LEc11 pdf - د.نهله

Pharmacology lecture

Dr. nahlah Othman

Drugs used in infectious diseases

Classification

Antibacterial drugs

Antiviral drugs

Antifungal drugs

Antiprotozoal drugs

Antihelminthic drugs

Introduction

Antimicrobials are also classified broadly into:

1. Bacteriostatic: those that act primarily by arresting bacterial multiplication, such

as sulphonamides, tetracyclines, chloramphenicol.

2. Bacteriocidal: those that act primarily by killing bacteria, such as penicillins,

aminoglycosides and rifampicin

How antimicrobials act-sites of action
The cell wall
The  cell  wall      gives  the  bacterium  its  characteristic  shape  and  provide  protection
against the lower osmotic pressure of the environment. Antimicrobials interfere with
synthesis  of  the  cell  wall  during  multiplication.  Example:    penicillins  ,
cephalosporines

The cytoplasmic membrane
Interfere with is its structure such as polynes (nystatin)

Protein synthesis
Interfere with the build-up of peptide chains on the ribosome of the organism, such as
tetracyclines, chloramphenicol

Nucleic acid metabolism
Directly with microbial DNA or its replication or repair, e.g rifampicin.
Indirectly on nucleic acid synthesis, e.g. sulphonamides, trimethoprim

Principles of antimicrobial therapy

1-  Make a diagnosis
2-  Remove barriers of cure
3-  Decide whether the drug is really necessary
4-  Select the best drug
5-  Administer the drug
6-  Continue therapy
7-  Test for cure
8-   prophylactic chemotherapy
9-  Carriers of pathogenic or resistant organisms

Antibiotic combinations

Antibiotics are combined for the following reasons:

1-Avoid the development of drug resistance.
2-Broaden the spectrum of antibacterial activity
3-Obtain   potentiation
4-Enable  reduction  of  the  dose  of  one  component  and  hence  reduce  the  risks  of
adverse drug reactions.
Problems with antimicrobial drugs

1-  Resistance
2-  Superinfection
3-  Masking of infections

Resistance

Mechanism of resistance

Naturally resistant strains

Spontaneous mutation

Transmission of genes from other organisms

Resistance is mediated

Production of enzymes that modify the drug e.g. aminglycosides are
phosphorylated, B-lactamases hydrolyse penicillins

Decreasing the passage into or increasing the efflux of drug from the
bacterial cell (e.g. imipenem resistance in Pseudomonas aeruginosa)

Target site so that the antimicrobial binds less effectively

By passing of inhibited metabolic pathways e.g. resistance to trimethoprim
in many bacteria

Superinfection
When any antimicrobial drug is used, there is usually suppression of part of
the normal bacterial flora of the patient that is susceptible to the drug. Often,
this causes no ill effects, but sometimes a drug- resistant organism, freed from
competition, proliferates to an extent that allows an infection to be established.

Masking of infections
Masking of infections by chemotherapy is an important possibility

  A course of penicillin adequate to cure gonorrhea, may prevent
simultaneously contracted syphilis from showing primary and     secondary
stages without effecting a cure; a serological test for     syphilis should be 3

months after treatment for gonorrhea

1- Antibacterial drugs

They are classified into

A-Inhibition of cell wall synthesis

B- Inhibition of protein synthesis
C- Interfere with nucleic acid

A-

Inhibition of cell wall synthesis

1- β-lactam antibacerials
a- Penicillins

1-  Narrow spectrum penicillins
2-  Broad spectrum penicillins
3-  Mecillinam
4-  Monobactam
5-  Antipseudimonal penicillins

b- Cephalosporins
c- Other β-lactam antibacerials

Carbapenems

d- Other inhibitors of cell wall synthesis and membrane function

Vancomycin
Teicoplanin
Daptomycin

B-

Inhibition of protein synthesis

Aminoglycosides
Tetracyclines
Macrolides
Chloramphenicol
Sodium fucidate
Quinupristin-dalfopristin
Linezolid

