Nirav Sharma Monday, 13 June 2016

Protein synthesis inhibitors.

Overview.
- These drugs act on the bacterial
ribosomes. These ribosomes are
smaller compared to those in the
human cell i.e. A bacterial ribosome is
70s compared to the 80s of the
mammalian cell and 50s and 30s
subunits compared to the 60s and 40s
subunits of the mammalian cell.
- Because of this difference, these
drugs have a selective toxicity against
the bacterial ribosomes. However, at
high level of drugs like the tetracycline
and aminoglycoside, they may have
toxic effects in the body due to
interaction with the human ribosomes.
- There are 3 considerations regarding
these drugs;
1. these drugs either target the
30s ribosomal sub unit or the
50s ribosomal sub unit.
2. In addition to the bacterial
ribosomes, they can also act
on the mitochondrial or
cytosolic ribosomes. This
leads to the adverse effects
that are observed e.g. this is
seen in chloramphenicol, which has limited its usage.
3. Complete inhibition of the bacteria isn't enough to kill the bacteria.

Tetracyclines.
- These drugs are classified in to two; natural i.e. Demeclocycline, Chlortetracycline,
Oxytetracycline; semisynthetic i.e. minocycline, tetracycline, doxycycline, methoxycycline and
tigecycline.
- Chlortetracycline, Oxytetracycline and tetracycline are examples short acting tetracyclins
(6-8 hrs); Methacycline and Demeclocycline are intermediated acting tetracycline (12 hrs)
and Doxycycline and Minocycline are long acting tetracycline. (16 hrs)
- The members of this family of drugs has 4 fused rings with a system of conjugated bonds,
and its at these rings at which substitutions can occur and hence the individual drugs
produced have different pharmacokinetics.

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Mechanism of action.
- They enter the susceptible cells by passive
transport and by energy dependent transport
proteins that are found in the inner cytoplasmic
membrane.
- On entry into the cell, it reversibly binds to the 30s
subunit, on doing so it blocks the aminoacyl- tRNA
(these are tRNAs carrying specific amino acids),
hence preventing protein synthesis. Because of this
mechanism, it is referred to as being bacteriostatic.

Antibacterial spectrum.
- They are broad spectrum antibiotics with activity
against many of the gram positive and negative,
Chlamydia, spirochetes(Borrelia burgdoferri which
causes lyme disease; Leptospira interrogans),
Mycoplasma pneumoniae, Rickettsia rickettsia (that
causes Rocky mountain fever), and some protozoa
e.g. amoeba.
- The antibacterial activity of all the drugs is similar
however, the tetracycline resistant species maybe
susceptible to Doxycyclin, minocycline and
tigecycline, all of which are poor substrates for the
efflux pumps.

Resistance
- There are three modes of resistance;
1.Decreased accumulation within the cell, this is
through the efflux pumps which are plasmid
encoded protein TetA. This is efflux pump is a
Mg2+-dependent. This efflux pump is effective
against the older tetracyclines i.e.
2.Production of proteins that prevent the binding of
the tetracyclines with the 30s subunit.
3.Enzyme inactivation.

Pharmacokinetics.
- Absorption - All are adequately absorbed from the
GIt. However,dairy products containing Ca2+, and
other divalent products as well as antacid
medications cause chelations with tetracyclines i.e.
preventing absorption of the tetracycline. Therefore,
it is recommended to take it on an empty stomach.
Also an alkaline pH affects their absorption. NB. Minocycline and Demeclocycline are
virtually completely absorbed.
- Absorption after oral administration is approximately 30% for chlortetracycline; 60
70% for tetracycline, oxytetracycline, demeclocycline, and methacycline; and 95
100% for doxycycline and minocycline. Tigecycline is poorly absorbed orally and

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must be administered intravenously. A portion of an orally administered dose of
tetracycline remains in the gut lumen, alters intestinal flora.
- Distribution - Is mainly conc. in the liver, kidney, spleen, skin, Ca2+ conc. tissues like
teeth or bones also in tumours with high Ca2+ conc. e.g. gastric carcinomas.
- Minocycline unlike other tetracyclines, enters the CNS at therapeutically
efficacious levels also in the absence of inflammation of the meninges.
- 40-80% of the drug is protein bound.
- All cross the placental barrier and accumulate in the fatal bones and
dentition causing improper development.
- Metabolism - is metabolised in the liver and conjugated into soluble glucoronides.
- Elimination - The parent drug/ the metabolite are secreted in the bile of which most is
reabsorbed by the enterohepatic circulation. Is excreted in faeces as well as in the urine.
- In renal dysfunction and bile blockage, the half life of the drug is
increased. However, doxycycline can be given to the renal dysfunction
patients coz it is preferentially excreted in bile.
- Is also excreted in breast milk.
- Carbamazepine, barbiturates, phenytoin and chronic alcohol consumption
reduces its half life coz of decreased hepatic metabolism.

