Yekatit 12 Hospital Medical

College: New Innovative

Medical Education Program--
Pharmacology Modules for
Doctor of Medicine PC II
Students 1
Disclaimers
• This pharmacology lecture material is compiled &
designed for preclinical medical students or year
II undergraduate medical students. Various drug
doses mentioned in different part of the material
are obtained from selected pharmacology
textbooks. As this is not guideline or treatment
protocol & the sole purpose is to teach
pharmacology, students are recommended &
must look up to date or current guidelines &
protocols for the appropriate treatment options
& doses to be used in their clinical practices.
2
 Discussion Points
P’cology of 1)P’cology of
Aminoglycosides Aminoglycosides
& Spectinomycin 2)P’cology of
Individual
Aminoglycosides
Endalk Gebrie
B. Pharm, MSc. in 3)P’cology of
Pharmacology Spectinomycin

3
 Aminoglycosides
•Semisynthetic derivatives of a cpd
obtained from soil actinomycetes
1) •Inhibit protein synthesis by interfering
P’cology with ribosomal function, bactericidal

of •Mainly useful against G-ve bacteria

Aminogl •Also used in comb with other agents

( serious G-ve infs, endocarditis &
ycosides tuberculosis), protozoal parasites
•H2O soluble, stable in solu, more
active in alkaline pH than acidic pH
4
Aminoglycoside MOAs
• Irreversible inhibitor of protein synthesis
• Binds with 30S subunit (S16 in the case of
streptomycin)--cidal action
• Three mechanism postulated
 Block of formation of the initiation complex
 Miscoding of amino acids in the emerging
peptide
 Block of translocation on mRNA & premature
termination of translation of mRNA 5
Aminoglycoside MOAs(2)

6
Aminoglycoside MOAs(3)
• Transport across the • Transport across the
CM inhibited by CM enhanced by
 Low extracellular pH  Cell wall synthesis
inhibitors
 Anaerobic conditions
(vancomycin &
 Divalent cations (e.g., penicillins)---
Ca2+ & Mg2+), synergetic
hyperosmolarity interaction

7
Aminoglycosides MORs
1) Inactivation by microbial enzyme
(acetyltransferase)--principal mechanism
Amikacin resistant to inactivation
2) Failure to penetrate --enhanced by penicillin
&/or vancomycin comb
3) Efflux pumps
4) Deleted or altered 30s as a result of mutation
which result low affinity of the drug
8
Aminoglycosides AMAs
• Active against many G-Ve & limited G+ve activity( not
used alone)
• Most widely used against G-ve enteric organisms & in
sepsis

• Active against MDR, such as P. aeruginosa, Klebsiella

pneumoniae & Enterobacter sp
• With penicillin in tx of infection caused by Listeria sp.
& P. aeruginosa

• Synergestic with penicillin for tx E. faecalis & E.

faecium infective endocarditis 9
Aminoglycosides AMAs (2)
• Limited activity against anaerobic or facultative bacteria
under anaerobic conditions

• Gentamicin most commonly used

• Tobramycin for P. aeruginosa (preferred for UTI, but

with antipseudomonal beta lactam for pneumonia)

