Principles of Antimicrobial

Pharmacology
Dr Akoko Sokiprim
Introduction:

• The terms antimicrobial, antibiotic, and anti-infective encompass a wide

variety of pharmaceutical agents that include antibacterial, antifungal,
antiviral, and antiparasitic drugs. Of these, antibacterial agents are by
far the most commonly used and thus are the focus of this article,
although similar principles apply to the other agents as well.
• Note that the term “antibacterials”, being the largest and most widely
known and studied class of antimicrobials, is often used
interchangeably with the term “antimicrobials”
• All antibiotics are antimicrobial but not all antimicrobial are antibiotics
ANTIMICROBIAL CREED
• M- Microbiology guides therapy wherever possible
• I- Indications should be evidence based
• N- Narrowest spectrum required
• D- Dosage appropriate to the site and type of infection
• M- Minimize duration of therapy
• E- Ensure monotherapy in most cases
Host Factors to Be Considered in Selection of Antimicrobial
Agents

• Renal and Hepatic Function

• Age
• Genetic Variation
• Pregnancy and Lactation
• History of Allergy or Intolerance
• History of Recent Antimicrobial Use
• Toxicity
• Drug resistance
• Nutritional deficiencies
Benefits of Antimicrobial Therapy to man:

• Reduction of pain and suffering;

• Assurance of continuous growth and reproduction;
• Prevention or minimizing shedding of zoonotic bacteria into the
environment and the food chain;
• Containment of potentially large-scale epidemics that could result in
severe loss of human lives.
ANTIBIOTICS

• They are synthesized from living cell. “Antibiotic” refers to substances

produced by microorganisms that act against another microorganism.
Several ways antibiotics can be used
• Prophylactic- used to prevent infection
• Preemptive- Used to abort infection
• Empiric- Used to provide initial control of infection in the absence of
knowledge of its etiology
• Definitive- Used to definitively cure infection of a known etiology or
its antimicrobial susceptibility
CLASSIFICATION OF
ANTIBACTERIAL AGENTS
Antimicrobials are classified in several ways, including:
• spectrum of activity
• Effect on bacteria
• Mechanism of Action(MOA)
• Chemical structure
Factors guiding choice of empirical use of
antibiotic
• Inappropriate therapy is associated with increased mortality
• Antibiotic therapy must be initiated rapidly
• Site of infection and like hood of antibiotic resistance
• Identify likely pathogen
• Implement source control
• Allergies
• Increased risk of direct toxicity
• Drug-drug interaction
CLASSIFICATION OF
ANTIBACTERIAL AGENTS
Antimicrobials are classified in several ways, including:
• spectrum of activity
• Broad spectrum antibacterials are active against both Gram-positive and Gram-negative
organisms. More water soluble Examples include: tetracyclines, phenicols, fluoroquinolones,
“third-generation” and “fourth-generation” cephalosporins.
• Narrow spectrum antibacterials have limited activity and are primarily only useful against
particular species of microorganisms. For example, glycopeptides and bacitracin are only effective
against Gram-positive bacteria, whereas polymixins are usually only effective against Gram
negative bacteria. Aminoglycosides and sulfonamides are only effective against aerobic organisms,
while nitroimidazoles are generally only effective for anaerobes.
• Very Narrow spectrum antibacterials : β–lactamase resistant. examples include Natecillin,
methicillin etc
• Extended spectrum antibacterials, antipseudomonal : β–lactamase sensitive. Examples include:
Ticarcillin, piperacillin, aziocillin, carbanicillin. They have activity against gram negative rods-
Pseudomonas. They work in synergism with the aminoglycosides.
Effect on bacteria

• Bactericidal drugs are those that kill target organisms. Examples of drugs
include aminoglycosides, cephalosporins, penicillins, and quinolones.
• Bacteriostatic drugs inhibit or delay bacterial growth and replication.
Examples of such include tetracyclines, sulfonamides, and macrolides.
• Some antibiotics can be both bacteriostatic and bactericidal, depending on
the dose, duration of exposure and the state of the invading bacteria. For
example, aminoglycosides, fluoroquinolones, and metronidazole exert
concentration-dependent killing characteristics; their rate of killing increases
as the drug concentration increases.
Mechanism of Action
MOA
Inhibitors of bacterial cell wall
synthesis
Inhibitors of bacterial Protein
Synthesis
Inhibitors of nucleic acid synthesis
Inhibitors of Folic Acid synthesis
Inhibitors of cell membrane
function
Antimicrobial Agent
Penicillin, cephalosporins,
Imepenem/Meropenem,
Aztreonem, Vancomycin
Aminoglycoside, chloramphenicol,
macrolides, tetracyclines,
stroptogramins, linezolid
Fluroquinolones, rifampicin
Sulfonamides, trimethoprim,
pyrimethamine
polymixin B and colistin.
Antibiotic Resistance mechanism
Antimicrobial Agent
Penicillin and Cephalosporin
Primary Mechanism of Resistance
 Production of β–lactamase, which cleaves β–
lactam ring structure
 Change in penicillin binding protein
 Change in the Porin structure by an Efflux pump