Adverse effects.
1. Gastric distress e.g. nausea, vomiting, and diarrhoea due to irritation of gastric
mucosa. This can be reduced by taking the drug with food or carboxymethylcellulose,
reducing the dosage or discontinuing the drug.
2. Deposition in bones and teeth of young children leading to discolouration as well
as temporary stunted growth. In the fatal teeth, it can cause fluorescence, enamel
dysplasia and discolouration.
3. Fetal hepatoxicity in mothers taking high doses and have pyelonephritis.
4. Phototoxicity esp after using doxycycline, tetracycline, and demeclocycline.
5. Vestibular problems such as dizziness, nausea and vomiting.
6. Pseudotumour cerebri, a benign intracranial hypertension that is characterised
by headache and blurred vision.
7. Superinfection esp by the overgrowth of candida and also can cause
pseudomembranous colitis by the overgrowth of Clostridium deficile.
8. IV can cause venous thrombosis and IM produced painful local irritation and should
be avoided.
9. Black hairy tongue (an elongation of the filiform papillae with a brown or black
discolouration)

Contraindications.
- Shouldn't be given to the renal impaired unless giving doxycycline as it increases azotemia
(Increased levels of blood urea or nitrogen containing compounds).

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- Shouldn't be given to pregnant mothers.
- Shouldn't be given to children below 8 years.
Uses
- Used to treat infections caused by - Acne
rickettsia, excellent against
Mycoplasma pneumoniae, Clostridia
- Exacerbation of bronchitis
and some anaerobes. - Leptospirosis
- Treat gastric and duodenal ulcers - Lyme disease.
caused by H.pylori.
- Prophylactic treatment of parasitic
- Treatment of cholera. infections e.g. those caused by
P.falciparum.
Glycyclines.
- Includes Tigecycline, a derivative of minocycline, and is structurally similar to the
tetracyclines.

Mechanism of action - Binds to the 30s ribosome, prevents translation hence protein
synthesis.

Antimicrobial spectrum - Is active against the MRSA, VRSA, multi-drug resistant

S.pneumoniae, extended spectrum for the lactamase gram -ves, Acinetobacter baumannii
and many anaerobic organisms. However, it is ineffective against Proteus sp, Pseudomonas
sp or Providencia.

Pharmacokinetics - Should be given every 12 hours intravenously and rapidly distributed in

the body tissues, and hence coz of this it is not given in patients with bacteraemia.
- Is metabolised by the liver and is excreted by bile/biliary excretion.
- It can be given in the patients with renal dysfunction however, not given in patients
with hepatic dysfunction.

Adverse effects - causes nausea and occasionally vomiting.

Uses - Is effective for usage in skin infections and intra-abdominal infections as well as
community acquired pneumonia.

Drug interactions - Increases the half life of warfarin hence the anticoagulation should be
closely monitored. It also increases the half life of digoxin. However, when it is taken with
oral contraceptives, the contraceptives become less effective.

Aminoglycosides.
- These include; neomycin, gentamicin, streptomycin, tobramycin, amikacin, sisomicin,
kanamycin. Of these, gentamicin, tobramycin and amikacin are widely used coz of the broad
spectrum as well as a lower toxicity.
- Those that are derived from Streptomyces, have a suffix mycin whereas those derived from
micromonospora have the suffix micin.