• Amikacin has the widest spectrum & effective for

infections resistant to gentamicin & tobramycin
• Streptomycin effective for gentamicin resistant strains
of enterococci ( modified by different enzyme)
10
Aminoglycosides P’kinetics
• Highly polar cpds (polycations), 1% oral or rectal F,
given IV or IM
Exception neomycin ( given PO prior to colorectal
surgery & topically )
• Cross the placenta, but not BBB( CNS infection
intrathecal or intraventricular routes)
• Penetrate into the vitreous humor of the eye,
modestly to other body secretion & body fluid
• Plasma t1/2 =2-3hrs, Cmax for IM(30–90 min)
• Virtually eliminated by GF, 60-90% excreted
unchanged in 24hrs 11
Aminoglycosides P’kinetics (2)
• Absorption from oral route ↑ed by GIT
disease ( IBD, ulcers)
• Traditionally BID or TID but OD dosing is
preferred (WHY???)--↓nephrotoxicity &
↑ convenience
• Have significant PAE
• Have concentration-dependent killing
(↑[] above the MIC↑ proportion of killing
& rate of killing) 12
Aminoglycosides P’kinetics (3)
• Exhibit synergistic killing with beta lactam & vancomycin
(> additive)
• Vd equivalent to extracellular fluid
• Higher [] in the renal cortex & the endolymph & perilymph
of the inner ear→ toxicity
• Impaired renal function ---↑accumulation---↑t1/2 (24-
48hrs) & toxic effect (ototoxicity & nephrotoxicity)—linear
r/s wit Scr—needs dose adjustment ( neomycin in the
feces)
• Usually given IV as a 30–60 minute infusion but inhalation
route tobramycin ( cystic fibrosis), neomycin—PO or
topical 13
Aminoglycosides Dosing & Monitoring
• High-dose, extended-interval administration
implemented ---PAEs, less toxic
Daily multiple doses are associated with higher toxicity
• Daily multiple doses are appropriate for pregnancy,
neonates, pediatrics , endocarditis pts, obesity pts &
significant RI pts( CrCl<25ml/min)
• Need TDM (gentamicin, tobramycin & amikacin) due
to interpatient variations (trough [] <1 mcg/mL18-
24hrs after dosing, > 2 mcg/mL is predictive of
toxicity)
14
Aminoglycosides Dosing & Monitoring(2)

15
Aminoglycosides Adverse Effects
•Time & dose Aminoglycoside Ototoxicity
related, serious
• Destruction of sensory cells (cochlea &
adverse effects may
↑ as the tx vestibular organ)-- usually irreversible
proceeds(>5days)— • Manifest as
use limited to serious
infection  Vestibular damage; vertigo, ataxia & loss
of balance
•The two most
hazardous adverse  Cochlear damage; tinnitus & other
effects are ; auditory disturbance /deafness/ high-
frequency hearing loss
1)Ototoxicity
• Class effect, incidence as high as 25%;
2)Nephrotoxicity
related to dose & duration of therapy
3)Other toxicities
16
Aminoglycosides Ototoxicity (2)
• Streptomycin & gentamicin most likely ---
vestibular function interference
• Neomycin, kanamycin & amikacin interferes with
cochlea/auditory damage
• Tobramycin affects both equally
• Netilmicin--- less ototoxic than others &
preferred if prolonged tx required
• Potentiated with loop diuretics & ethacrynic
acid, cisplatin
17
Aminoglycosides Nephrotoxicity
• Damage to the renal tubule --disrupts calcium-
mediated transport processes →mild, reversible
renal impairment to severe, potentially
irreversible acute tubular necrosis
• Risk ↑ with;
 Pre-existing renal disease, elderly, prolonged use
 In condition urine volume reduced
 Use of other nephrotoxic drugs (eg.,
amphotericin, vancomycin, ACEIs, cisplatin &
cyclosporine) 18
Aminoglycosides Nephrotoxicity (2)
• Have cascade toxicity(vicious toxicity)
• TDM required for most of them
• Neomycin, tobramycin & gentamicin are the most
nephrotoxic
• Streptomycin least nephrotoxic –not []ed in the
renal cortex
• High-dose/ extended- interval dosing or OD dosing
→↓ this adverse effect
• In renal dysfunction doses adjusted based on CrCl
19
Aminoglycosides Other Toxicities
• Curare like effect [ reversed by calcium gluconate given
promptly or neostigmine]
↓ Potency of blockage neomycin, kanamycin, amikacin,
gentamicin & tobramycin
Cause respiratory paralysis
Toxicity pronounced when given with anesthesia & other
NMB drugs, risk higher in pts with myasthenia gravis
• Rare HSR occurs, associated with lesser degree
Clostridium difficile
• Contact dermatitis with topical admin ( neomycin)
20
Aminoglycosides Clinical Uses Consideration
• Used against G-Ve bacteria
( pts @ ↑risk of drug-resistant
pathogens or in critically ill
pts)
• With beta lactam
 To ↑ coverage of
antimicrobial activities
 Synergetic interaction
(bactericidal effects at the site
& shorten tx duration)
 To ↓ emergency of resistance
• Gentamicin, tobramycin,
amikacin & netilmicin are
used intercheangabily;
Gentamicin ( long history &
lower cost)
• Restrict prolonged use (life-
threatening infection &
infections less-toxic agent is
CI or less effective)
• Selection of agent & dose
depends on the infection
being treated & the
susceptibility of the isolate
21
Aminoglycosides Clinical Uses
• As 2nd line for Tb( amikacin &
streptomycin)
• Amikacin for nontuberculous mycobacteria
( M. avium, M. abscessus, M. chelonae)
• Tx of UTIs (Genta & tobramycin)
• Tx of pneumonia ( with beta lactam, MDR
Gram –ve bacili)
22
Aminoglycosides Clinical Uses(2)
• Tx of Meningitis ( G-ve beta lactams
resistant organism, direct installation to
the CNS; preservative free gentamicin)
• Tx of Peritonitis ( given with dialyzing
fluid, gentamicin)
• Tx of sepsis ( MDR organisms involved,
tobramycin & amikacin)
• Tx of Cystic Fibrosis ( tobramycin)
23
Aminoglycosides Clinical Uses(3)
• Tx of Bacterial • Tularemia; Streptomycin
Endocarditis ( gentamicin)