C-

Inhibition of nucleic acid synthesis

Sulphonamides and sulphonamide combinations
Quinlones
Azoles

Inhibition of cell wall synthesis

A. Β-lactams

a. Penicillins

Mode of action (bacteriacidal)
Penicillin act  by inhibiting the enzymes (penicillin  binding proteins, PBPs) involved
in  the  cross-linking  of  the  peptidoglycan  layer  of  the  cell  wall.  Which  protects  the
bacterium  from  its  environment;  incapable  of  withstanding  the  osmotic  gradient
between its interior and it’s environment, the cell swells and ruptures.

The main defence of bacteria against penicillins is:to produce enzymes β-lactamases,
which open the β-lactamases, ring and terminate antmicrobial activity. Other possible
mechanisms include modifications to PBPs to render them unable to bind β-lactams,
reduced permeability of the outer cell membrane of Gram-negative bacteria

Side effects the main hazard with the penicillins is allergic reaction. These include
itching, rashes, (eczematous or urticarial), fever, and angio-oedema. Rarely (about 1

in 10000) there is anaphylactic shock, other such as diarrhoea, neutropenia, anaemia
and sometimes haemolytic, and thrombocytopenia or interstitial nephritis.

Calssification of penicillins



Narrow spectrum penicillins



Broad spectrum penicillins



Extended spectrum penicillins



Mecillinam



Monobactam



Antipseudomonal penicillins

1. Narrow-spectrum penicillins

 Benzlypenicillin (penicillin G): has short t½(0.5h) so it should given every 6h,

it can be given IV or IM(it very painful), benzlypenicillin is effective against
G+ bacteria such as streptococcus pneumonia, streptococcus pyogenes.

 Phenoxymethylpencillin is given orally, Pharmacokinetics: Gastric acid

detroyes  benzylpenicillin,  which  is  therefore  unsuitable  for  oral  use.  Others,
e.g. phenoxymethylpenicillin,  resist acid  and  are  absorbed in  the upper  small
bowel.  The  plasma  t½    of  penicillins  is  usually  less  than  2h.  Penicillins
distribute mainly in the body water and enter well into the cerebrospinal fluid
if the meninges are inflamed

 Antistaphylococcal penicillin

These group of penicillins are resist β-lactamase degradiation by possession of an acyl
side-chain  in  their  lactam  ring  by  stearic  hindrance    limits  access  of  the  drug  to  the
enzymes’  active  site.  However  its  effect  on  pneumococcus  and  β-haemolytic
streptococci and Neisseria 20 time less than benzylpenicillin so when there is mixed
infection,  antistaphlycoccus  as  well  as  a  benzylpenicillin  should  be  given.  E.g.
Flucloxacillin , cloxacilllin, meticillin, oxacillin

2. Broad-spectrum penicillins

These semisynthetics penicillins act against G+ and G- cocci, in addition to some of
G- bacilli however they do not resist β-lactamases, and their usefulness has reduced
markedly because of the increased prevalence of organisms that produce these
enzymes. It activity against G+ are less than benzlypenicilline, it have useful activity
against Enterococcus faecalis and many strains of Haemophilus influenzae

ampicillin (t½ 1h)is acid stable and is moderately well absorbed when swallowed.
The oral dose is 250mg-1g 6-8hourly; im of iv 500mg 4-6hourly

Amoxicillin (t½ 1h) is a structural analogue of ampicillin. And is better absorbed
from the gut, diarrhoea is less frequent with amoxicillin than with ampicillin

3. Extend spectrum penicillins

Co-amoxiclav: Clavulanic acid is a β-lactam molecule with little interinsic
antibacterial activity, which binds irreversibly to β-lactamases. It competitively

protects the penicillin

4. Mecillinam

Pivmecillinam is an oral agent closely related to the broad-spectrum penicillins
but with differing antibacterial activity. It is active against G- organisms including
extended spectrum B-lactamase enterobateriaceae but inactive against G+

organisms

5. Monobactam

Aztreonam is the first member of this class of β-lactam antibiotics. It is active
against G- organisms including pseudomonas aeruginosa, Haemophilus influenzae
and Neisseria meningitidis and gonorrhoeae. Aztreonam is effective in
septicaemia and complicated urinary tract infections and gonorrhoea.