Streptomyces (mycin) Micromonospora (micin)

Streptomycin Amikacin

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Neomycin (Framycetin, Paromomycin, Gentamicin (Netilmicin, Sisomicin, Isepamicin)
Ribostamycin)

Kanamycin (Amikacin, Arbekacin, Bekanamycin, Verdamicin

Dibekacin, Tobramycin)

Hygromycin B Spectinomycin Astromicin

Paromomycin

Tobramycin

- These drugs are polycationic hence this prevents the easy passage of the drug into the
bacterial cell. They are active in alkaline pH and are water soluble.
- They are used in combinations with lactam drugs against resistant gram -ves, and with
vancomycin or lactam drugs for treating gram +ve endocarditis and tuberculosis.

Mechanism of action.
- They initially enter the cell through oxygen-dependant porin channels. They bind irreversibly to
the 30s ribosomal sub unit (16s rRNA) prior to ribosome formation.

At low concentrations, they cause misreading of the genetic code hence forming new
proteins that may be toxic to the cell. At higher concentrations, it completely inhibits
protein synthesis

the polysomes get depleted because the ahminoglycosides interfere with the process
of polysome disaggregation and assembly.

It may also cause an interference in the initiation complex of peptide formation.

- It on addition, to the bacteriostatic function, it also has bactericidal function that causes a
rupture of the cell membrane probably due to the new proteins that are formed as a result of
misreading of the genetic code.

Mechanisms of resistance.
Three mechanisms;

Production of transferase enzymes (that are specific to the aminoglycoside hence preventing
cross reactions) that inactivate the aminoglycoside by adenylation, phosphorylation or
acetylation.

Decreased entry in to the cells as a result of absence of the oxygen dependent porin
channels.

Alteration in the receptor sites, through mutations, of the 30s sub units hence preventing the
binding of the drug.

Antibacterial spectrum
- Has a great effect on the aerobic gram negative enteric bacteria and in sepsis. Is used
in combinations to treat strep infections as well as Listeria infections. Is effective
against gram negative rods like Brucella species, Yersinia pestis, Francisella
tularensis, Klebsiella species and Pseudomonas aeroginosa.
- They are effective against only the strictly aerobic species and not the anaerobic, this
is mainly due to the absence of the oxygen dependent porins.

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Pharmacokinetics.
- Administration - These drugs coz of their high polarity and polycationic structure, can't easily
be absorbed except neomycin, however, its used topically cause of its systemic effect, causing
nephrotoxicity. Neomycin is used to prepare bowel for surgery.
- The bactericidal effect is concentration dependent i.e. the greater the
concentration, the greater the rate at which the organisms die. Portray a
PAE (i.e. the activity of the drug persists beyond the time during which the
measurable drug is present), and because of these effects, they can be
given once a day.

NB. This medication however, in the pregnant women, neonatal

infections as well as those with bacterial endocarditis should be given
every 8 hrs.
- When administered with a lactam, it portrays a synergistic activity.
- Distribution - Distribution in other tissues is low and the penetration in to the body fluids is
variable. They don't accumulate in the CNS even though the meninges are inflamed.
Exception to this is Neomycin.
- It accumulates highly in the perilymph and endolymph causing ototoxicity and also
accumulation in the renal cortex leading to nephrotoxicity.
- They cross the placenta barrier and may accumulate in the foetal plasma and
amniotic fluid.
- Metabolism - Doesn't occur in the host.
- Elimination - All are excreted by the glomerular filtration and is excreted in the urine.
Adverse effects.
- These effects are both concentration and time dependent, the adverse effects appear as a
result of the concentration reaching the threshold level, and on reaching this level, the time
beyond the threshold is very critical.
- When these drugs are administered two or three times a day, both the peak levels and trough
levels are measured, however for one daily dosage, only the trough levels are required.
- NB.therapeutic dosing of a drug seeks to maintain
- the peak (highest) plasma drug concentration below the toxic concentration,
- and the trough (lowest) drug concentration above the minimally effective
level.
- The adverse effects include the following;
ototoxicity - This is due to the accumulation of the drug in the endolymph and perilymph, and
the toxicity is related to the number of hairs damaged in the organ of Corti. Can lead to
deafness (this can be due to amikacin or kanamycin), which has been known to affect
foetuses in utero. Can also lead to vertigo and loss of balance; this can be due to gentamicin
or tobramycin.

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Old age, repeated administration of the aminoglycosides as well as some ototoxic
drugs like cisplatin or loop diuretics like furosemide, bumetanide or ethacrynic acid.

nephrotoxicity - This is due to retention of the aminoglycosides by the proximal tubules in the
kidney, this disrupts calcium mediated transport, leading to mild to reversible renal
impairment to severe and irreversible renal necrosis.