Aminoglycosides (Gentamincin, Streptomycin,  Formation of enzyme that inactivates the drug

Amikacin etc)  Conjugation reaction that transfers acetyl
phosphate or adenylyl group, making the drug
more water soluble hence short half life, increased
clearance ,so can not enter the cell.

Macrolides(Erythromycin, clarithromycin and  Formation of methotransferase that alters binding

clindamycin) site on the 50s ribosomal subunits
 Esterases that inhibits the drugs

Tetracyclines  Non selective pump called glycoprotein that

allows cell to pump out tetracycline

Quinolones  Change in number and shape of enzyme

A. Inhibitors of cell wall Synthesis
• Penicillins
• Cephalosporins
• Imepenem/Meropenem
• Aztreonam
• Vancomycin
Common Side effects
• Penicillin
• HSR; interstitial nephritis with methicillin (tubular necrosis), GI distress, Jarisch-
Herxheimer reaction(malaise, fever, joint pain and swelling) in the treatment of syphilis
• Cephalosporin and cephamycin
• HSR, Disulfiram like effect- cefeperazone, cefamandole , hypoprothrombinaemia
• Imepenem/Meropenem
• CNS effects including seizures
• Aztreonam
• FIND OUT???
• Vancomycin
• Redman syndrome, ototoxicity, nephrotoxicity, Type 1 HSR
B. Protein Synthesis Inhibitor
Event
Formation of Initiation complex
Amino Acid Incorporation
Formation of peptide bond
Translocation
Antibiotic and Binging Site
Aminoglycoside (30s)
Linezolid (50s)
Tetracycline (30s)
Dalfopristin/Quinopristin (50s)
Streptogramins
Chloramphenicol (50s)
Macrolides and
Clindamycin(50s)
MOA
Interfers with initiation code
function; blocks association of
50s ribosomal subunit of
mRNA-30s(static); misreading of
code incorporation of wrong
Amino acid(cidal)
Block attachment of Amino Acyl
tRNA to acceptor
Inhibits the activity of peptidyl
transferase( static)
Inhibits translocation of
peptidyl-tRNA from acceptor to
donor site
 Drug of Choice and Common Side effects of
Protein
S/No Drug
synthesis inhibitors
Uses SE
1 Aminoglycosides • Streptomycin in TB
• DOC in Plague, Tuleramia
• Neomycin is used topically;
sometimes used orally for gut
flora and liver concerns to
reduce ammonia
2 Tetracyclines • H.pylori, vibro, chlamydia
• Doxycycline- Prostitis
• Minocycline- Acne
• Demeclocycline- SIADH
3 Chloramphenicol
4
Nephrotoxicity, ototoxicity,
Neuromuscular blockade,
contact dermatitis
Tooth enamel dysplasia, possible
decrease in bone growth in
children
Phototoxicity-> demeclocycline,
doxycycline
GI distress, vestibular
dysfunction->minocycline
CI- Pregnancy
Dose dependent bone marrow
suppression
Grey baby syndrome
 Drug of Choice and Common Side effects of
Protein
S/No Drug
synthesis inhibitors-
Uses
contd
SE
4 Macrolides Erythromycin- gram positive cocci They stimulate motilin receptor
Azithromycin- mycobacterium and cause GI distress, reversible
Avium, *COVID-19 deafness at high doses,
Clarythromycin- mycobacterium Erythromycin- cholestasis
Avium, H.Pylori Jaundice
5. Clindamycin Osteomyelitis Pseudomembranous colitis
which is usually treated with
metronidazole and vancomycin
6. Linezolid Drug resistant pneumonia Bone marrow suppression
7. Quinopristin- Dalfipristin
 C. Inhibitors of Folic acid synthesis
• Sulfonamide
• Trimethoprim
• Pyrimethamine
Pteridine +PABA

↓DHT Synthetase (Sulfunamides inhibits)

