospreptococcus
What is the killing mechanism of metronidazole?
concentration dependent
- peak concentration
- no time requirement i.e. for bacterial division
- important relevance for dosing
- ensure concentration is sufficiently high - bacterial killing assured
What is the % oral absorption of metronidazole?
near to 100% - almost as effective orally as IV
What is the half life of metronidazole?
8 hours
What is the peak serum level of metronidazole?
4-6.5ug/mL
What is the peak serum time of metronidazole?
60-120 mins
What is the NPB serum level of metronidazole?
0.8ug
What is the % protein binding of metronidazole?
8-11%
Does food affect metronidazole peak serum levels?
yes
Is a loading dose needed for metronidazole?
no
What is the distribution of metronidazole?
wide volume distribution
- penetrates saliva
- CNS penetration
- foetal circulation (suggested to avoid in 1st trimester)
Where is metronidazole metabolised, and what does this process result in?
- metabolised in the liver
- biotransformed into 5 metabolic products all of which have some anti anaerobic activity
How is metronidazole eliminated from the body?
by the kidney
- may cause reddish brown urine discolouration
What is a main reason for metronidazole having a high safety margin?
no lethal dose found in humans
What patients should you be caution prescribing metronidazole to?
- severe hepatic dysfunction (metabolism reduce, may consider reducing dose)
- not significantly altered in renal impairment but be cautious particularly in end stage renal disease
- pregnancy - avoid 1st trimester
- nursing mothers - avoid (breastmilk levels close to serum levels)
What are the oro-dental indications for metronidazole?
- anaerobes suspected
- acute necrotising forms of gingivitis
- pericoronitis (with systemic involvement)
- dental abscess
- beta-lactamase producing anaerobes
- alternative to pencillin (allergy)
What are the notable things which metronidazole interacts with?
- ALCOHOL
- CYP450 (a liver enzyme)
- phenytoin
- phenobarbitol
- cimetidine
- lithium
- warfarin
- vit K gut flora
- inhibition CYP450 enzymes
What type of reaction does metronidazole have with alcohol?
a disulfiram type reaction
What enzyme pathway is metronidazole metabolised by?
the CYP450 enzyme pathway in the liver
What results from the interaction of enzyme inducers such as phenobarbitol and phenytoin with metronidazole?
may reduce the half life of metronidazole, essentially increasing the metabolism
What does the interaction of climetidine with metronidazole result in?
decrease microsomal enzyme activity resulting in decreased plasma clearance of metronidazole therefore increasing the half life
What is the effect of interaction between metronidazole and warfarin?
reported to potentiate the anticoagulant action of the likes of warfarin, leading to prolonged prothrombin time and the same mechanism inhibits the CYP450 liver microsomal enzymes responsible for metabolising warfarin
What are the main GENERAL adverse effects of metronidazole?
gastrointestinal
- nausea, vomiting, anorexia, diarrhoea, epigastric distress and abdominal cramping
- constipation has also been reported
some of the effects of these are sufficient to force the patient to stop taking the drug
What are the main adverse effects of metronidazole which are primarily associated with prolonged or intensive use?
- convulsive seizure
- peripheral neuropathy (paraesthesia extremities)
- also: dizziness, vertigo, incoordination, ataxia, irritability, depression, weakness, insomnia
What are the main ORAL adverse effects of metronidazole?
- unpleasant taste (varied)
- sharp/metallic
- taste disturbance
- furred tongue
- glossitis
- stomatitis
- candida
What are the main very rare adverse effects of metronidazole?
- blood dyscrasias
- temporary neutropenia
- thrombocytopenia
rare but reversible
What is the main mechanism of metronidazole resistance?
chromosomal/plasmid mediated
- reduction is the activity of the oxidoreductase/nitroreductase enzymes
Although there is limited resistance to metronidazole, where is there increasing resistance to it?
- in developing countries where metronidazole is routinely used for managing parasitic disease there are high resistance patterns
- main exception to this in developed counties is the treatment of helicobacter pylori, resistance of this to metronidazole reduces the effectiveness of other treatments being used
Structurally speaking, why does metronidazole have an bad interaction with alcohol?
has structural similarities to tetraethylthriuram disulfide, a drug given to struggling alcoholics which produces undesirable effects if alcohol is consumed
Why do tetraethylthiuram dislufide and metronidazole cause a negative reaction alcohol?
conversion of acetaldehyde to acetate via aldehyde dehydrogenase is blocked, resulting in excessive build up of acetaldehyde in the body
What effects does acetaldehyde build up have on the body?
- vasodilation
- subjective feeling of hotness and facial flushing
- increased heart rate and respiration rate
- lowered blood pressure
- dry mouth or throat
- bronchoconstriction
- allergy reactions
- nausea
- headache
essentially a massive HANGOVER
What is the dose of metronidazole?
200mg-400mg (usually 400mg now)
What is the interval of taking metronidazole?
8-12 hourly
What is the duration of taking metronidazole?
3-5 days
What is the route of taking metronidazole?
oral
What kind of metabolism does metronidazole undergo?
hepatic metabolism
Summary slide (metronidazole):