Side.Effects: rashes, GIT upset, hepatits, thrombocytopenia, neutropenia

6. Antipseudomonal penicillins

 Carboxypenicillins
 Ureidopenicillins

Carboxypenicillins
These  have  the  same  antibacterial  activity  as  ampicillin  (destroyed  by  β-lactamase),
but  have  additional  activity  against  Pseudomonas  areuginosa  and  indole-positive
Proteus  spp  e.g.  ticarcillin  is  presented  is  combination  with  clavulanic  acid,  so  to
provide greater activity against organisms producing β-lactamase (ticarcillin disoduim
salt and each 1g delivers 5.4mmole sodium)
Ureidopenicillins
Their  major  advantages  over  the  carboxypenicillins  are  higher  efficacy  against
Pseudomonas  aeruginosa  and  that  as  monosodium  salts  they  are  safer  in  respect  of
sodium over load. they exhibit saturation kinetics e.g. Piperacillin, Azlocillin.

b. Cephalosporins

Mechanism of action is the same as penicillins so it bactericidal. Addition of various
side  chains  on  the  cephalosporin  molecule  confers  variety  in  pharmakinetic  and
antibacterial activities because the B-lactam ring is protected. The result is a range of
compounds  with  improved  activity  against  G-  organisms  but  having  less  anti-G+
activity, the Cephalosporins resist attack by B-lactamases

Pharmacokinetics: most ceph enter the urine unchanged, cephalosporinsin general
have a t½ of 1-4h, but with exceptions, e.g. ceftriaxone t½8h. Wide distribution in the
body allows treatment of infection at most sites, including bone, soft tissue, muscle
and CSF (in some cases)

Adverse effects

  Allergy (cross allergy with penicillin 10%)
  Sites of IV or IM injection may be painful
  If  continued  for  more  than  2  weeks  may  cause  reversible  thrombocytopenia,

hemolytic anemia, interstitial nephritis or abnormal liver function tests

 The third generation of cephalosporin may predispose to opportunist

infections

generation

Clinical use

 They active against staph infections but the newer cephalosporin are better.
 They active against streptococcus pneumonia and Moraxella catarrhalis but

have lower activity against Hemophilus influenzea and also active against
E.coli.so it can given for treatment of upper and lower RTI, UTI and soft
tissue infection e.g. cephalexin, cefadorxil, cefazolin

generation

 In addition to the uses of 1

gentration they use for community-acquired

pneumonia (not when causal organism is Mycoplasma pneumoniam
legionella or chamydia) e.g cefuroxim.

generation

 The parenteral such as ceftriaxone, cefotaxime, ceftizoxime are used in case of

pneumonia, septicemia and meningitis.

 Oral such as cefixime,and cefpodoxime, proxetil used for upper and lower

RTI and UTI.

c. Carbapenems

The members of this group is widest spectrum of all currently available antibacterial,
they active against G- and G+ aerobic and anaerobic pathogenic bacteria. they resist
to hydrolysis by most B-lactamases e.g. imipenam metabolized by kidney to products
that are potentially toxic to renal tubules; combining imipenem with cilastatin (the
enzyme responsible for its renal metabolism)

Clinical used

1.  intra-abdominal infection,
2.  septicamia,
3.  nosocomial pneumonia.