Dihydropteroic Acid

+Glutamate ↓

Dihydrotolic Acid

↓Dehydrofolate reductase( Trimetoprim and

pyrimethamine)

Tetrahydrofolic Acid
Sulfonamide

• Due to resistance it is not used alone; synthetic antimicrobial

• Pharmacokinetics:
• It is acetylated by the liver, then excreted by the kidneys. Note: Crystalluria is avoided by taking more water with
medications.
• Has a high protein binding side hence risk for drug-drug interaction and kernicterus in neonates
•
• Uses:
• In combination with dihydrofolate reductase inhibitors
• To decrease resistance and for synergy
• Septrin- DOC in Norcardia; Mycobacterium, Pneumocystic carinii(fungal), toxoplasma gondii- protozoal (SP); gram
negative infection- Ecoli, Salmonella; Strep, Staph, H. Influence.
• Side Effects:
• Hypersensitivity
• Phototoxicity
• GI distress
• Haemolysis in G6PD deficient individual
• Enterocolitis and BMS ( Trimethoprim/Pyrimethamine)
D. Inhibitors of Nucleic Acid
Quinolones

• Examples include : Ofloxacin, levofloxacin, ciprofloxacin

• Pharmacokinetics
• Iron, Ca2+ limits absorption
• Eliminated by the kidneys
• MOA:
• Bactericidal
• Interfere with DNA synthesis
• Inhibits Topoisomerase II( DNA Gyrase) and Topoisomerase IV responsible for separation of DNA replication during cell
division
•
• Uses:
• UTI; STD, PID, Skin/Soft tissue and Bone infections, Diarrhoea, Drug resistant Pneumococci
• Side effects:
• GI Distress, Phototoxicity, rash, Tendonitis, Tendon rupture,
• CVS Effects: increased QT interval, arrhythmias
• Contra Indication: In pregnancy and children
METRONIDAZOLE

• It acts by producing free radicals; decreases glucose uptake and

decreases microtubular structure.
• Used for antiprotozoal infections- Trachoma; DOC for
pseudomembranous colitis, Amebiasis, giardiasis,Trichomoniasis;
Intestinal nematode.
• Side Effects include: Stomatitis, metallic taste in mouth, cystitis,
nausea, diarrhoea, Disulfiram like reaction, reversible peripheral
neuropathy
Anti TB
DRUG MOA SE
Isoniazid (INH)  Inhibits mycolic acid synthesis Hepatitis (Age dependent), peripheral
 High level resistance- Delection of KatG neuritis(use with vitamin B6), Sideroblastic
gene(encode catalase needed for INH anaemia, Haemolysis in G6PD deficiency, SLE
bioactivation) in slow acetylators
 Low level resistance- Delection in inh A gene
encodes acyl carrier protein

Rifampin  Inhibits DNA dependent RNA polymerase Hepatitis, induction of P450, Red-orange
(Nucleic acid inhibitor)<- inhibits translocation metabolites in the urine
 Resistance occurs via change in the enzyme

Ethambutol Inhibits synthesis of arabinogalactan(cell wall Dose dependent retrobulbar

component) neuritis,Decreased visual acuity amd red-green
discrimination
Pyrazinamide Unknown but activated by the bacteria Increase porphyrin synthesis, phototoxicity,
rash, myalgia, Hepatitis, hyperuricaemia
ANTIFUNG
AL
Antifungal Classification based on site of
action
• Alter cell membrane permeability (Pore formation) examples include:
Azoles, Polyenes, Allylamines
• Block β Glucan synthesis (essential cell wall component) examples:-
Echinocandins
• Block Nucleic acid synthesis (competes with a natural substrate in
enzymatic process inhibiting cell growth) example:-Flucytosine
• Microtubule function disruption(fungostatic):- Griseofulvin
ANTIFUNGAL
• Polyenes(Amphotericin B, Nystatin)
• Azoles
• Imidazoles- Ketoconazole, miconazole, clotrimazoles, Fenticonazole,
Isaconazole, butoconazole
• Triazoles- Fluconazole, itraconazole, variconazole, Posaconazole,
Isavuconazole
• Allylamine (Terbinafine)
• Echinocandins(Caspofungin)
• Flucytosine
• Griseofulvin
Site of Drug Action-1
Site of drug action-2
AntiHelminthics
• Benzimidazole
• Inhibits mitochondrial malate reductase; reduce glucose uptake; uncoupling of oxidative
phosphorylation; Binds to B-tubulin to inhibit microtubule polymerization
• Uses: Nematodes
• Diethylcarbamazin
• Uses: W. Bancrofti, B, Malayi, L.Loa
• CI: Onchocerciasis
• Ivermectin
• Uses: Onchocerciasis, COVID-19
• SE: mazzoti reaction due to death of microfilarial worm
• Niclosamide
• 2nd DOC for taenia
AntiHelminthics
• Oxaminiquine
• 2nd DOC for schistosoma spp
• Piperazine
• Acts on GABA receptor agonist, increases chloride in the worm causing
hyperpolarization and flaccid paralysis.
• Praziquantel
• Increase calcium influx, Increase vacuolization
• Uses most cestodes (tapeworm) and trematodes (flukes)
• Pyrantel Pamoate
• NM agonist leading to spastic paralysis
• Uses: Most intestinal nematode(pin worm)
•ANTIVIRAL
AGENT
Introduction