Factors potentiating this are old age, shock, dehydration, renal failure and drugs like
vancomycin, cisplatin and cyclosporin.

Gentamicin and tobramycin are most nephrotoxic.

Neuromuscular paralysis - is through through decreasing the release of ACh at the
presynaptic membrane and reducing the sensitivity at the post synaptic site. These effects
are due to the direct infusion intraperitoneal or intrapleural. These effects can be reversed by
infusion of calcium gluconate or neostigmine.

Allergic reactions - Contact dermatitis by neomycin.

Clinical uses - Useful in the treatment of infections caused by aerobic gram negative like
E.coli, Proteus, Serratia, Providencia.
- When used with a lactam, they have activity against gram positives.
- Streptomycin in combination with a penicillin is used in the treatment of
enterococcal endocarditis, TB, plague, and Tularaemia.

NB. Streptomycin is an aminocyclitol related to the aminoglycosides. Its

a backup drug and is used in the treatment of gonorrhoea in lactam
allergic patients. It causes pain at the site of injection, its given IM. The
most serious effect is vertigo and loss of balance and the frequency
depends on the age, blood levels of the drug and duration of the
administration.

Contraindications
Pregnant mothers
Old aged persons
Renal failure.
Myasthenia Gravis patients.

Macrolide.
These have a lactone ring (with 14 or 16 C) to which is attached one or two deoxy sugars.
- Erythromycin is the prototype of this group and was originally got from Streptomyces
erythreus. Clarithromycin and Azithromycin are semisynthetic derivatives; these two have a
broader spectrum and are more tolerated compared to Erythromycin. Telithromycin is
another semisynthetic derivative however, the distinguishing factor is the it is a Ketolide.
- Following shows macrolide classification;
14 C - Erythromycin, clarithromycin
15 C - azithromycin.
16 C - Rokitamycin, Micamycin

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Mechanism of action.
- Reversibly binds to the 50s ribosomal subunit, and inhibits
translocation of the tRNA i.e. movement of the tRNA from the A site to
the P site.
- These may also interfere with the process of transpeptidation as well
as the formation of the 50s ribosomal unit. These drugs are
bacteriostatic however, at higher doses act as bactericidal. They are
much more active at alkaline pH.

Antibacterial spectrum.
- Erythromycin - They are effective against a similar spectrum like
penicillin G and can be used in case of penicillin allergy. The spectrum
include gram positive pneumococci, Streptococci, Corynebacteria,
Mycoplasma sp, Ureaplasma sp, Clostridium sp, Legionella
pneumophilia; and gram negative like the Neisseria sp, Bordetella
pertusis, Bartonella sp, as well as some Rickettsia, Treponema palidum
and Campylobacter.
- Clarithromycin - Similar to Erythromycin but addition of H.influenza and
Toxoplasma gondii. Its activity against the intracellular pathogens i.e.
Chlamydia, Legionella, Ureaplasma and Mycoplasma is greater than
that of Erythromycin. Also has increased acid stability compared to erythromycin.
- Azithromycin - Has less activity against the Strep and staph compared to the previous two,
but is highly active against Chlamydia sp, a reason as to which they are used in treatment of
urethritis. Has similar spectrum as clarithromycin.
- Telithromycin - Spectrum similar to Azithromycin. Its structure aids it resistance from the
resistance mechanisms that make the macrocodes ineffective for it being a ketolide.

Resistance.
- Three main mechanisms;
Efflux pumps that decrease the permeability in to the bacterium.
Production of esterase enzyme that hydrolyses macrolide
Alteration of the ribosomal binding site by a chromosomal mutation or constitutive
methylase production, which is a major form of resistance in the gram +ve bacteria. This
enzyme methylates adenine in the 23s rRNA.

Pharmacokinetics.
- Administration - Erythromycin base unlike the other macrolides, is inactivated by the stomach
acid hence given in an enteric coated form or esterified form. Another factor affecting the
absorption of erythromycin and azithromycin is food hence should administered at least 1-2
hrs after meals.
- Distribution - Distributes well in to the tissues, doesn't penetrate the CSF, however it does so
in the prostate. They are concentrated in the liver. Azithromycin is unique in that its serum
level is less and is more concentrated in the macrophages, neutrophils and fibroblasts.
- Elimination - Is extensively metabolised within the liver and inhibits oxidation of drugs through
its interactions with P450. Clarithromycin is metabolised to the 14C derivative that remains
active.