Enterococcal • Plague; streptomycin ( gentamicin)

endocarditis ( penicilin • Topical Applications
+ gentamicin)
 Neomycin (skin & mucous
Selected cases of membrane infections, orally
staphylococcal “bowel prep” prior to surgical
tricuspid native-valve procedure )
endocarditis
 Paromomycin ( protozoal infection;
(gentamicin + nafcillin) lishmaniasis, cryptosporidiosis,
giardiasis & amebiasis)
24
 a) Streptomycin

2) b) Gentamicin
P’cology c) Tobramycin
of d) Paromomycin
Individual
e) Neomycin
Aminogly
cosides f) Others; Kanamycin,
Amikacin & Netilmicin
25
 a) Streptomycin

•Isolated from a strain of Streptomyces griseus

•Has similar AMAs, MOAs & MORs to other drugs
in the class
•Resistance emerging, restricting usefulness
•Generally used in combination with other agent
•Less active against aerobic gram-negative rods
as compared to other members of the class
•Can be used for microbes resistant to gentamicin
26
Streptomycin Peculiar Adverse Effects

 HSRs (prolonged uses in TB tx); fever, rashes &

others
 Higher vestibular damage-- irreversible
 Gentamicin—more of nephrotoxic—reversible--
preferred for most infection
 CI in pregnancy; cause deafness in the new born
 Cause dysfunction of the optic (scotomas,
presenting as enlargement of the blind spot)
 Peripheral neuritis—the least toxicity
27
Streptomycin Therapeutic Uses
• Streptomycin [ IV or IM(painful)]
With other anti TB meds 2nd line agent in
the tx of TB
With beta lactam for Bacterial
Endocarditis
Tularemia & Plague

28
 b) Gentamicin

•Mixture of three closely related constituents,

C1, C1A, & C2 isolated from Micromonospora
purpurea
•Effective [Gram-+ve (limited) & Gram –ve]
•Other properties →aminoglycosides
•No activity against anaerobes
•First choice; low cost & reliable activity
against all but the most resistant gram-ve
29
Gentamicin(2)
• Streptococci & enterococci are relatively
resistant—needs comb with CW active
agents
• Resistance is mediated by modifying
enzyme
• Gentamicin resistant strains retains
susceptibility to amikacin
• Used interchangeably with Tobramycin,
amikacin & netilmicin
30
Gentamicin Peculiar Adverse Effects
• Associated with higher nephrotoxicity (reversible)--
5–25% of pts receiving gentamicin for longer than
3–5 days