Side effect GIT upset including nausea, blood disorders, allergic reaction, confusion
and convulsion.
Other carbapenems such as meropenem (not affected by renal dihydropeptidase) and
ertapenem not active against pseudomonas erugnosa

B. Other inhibitors of cell wall synthesis and membrane function

Vancomycin (8h)
Glycopeptide  (peptolide)  acts  on  multiplying  organisms  by  inhibiting  cell  wall
formation  at  a  site  different  from  that  of  the  B-lactam  antibacterials.  vancomycin
activate  against  clostridia  (including  Clostridium  difficile),  almost  all  strains  of
Staphlyococcus  aureus  (including  those  that  produce  B-lactamase  and  meticillin-
resistant  strains),  coagulase-negative  staphylococci.  Viridans  group  streptococci  and
enterococci

Pharmacokinetics: is poorly absorbed from the gut and the I.V. route is necessary for
systemic infections, there being no satisfactory I.M. preparation. It distributes
effectively into body tissues and is excreted in urine.
Clinical

uses:

treatment

pseudomembranous colitis,

combined with

aminoglycoside for treating streptococcal endocarditis in patients who are allergic to
benzylpenicillin.

Adverse effects

  Tinnitus and deafness may arise.
  Nephrotoxicity and allergic reactions also occur.
  Rapid  i.v.  infusion  may  cause  maculopapular  rash  possibly  due  to  histamine

release (the red person syndrome).

C. Other inhibitors of cell wall synthesis and membrane function

Other members of this category is:



Teicoplanin (is similar to vancomycin)



Daptomycin: lipopeptide antibiotic naturally produced by streptomyces
roseosporus with activity against virtually all G+ bacteria.

B- Antibiotics that inhibit protein synthesis

They include the following groups
Aminoglycoside
All aminoglycosides are resemble in their mode of action and in their
pharmacokinetics, therapeutic and toxic properties. The main difference in their range
of antibacterial activity, cross resistance is variable.

Mode of action
Binding  to  ribosome  in  such  a  way  wrong  amino  acid  sequences  enter  into  peptide
chains. The resulting abnormal proteins are fatal to the microbe. So it bactericidal and
exhibit concentration-dependent bacterial killing.

Pharmacokinetic
Aminoglycoside  water  soluble,  not  cross  readly  cell  membrane  or  absorbed  by
intestine.  So  it  is  given  iv  or  im.  The  t½range  from2-5h.  Aminoglycoside  are  active
against  staphylococcus  aureus,  aerobic  G-  organisms  including  almost  all  of  the
enterobacteriaceas
Note aminoglycoside has no activity against anaerobics

Clinical uses

1.  Gastrointestinal -  bacllary infection, particularlly septicemia
2.  Bacterial endocarditis.
3.  Tuberculosis, brucellosis, tulareamia, and plaque.
4.  Topical uses neomycin, framycetin, and Tobramycin for cystic fibrosis.

Adverse effects

1.  Nephrotoxicity
2.  Ototoxicity
3.  Neuromuscular blockade

Individual aminoglycosides

1. Gentamicin
2. Tobramycin is similar to gentamicin; it is more active against most strains of

Pseudomonas aeruginosa and may less nephrotoxic.

3.  Amikacin
4.  Neomycin: it is use locally because it is toxic
5.  Streptomycin: it was the first aminoglycoside discovered and its use is limited

because of the its autotoxicity

6. spectinomycin

Tetracyclines

Mechanism of action
Tetracycline  interfere  with  protein  synthesis  by  interfere  with  ribosome  it    is
bacteriostatic.
Clinical uses
Act of most G+ and G- pathogenic bacteria, but increasing bacterial resistance
  and low innate activity limit clinical use. Tetracycline remain the first choice for
infection with Chlamydia, mycoplasma (pneumonia), and rickettsiae.

Adverse effects
Heart  burn,  nausea  and  vomiting  due  to  gastric  irritation  are  common,  and  attempts
to reduce this with, diarrhea and opportunistic infection.
Disorder of epithelial surfaces, perhaps due partly to vitamin B complex deficiency
and  partly  to  vitamin  B  complex.  Tetracycline  selectively  enter  teeth  and  growing
bone of the fetus and of children.