• To fully understand the pharmacology of antiviral agents, its

important to understand the viral replication pathway.

• A quick summary will be that Viral adsorption ->

Penetration -> Viral Uncoating -> Nucleic Acid Synthesis -
>late Protein synthesis and processing ->Viral packaging
and assembly -> Viral Release.
• In each of these steps the antiviral agent significantly
affects it to inhibit the virus process. Enfurvitide fusion
inhibitor will act receptor specific to it to inhibit the viral
cell from attaching to the host cell. Amantadine,
Rimantidine are known to inhibit Viral adsorption,
pentration and uncoating and effective for influenza
viruses.
Introduction

• A large group of the antiviral agents are seen to inhibit the

nucleic acid synthesis, especially the drugs used for
HIV/AIDS management. Examples of drugs that inhibit viral
DNA polymerases include- Acyclovir, foscarnet, ganciclovir;
drugs that inhibit viral RNA polymerases- Foscarnet,
Ribavirin. Inhibitors of viral reverse transcriptases include-
zidovudine, stavudine, efavirenz, didanosine, zalcitabine,
nevirapine.
• The other group where drug action are seen are inhibition
of aspartate protease- lopinavir/ Ritonavir, indinavir,
sequinavir etc and inhibitors of viral neuramidases-
Oseltamivir, Zanamivir .
•AntiViral
Agents for HIV
Management
AntiViral Agents for HIV Management

• Commonly, 2NRTIs are used with 1 Protease inhibitor.

These combination is referred to as Highly Active Anti
Retroviral Therapy(HAART).
• HAART decreases viral RNA, Improves CD4 count, and this
in turn reduces opportunistic infections.
• HAART strategy is to reduce resistance and improve immune state
HIV Pathway
Classification of Anti HIV Agent
• NsRTI
• Zidovudine, Emtricitabine, stavudine, abacavir, tenofovir, didanosine
• NNRTI
• Efavirenz, Nevirapine,delavirdine
• PI
• Indinavir, ritonavir, lopinavir, atazanavir
• Fusion Inhibitor
• Enfurvitide
• Entry Inhibitor
• Maraviroc
• Integrase Inhibitor
• Dolutegravir, Raltegravir
• NtRTI
• Tenoforvir, Adefovir

• READ UP on newer agents

MOA of Antiviral Agents
Nucleotide Reverse Transcriptase
Inhibitors side effects
Drug Side Effects
Zidovudine Haematotoxicity; Headache,
asthenia,myalgia, myopathy,
peripheral neuropathy
Didanosine Pancreatitis, peripheral
neuropathy, hyperuricaemia, liver
dysfunction
Zalcitabine GI distress, Pancreatitis,
peripheral neuropathy,
Neutropaenia and rash
Stavudine peripheral neuropathy,
myelosuppression
Lamivudine Least toxic with GI distress and
neutropaenia
Assignment

• a)What are First line drugs used in the management of

HIV/AIDS in
• Children
• Adult
• Prophylaxis
• b) What are the differences between a Nucleoside reverse
transcriptase and a nucleotide reverse transcriptase
inhibitor.