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- Excretion - Erythromycin and azithromycin are primarily excreted in bile, however, there is
partial absorption by the enterohepatic circulation. Its inactive metabolites like clarithromycin
and its metabolites are excreted in urine.

Adverse effects.
- Epigastric distress, e.g. erythromycin stimulates GIt motility by stimulation of the motilin
receptors causing nausea.
- Ototoxicity
- Cholestatic jaundice
Contraindication
- Hepatic impairment - these drugs have a tendency to accumulate in the liver.
- Children with congenital anomalies of the heart, in these telithromycin is contraindicated.
- Renal impairment
- Myasthenia gravis
Drug interactions
- Erythromycin, Tellithromycin and clarithromycin cause toxic accumulation of certain drugs
e.g. warfarin, atorvastatin, cyclosporin etc.
- Can lead to inactivation of the enzymes that inactivate the drug digoxin hence increased
reabsorption of digoxin.
Uses.

Used to treat gram negative enteric bacteria especially those that cause sepsis and are
resistant e.g. action of gentamicin against P.aeroginosa, Bacteroides, Klebsiella and
Acinetobacter.

Treatment of meningitis by the intrathecal administration of gentamicin.

They are used in combination with penicillin to achieve the function of being bactericidal and
also increase the coverage to gram positive bacteria.

Chloramphenicol.
Is very toxic hence restricted to life threatening conditions caused by gram -ve and +ve species.
It is bacteriostatic (majorly) or bactericidal depending on the organism.

Mechanism of action.
- Binds reversibly to the 50s ribosomal subunit, and inhibits the formation of peptide bonds i.e.
inhibition of the process of transpeptidation.
NB. Because of the similarity of the bacterial and mitochondrial ribosomes, protein
synthesis in this organelle can be affected at higher concentrations of the drug.

Antimicrobial spectrum
- Is a broad spectrum antibiotic with actions against gram +ve and -ve, of particular high
susceptibility are H.influenza, Neisseria meningitidis and some strains of Bacteroides. IS all
active against Rickettsia but not Chlamidyae.

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Mechanism of Resistance
-There are two main mechanisms;
Decreased permeability in to the cell.
Plasmid R encoded acetyl A trasnferases that inactivates
chloramphenicol.

Pharmacokinetics
-Administration and Absorption - Is given by IV or oral route,
however, due to its lipophilic nature its completely absorbed by the
oral route.
-Distribution - Widely distributes itself in the body as well as in the
CSF. It inhibits the hepatic mixed oxidases.
-Excretion - Is excreted mostly by the renal tubules, less by
glomerular filtration. Is also excreted in the breast milk.

Adverse effects.
-Oral or vaginal candidiasis as a result of alteration of the normal
flora
-It leads to anaemia. It can lead to haemolytic anaemia in those
with low levels of glucose 6 phosphate dehydrogenase enzyme.
Other forms include the dose related reversible anaemia and dose
independent aplastic anaemia which is an idiosyncratic reaction.
-Gray baby syndrome - this occurs in the young babies in who the
dose is high, this is because the babies don't have enough capacity to glucorynate the
antibiotic and also the renal function is underdeveloped as a result the drug accumulates and
affects the mitochondrial ribosomes. It presents as cardiovascular collapse, shock, gray
colour, vomiting, flaccidity, depressed breathing and can ultimately lead to death. The dose in
these babies shouldn't be more than 50mg/kg/d and in premature babies not more than 25mg/
kg/d.

Interactions - because of the inhibitory effect of this drug on the mixed oxidases in the liver, it
elevates levels of drugs such as phenytoin, warfarin, chlorpropamide, and tolbutamide.

Use is rare because of its toxicity. However, is used in the treatment against Rickettsial like
Rocky mountain fever.

Clindamycin.
Is an example of a lincosamide.

Mechanism of action - Has a similar mechanism as erythromycin i.e. preventing translocation

from the A site to the P site by binding to the 50s ribosomal subunit.