Individual tetracyclines

 Doxycycline

 Minocycline

 Tetracycline

Macrolides

Mechanism of action
bind to ribosome, so interfere with protein synthesis, (bacteriostatic) is effective
mostly with G+ and less in G-

Clinical use

 Erthomycin is an effective alternative to pencilline allergic patients infected

with staphylococcus and streptococcus.

 Mycoplasma pneumonia in children

 Legionella spp (including legionnair’s disease)

Adverse effects
It is remarkably non toxic but the estolate can cause cholestatic hepatitis, GIT
disturbances (28%) diarrhea and nausea.

Azithromycin

Is effective against a number of important G- including Haemophilus influenzae and
Neisseria gonorrhoeae,and against Chlamydiae, but is a little less effective than
erythromycin against G+ organisms

clinical uses

  Respiratory tract infections
  Soft tissue infections
  Sexually transmitted diseases. Especially genital chlamydia infections
  Travellers’ diarrhea

adverse effects
GIT disorders (9%)

Telithromycin

Is  the  first  of  the  ketolides  which  related  to  macrolides.  It  act  against  most
erthromycin-resistant  strains  of  streptococcus  pneumonia,  Staphylococci,  including
most MRSA.
Adverse effect
Diarrhea  more  than  macrolides,  and  some  patients  experience  transient  visual
disturbance.

Clindamycin
Structurally  a  lincosamide  rather  than  a  macrolide,  is  the  same  as  macrolide  but  it
have efficacy against anaerobes such as Bacteroides fragilis.
Clinical uses

  Staphylococcal bone and joint infections
  Dental infections
  Serious intra-abdominal sepsis
  Toxoplasma
  Severe acne and non sexually transmitted infection

Adverse effect

 Pseudomembranous colitis

٠١

Chlorophenicol

Has a broad spectrum of activity and is primarily bacteriostatic.

Clinical Uses

  Meningitis and brain abscess
  Haemophilus epiglottitis in children.
  Typhoid fever, salmonella septicemia
  Topical administration is effective for bacterial conjunctivitis

Adverse effects

 Systemic use of chloramphenicol is dominated by rare (1 in 18000-100,000

courses) serious aplastic anaemia which is Idiosyncratic reaction.

 Dose-dependent reversible depression of erythrocyte, platelet and leucocyte

formation.

 Grey baby syndrome occurs in neonates as circulatory collapse

Sodium fusidate
Is a steroid antimicrobial that finds use almost exclusively against B-lactamase
producing staphylococci.

Resistant rapidly developed against it by one-step mutation, the drug is combined
with another antistaphylococcal agent

Clinical uses

 Treating severe staphylococcal infections, including osteomyelitis.
 Conjunctivitis

Adverse effects

 Mild gastrointestinal upset is frequent
 Jaundice may develop, particularly with high doses given intravenously

Quinupristin-dalfopristin and linezolid (Resistance to antimicrobials):

Quinupristin-Dalfopristin

Mechanism of action
Is a bactercidal, it act only against G+ bacteria which resist vancomycin

Adverse effects
Injection to peripheral veins frequently causes phlebitis, arthralgia, myalgia

١١

Linezolid
Mechanism of action
A synthetic oxazolinidone, is the first member of this new class. Inhibiting formation
of the initiation  compelx  between transfer RNA,  messenger RNA and the ribosomal
subunits at the first stage of protein synthesis.
Bacteriostatic  against  most  G+  bacteria  including  staphylococci,  streptococci  and
enterococci  resistant  to  other  antimicrobial  agents,  but  is  bactericidal  against
pneumococci.