• Has higher vestibular toxicity than cochlear toxicity

 Ototoxicity- irreversible, genetically linked--

mutations in mitochondrial DNA

• Ototoxicity can occur in 1–5% for pts receiving

gentamicin for more than 5 days

• Loss of hearing can also occur

31
Gentamicin Therapeutic Uses
•Parenteral (IM or IV), ophthalmic & topical routes
•With beta lactam used tx of serious G-ve
infections (P. aeruginosa, Enterobacter,
Klebsiella, Serratia, & other species resistant to
less toxic abxs)
•UTI ( severe or complicated)
•Sepsis (granulocytopenia & suspected of P.
aeruginosa)
32
Gentamicin Therapeutic Uses(2)
•With beta lactams for tx of bacterial
endocarditis
•With beta lactams for tx of pneumonia (P.
aeruginosa)
•Peritonitis ( added to the dialysis fluid)
•Meningitis (species of Pseudomonas &
Acinetobacter), tx of Tularemia & Plague
•Topical for burns & ophthalmic infection
33
 c) Tobramycin
•AMAs, p’kinetics & toxicity similar to gentamicin
•Indication similar to gentamicin
•Has identical dosage & serum [] to gentamicin
•Interchangeable clinically with gentamicin
•TDM needed in renal insufficient pts
•Nephrotoxic & ototoxic agent, higher
nephrotoxicity than gentamicin
34
Tobramycin Therapeutic Uses
Solution (300 mg in 5 Ophthalmic
IM or IV mL) for inhalation
ointment &
Formulation •Tx of P aeruginosa
lower RTIs
drops
•Superior than complicating cystic
•Tx of
fibrosis
gentamicin superficial eye
•Results serum [] 1 hr
against P. after inhalation infections
aeruginosa— average 1 mcg/mL;
nephrotoxicity & •Less systemic
preferred agent ototoxicity rarely occur absorption
to be comb with •Preexisting renal,
vestibular, or hearing •Unlikely to
antipseudomonal disorders—cautions cause systemic
needed adverse effects
β-lactam abx
35
 d) Paromomycin
Structurally related to neomycin & kanamycin

Similar MOAs & MORs to other drugs in the class

But notably has antiparasitic activity & used for this

purpose than bacterial infecs

Used orally, topically & intravenously

Susceptible parasite include Leishmania spp.,

Entamoeba histolytica, Giardia lamblia &
Cryptosporidium parvum
36
Paromomycin Adverse Effects
• Oral doses cause dose related GI side effects: N,D
& abdominal pain
• Topical uses; skin irritation
• IV use for visceral leishmaniasis
 Significant nephrotoxicity & ototoxicity
 Auditory function is affected more than vestibular
function
 Deafness in renally impaired pts & prolonged uses
37
Paromomycin Therapeutic Uses
• Effective against visceral leishmaniasis
( IV), cutaneous leishmaniasis ( topical)
• Poor oral absorption ; PO used for
intestinal parasites;
Intestinal amebiasis, intestinal
cryptosporidiosis & giardiasis

38
P’ceutical Consideration with
Aminoglycosides
Incompatibility:
• Should not be mixed in the same solution
with penicillins, heparin, amphotericin B,
& the various cephalosporins
Cause inactivation of aminoglycoside with
significant degree

39
 Spectinomycin
•Structurally related to aminoglycoside

3)  but lacks amino sugars & glycosidic

bonds
P’cology
•Uses confined to tx of gonorrhea (Sole
of Use) in
Spectin Pts allergic to penicillins or pts
omycin infected with penicillin resistant
gonococci
•No cross resistance with other drugs
used in the tx gonorrhea 40
Spectinomycin(2)
• Rapidly absorbed after IM injection
• Standard dose; single dose of 2–4 g/d (40
mg/kg in children) given IM
• Adverse effects; pain at the injection site
& occasionally, fever & nausea
• Rarely cause nephrotoxicity & anemia
• With NMJ blockers cause paralysis
41
 References
1. Camille E. Beauduy & Lisa G. Winston . Aminoglycosides & Spectinomycin .
Bertram G. Katzung (14th Edition) Basic & Clinical Pharmacology ( Soft
Copy Version). United States of America: McGraw-Hill Companies; 2018. P.
826-834

2. H.P.Rang, M.M. Dale, J.M. Ritter, & R.J. Flower (6th Edition) Antibacterial
Drugs; Rang & Dales Pharmacology ;PP . Printed in China: Churchill
Livingstone ElSEVIER; 2007. P. 661-678

3. Conan MacDougall. Aminoglycosides. Laurence L. Brunton (13th Edition)

Goodman & Gilman’s the Pharmacological Basis of Therapeutics (e-book
version).United States of America: The McGraw-Hill Companies, Inc; 2018.
P. 1039-1049

4. Jacqueline Jourjy. Protein Synthesis Inhibitors. Karen Whalen, Carinda

Field & Rajan Radhakrishnan (7th Edition) Lippincott® Illustrated
Reviews: Pharmacology( Soft Copy Version).United States of America:
Walters Kluwer; 2019. P. 1088-1105 & P. 1106-1114
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