• SUBMIT 14DAYS FROM TODAY AS SOFTCOPY THROUGH

THE COURSE REP
• ENSURE TO INCLUDE REFERENCES
•Anti-
Influenza
agents
Pathophysiology of Influenza virus
Classification

• Matrix 2 (M2) Ion channel inhibitor

• Amantadine
• Rimantadine(longer half life)
• Endonuclease inhibitor
• Baloxavir
• Neuraminidase inhibitors
• Oseltamivir
• Peramivir
• Zanamivir
MOA of Anti Influenza agents
•Anti-
Hepatitis
agents
Pathway of HBV
Anti HBV Pharmacology
• Drugs are either nucleoside and nucleotide analogues
• Examples : Entecavir, lamivudine, Adefovir, telbivudine, Tenofovir
• MOA:
• Inhibit multiple functions of the HBV polymerase by competing with natural
substrates for incorporating into developing viral DNA strands resulting in
chain termination and inhibiting of reverse transcription and syntheses of the
Virus
• SE
Pathway of HCV
MOA of HCV Agents
Read Up
• Sofosbuvir: Nucloetide analogue leading to inhibition of RNA
polymerase
• Simeprevir: Hepatitis C Protease inhibitor
•ANTIMALARIALS
Cycle
Causal&
Radical
Clinical
Supressive
Sporozoitocides
Gametocides
prophylaxis
cure
prophylaxis
Drugs site
of action
Classification of Antimalarial Drugs
• 4- Aminoquinolines
• Chloroquine, Amodiaquine
• Quinoline-methanol
• Mefloquine
• Acridine
• Mepacrine(Atabrine, Quinacrine)
• Cinchona Alkaloid
• Quinine
• Biguanides
• Proquanil (Chloroguanide)
• Diaminipyrimidines
• Pyrimethamine
• 8-Aminoquinoline
• Primaquine, Bulaquine Sulfadoxine, Dapsone
• Sulfonamides and sulfone
• Sulfadoxine, Sulfamethopyrazine, Dapsone
• Tetracyclines
• Tetracycline, Doxycycline
• Sesquiterpine lactones
• Artesunate, Artemether, Arteether
Anticancer Drugs
• Anticancer drugs may be Cell cycle specific or non specific
• Principles and Hypothesis
• Log-kill hypothesis
• Cytotoxic actions of anticancer drug follow 1st order kinetics eg Tumor 1010 ,drug kill
99.999%
• Growth fraction
• Cytotoxic drugs are more effective against tumors that have a high growth fraction(Large
percentage actively dividing).
• Cell cycle specificity
• Drugs that act specifically on phases of the cell cycle specific (CCS)and are more effective in
tumours with high growth fraction(leukaemia, lymphomas)
• Drugs that are CCS(may bind to and damage DNA) can be used in tumour with low growth
fraction as well as tumour with high growth fraction
• Examples:
• S Phase Specific: cytarabin, 6 mercaptopurine, 6 thioguanine, methotrexate, hydroxyurea,
etoposide
• G3 Phase : Alkylating agent, Antitumor antibiotics, Nitrosurea, Cisplantin
• G2 Phase: Bleomycin
• M Phase: Vinblastin, vincristine, Paclitaxel

• Cell cycle non specific

• Examples:
• Cyclophosphamide- Haemorrhagic cystitis
• Cisplantin- Does not cause BMS; FIND OUT
• Procarbazine- BMS
• Doxorubicin- BMS, dilated Cardiomyopathy
• Methotrexate- BMS
• 5FU- BMS
DRUG MOA USES SE
Cyclophosphamide Alkylating Agent Ovarian, Breast cancer
Cisplatin Alkylating Agent
Procarbazine Alkylating Agent
Doxorubicin
Methothrexate
5FU BMS, GI Irritation,
Alopecia
6 Mercaptopurine
Bleomycin
Vincristine,
Vinblastin,Paclitaxel
Toxicity of Anticancer Drugs
• Rapidly proliferating such as the bone marrow, GI tract mucosa, hair
follicles and gonads are most sensitive to cytotoxic cell specific drugs
• BMS is dose limiting
• Doses are carefully titrated to avoid neutropaenia and
thrombocytopaenia
Toxicity of Anticancer Drugs
Toxicity Drugs
Renal Cisplatin, methotrexate
Hepatic 6MP, busulfan, cyclophosphamide
Pulmonary Bleomycin, Busulfan, procarbazin
Cardiac Doxorubicin, Daunorubicin
Neurologic Vincristin, Paclitaxel, Cisplatin
Immunosuppressive Cyclophosphamide, methotrexate
Others Cyclophosphamide- Haemorrhagic cystitis; Procarbazine- Leukaemia; Asparaginase-
Pancreatitis
Resistance
Mechanism Drug or Drug Group
Change in sensitivity(or increase level) or decrease Etoposide, methotrexate, Vinca Alkaloid, Estrogfen
binding affinity of target Enzyme or receptor and androgen receptors
Thank you for staying awake