Adverse effects
Nausea,  Vomiting  and  headache,  Irreversible  peripheral  neuropathy  occur,    Bon
marrow suppression

D- Antibiotics that interferes with nucleic acid

Sulphonamides

Amongst  the  first  successful  chemotherapeutic  agent.  It  usually  combined  with
trimethoprim  because  of  its  adverse  effects  its  use    is  restricted  to  specific
indications

Classification

    Systemic use
    (sulfamethoxazole (sulphonamide)+trimethoprim combination)
1.  urinary tract infection (UTI)
2.  dysentry due to shigellosis

    Topical application
1.  Silver sulfadiazine
2.  Infected burns, leg ulcers.
Side effects
Crystalluria, Hemolytic anemia, Kernicterus , Hypersensitivity

Trimethoprim

Following its extensive use in combination with sulphonamides, trimethoprim has
emerged as a useful broad-specrtrum antimicrobial on its own

Side effect
Skin rash , Anorexia , Nausea, Vomiting , Abdominal pain, and diarrhoea

Quinolones

All the fluoroquinolones are bactericidal. Like aminoglycosides, the

quinolones exhibit concentration-dependent bacterial killing.

Act  principally  by  inhibiting  bacterial  DNA  gyrase,  thus  preventing  the
supercoiling  of    DNA,  a  process  that  is  necessary  for  compacting  chromosomes
into the bacterial cell
It  has  become  common  practice  to  classify  the  fluoroquinolones  into  4
generations.

٢١

  First generation (naldixic acid)
  Second generation (Ciprofloxacin and norfloxacin)
  Third generation (levofloxacin)
  Fourth generation (moxfloxacin)

In general, they are effective against gram-negative organisms, chlamydia, and

mycobacteria. They are effective in the treatment of gonorrhea but not syphilis

The newer agents (for example, levofloxacin and moxifloxacin) also have

good activity against some gram-positive organisms, such as Streptococcus
pneumoniae. Moxifloxacin has activity against many anaerobes.

If used prophylactically before transurethral surgery, fluoroquinolones lower

the incidence of postsurgical urinary tract infections (UTIs).

  Adverse effects
  Gastrointestinal  disorder,  Allergic  reactions,  CNS  effects,  Connective  tissue
problems

Azoles

This group includes

1.  antibacterial and antiprtozoal (Metronidazole and Tinidazole)
2.  antifungal (Fluconazole, itraconazole, clotrimazole)
3.  anthelminthic drugs (Albendazole, Mebendazole)

Metronidazole

Mechanism of action
Is converted into an active form by reduction of its nitro group; this binds to DNA and
prevents nucleic acid formation. It is bactriostatic

Clinical uses (active against a wide range of anaerobic bacteria, and protozoa).

 Treatment of sepsis to which anaerobic organisms, e.g. Bacteriodes spp

and anaerobic cocci

  Antibiotic-associated pseudomembraneous colitis
  Trichomoniasis of the urogenital tract in both sexes
  Amoebiasis(entamoeba histolytica)
  Giardiasis
  Acute ulcerative gingivitis
  Anaerobic vaginosis

Side effects

GIT disorders, allergic reactions, peripheral neuropathy, disulfiram-like effect

Tinidazole

Is very similar to metronidazole but has a longer half life=13 hours. Used as single
dose for treatment of giardiasis, trichomonisasis and acute ulcerative gingivitis

٣١

Rifampicin
has bactericidal activity against the tubercle bacillus.
Mechanism of action
Acts by inhibiting RNA synthesis, In addition to tubercle bacillus it has a wide range
of  antimicrobial  activity.  So  can  used  against  leprosy,  severe  legionnaires’  disease
(with  erythromycin  or  ciprofloxacin)  And  severe  staphylococcus  infection  (with
flucloxacillin or vancomycin).
Note: you should save rifampicin for TB in the third world
Pharmacokinetic
Enter into the CSF when meninges are inflamed is sufficient to maintain therapeutic
concetration at normal doses but transfer is reduced as inflammation subsides.

Is metabolized in the liver Is a very effective enzyme inducer

Adverse reactions Flushing, and itching with or without a rash, Thrombocytopenia,
Hepatitis, Flu-like syndrome, Acute hemolytic anemia, Red discoloration of the urine,
tears, and sputum.