Mechanism of resistance - Similar to that of erythromycin i.e. efflux pumps to reduce

penetrability, alteration of the binding site on the ribosomal subunit by a constitutive expressed
methylase, and encoding of esterase enzymes that inactivates the drug.

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Spectrum - Is mainly active against the anaerobic bacteria esp Bacteroides fragilis that causes
abdominal infections. is also active against the non-enterococci, gram positive and negative
cocci also the MRSA strains. Enterococci and gram negative aerobic organisms are usually
resistant. Isn't effective against Chlamidya.

Pharmacokinetics - Can be given orally or by IV. It is absorbed well in to the tissues, however,
the therapeutically levels aren't reached in the CSF even when the meninges are inflamed. It
penetrates well in to the bones.

Is extensively metabolised to form inactive products. Is eliminated majorly by glomerular

filtration in to urine or into bile.

Adverse effects - Skin rash and pseudomembranous colitis caused by Clamidya deficille.

Use - Used for skin and soft tissue reaction and also against anaerobic bacteria. Is used for
prophylaxis in patients with endocarditis or valvular heart disease instead of erythromycin.

Streptogramins.

Its main example is Quinupristin-Dalfopristin, which is a combination of two streptogramins i.e.

Quinupristin (Streptogramin B) and Dalfopristin (Streptogramin A) in the ratio of 30:70.

Its derived from a streptomycete and chemically modified. Its main use is in the treatment of
Vancomycin resistant Enterococcus faecium (VRE) or Streptococcus progenies resistant.

Mode of action - they inhibit protein synthesis by binding to the 50s subunit. Dalfopristin alters
the structure of the ribosome so as for the quinupristin to fit the binding site of the ribosome.
Quinupristin has the same binding site as for macrolides and clindamycin hence inhibit protein
synthesis in a similar manner and dalfopristin inhibits peptidyl transferase reaction.

- this combination drug is bactericidal and has a long PAE.

Antibacterial spectrum - Is active against the resistant strains of strep, staph and also the
enterococci (faecium but not faecalis).

Mechanisms of resistance
- There can be an methylase mediated - An active efflux pump
alteration in the binding site of
- Plasmid mediated acetyl transferase that
quinupristin (MLS-B resistance).
inactivates dalfopristin.
- Also an enzymatic alteration in the
action can lead to a change from
bactericidal to bacteriostatic.
Pharmacokinetics

- Administration - Is administered by IV
- Distribution - distributes well into the polymorphonuclear cells and the macrophages (This
property is important in the fact that VRE is intracellular).

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- Metabolism - Are metabolised in the liver, with the metabolites of quinupristin not as active
as those of dalfopristin that are equally active.

- Excretion - Is almost entirely excreted in faeces, urine is a secondary form of excretion.

Adverse effects
- Venous irritation
- Arthralgia and myalgia
- Hyperbilirubinemia
Drug interaction - Inhibits the cytochrome oxidase enzyme CYP3A4 that leads in the increase
of serum concentration of drugs like warfarin, non-nuclear anti-retroviral drugs, cyclosporin
and also digoxin.

Use- is used in the treatment of MRSA, VRE.

Oxazolidinone

- Linezolid is an example of synthetic oxazolidinone.

- Mechanism of action - prevents protein synthesis by preventing the formation of 70s ribosome
by binding to the 50s ribosomal subunit.

- Resistance - Decreased affinity of the linezolid to its binding site. There is no cross resistance
- Antibacterial spectrum - Is very active against the methicillin and vancomycin resistant
S.aureus as well as E.faecalis and E.faecium. Is primarily targeted against the gram +ve
bacteria like the Staph, Strep, and Enterococci as well as L.monocytogenes and
Corynebacteria sp. Has moderate activity against M.tuberculosis.

- Pharmacokinetics.
Administration - Is available in both oral Metabolism - Is metabolised by oxidative
and IV form, however its absorbed metabolism to yield two inactive
completely in the oral route. products.

Distribution - Is widely distributed in the Excretion - Is excreted by both renal and

body. non-renal routes.
- Adverse reactions.
Thrombocytopenia
Diarrhoea, and vomiting
Rash
Inactivates the mono amine oxidase (MAO). Hence patients are advised not to consume a
lot of tyramine-containing foods.

Peripheral neurpathies and optical neuritis.

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