grSummary of drugs

Anti-bacterial

Cancer

Viruses

Fungus

Antimalarial drugs

Antibacterial agents

Protein synthesis 30S

Tetracyclines

General facts

Discovered in 1940s, are bacteriostatic

Derived from streptomyces

2nd generation: doxycycline and minocycline

Mechanism of Action

• Goes through the outer membrane via passive diffusion and active transport in G+
• Transverses through OmpF & OmpC porin channels in G -
• Then active transport through cell membrane
• Binds to the 30S subunit: Competes with the Aminoacyl-tRNA on the A site, and thereby prevents formation of the polypeptide chain

Pharmacokinetics:

• Administration: Orally or IV (only doxycycline in clinical setting)
• Absorption - administered with dairy products - can form nonabsorbable chelates with mg, Fe & Ai cations.
• Distribution - Everywhere. Undergoes calcification in teeth, bones and tumours with high Ca2+ content. Only doxycycline & minocycline cross BBB
• Metabolism - first generation not metabolized, 2nd generation partly metabolised in liver
• Excretion - by kidneys in urine, accumulates in renal failure. 2nd gen: excreted in bile.

Spectrum of activity

• Very wide, including G+ & G- bacteria, mycoplasma, rickettsiae, spirochaetes, protozoa
• Were taken preventatively and therefore there has become a lot of resistance

Clinical use

• Peptic ulcer disease
• Lymes disease (e.g. borellia)
• Mycoplasma pnemoniae
• Cholera
• Chlamydia
• etc…

Side effects

• GIT disturbances: nausea, bowel upset
• Deposition in calcified tissues: lead to discoloration and hyperplasia of teeth
• Photosensitivty: can cause sunburn
• Hepatotoxicity: rare, pregnenant women
• Vestibular disfunction: dizziness, vertigo & tinnitus
• Haematolofic toxicity
• Fanconi syndrom: electrolyte imbalance
• Pseudotumor cerebri: hypertension in brain - headaches & blurred vision

Resistance

• Big problem!
• Efflux pumps
• Enzymatic inactivation, a bit rarer
• Ribosomol protection: blocking the tetracyclines from binding, distorting structure or dislodging tetracycline.

Protein synthesis 50S

Chloramphenicol

General facts

• First broad-specturm antibiotic discovered
• Chloromycetin in the US
• Bacteriostatic, but can be bactericidal at high concentrations

Mechanism of Action

• penetrates through facilitated diffusion
• Binds to the 50S subunit, causing a conformational change. This will slow the binding of the tRNA to the A-site, and inhibits transpeptidation process (movement of peptide chain).
• Obs - it competes in binding the ribosome with macrolides & lincosamide, so combination treatments have no benefits.

Pharmacokinetics:

• Administration - oral, IV or topical as ear & eye drops
• Activation - the oral & IV are prodrugs: they are activated by hydrolysis in small intestine (oral) or converted to active form in circulation (IV).
• Absorption - oral rapidly absorbed from GIT, peak blood conc. after 2hrs. IV, serum levels are dependent on the patients metabolism. Plasma T1/2 ~4hrs.
• Distribution - everywhere, 60% in blood because binds to plasma proteins, can accumulate in braintissue.
• Metabolism - by hepatic glucuronyl transferase into inactive metabolites in liver
• Excretion - renal tube and excrete in bile, ~10% of drug excreted unchanged

Spectrum of activity

• Salmonella
• Chlamydiae
• Rickettsiae
• Spirochetes
• Mycoplasma

Clinical use

• Last resort drug for serious & life-threatening infections because there’s high toxicity
• Systemic uses include typhoid fever, cholera, anaerobic infections etc.

Side effects

• Anemias, causes bone marrow depression
• Drug interactions, can inhibit some liver drugs and therefore prevent the metabolism of drugs
• Occular irritation and toxicity, can cause blurred vision
• Grey baby syndrome
• Gastrointestinal disturbances, e.g. nasuea, vomiting, diarreah
• CNS effects, e.g. headach, depression, confusion

Resistance

• Enzymatic inactivation through acetylation by chloramphenicol acetyltransferase
• Decreased permeability
• Presences / increased presence in efflux pumps: the bacteria pumps out the drug
• Ribosomal protection, due to modification of binding site

Nucleic synthesis

There’s five ways to interfere with nucleic acid synthesis:

1. Alteration of the base-pairing properties of the template
2. Inhibition of either DNA or RNA polymerase
3. Direct effects on DNA itself
4. Inhibition of DNA gyrase
5. Inhibition of Nucleotide synthesis

Acridines: Alternation of base-pairing properties

General facts

• are intercalating agents: meaning that they produce mutations by getting in between adjacent bases in the DNA, and therefore distorting the 3D structure of the helix.
• Examples are proflavine and acriflavine

Mechanism of Action

• Intercalcates into the DNA
• This doubles the distance between the pairs, causing disruption in DNA synthesis
• Causes frameshift mutations and therefore prevents bacterial reproduction

Clinical use

• Used as antibacterial agent during WW2 against G+ bacteria
• Only as a surface disinfectant or treating superficial wounds nowadays.

Toxicity

• Super toxic - cannot be used systemically.
• It’s carcinogenic in animals, because it gets into your DNA and stays there.

Actinomycin D: Inhibition of DNA or RNA polymerase

General facts

• E.g. actinomycin D, pilcamycin
• Intercalcalating

Mechanism of Action

• Intercalates in the minor groove of double helix between guanine-cytosine. GC-rich regions are proliferation genes
• It interferes with movement of RNA polymerase along the gene, therefore preventing transcription and triggers apoptosis of the cell

Spectrum of activity

• High inhibitory effect on gram +, - and some fungi

Clinical use

• Not first line of treatment due to strong side effects
• Used in combination with surgery for treatment of Wilm’s tumour and other rare diseases
• Part of combination chemotherapy, because it kills all cells in your body :-)

Pharmacokinetics

• Administration: By I.V.
• Absorption: Poorly via GT, therefore IV
• Distribution - Fast into tissue, mostly in bone marrow & nucleated cells. No BBB, but crosses placenta. Is free floating in blood.
• Metabolism - minimally metabolized in liver
• Excretion - excreted via bile (50-90%) and urine

Side effects

• Irritating to tissues
• Gastrointestinal distress - abdominal pain, diarrhoea, nasua etc
• Hepatotoxicity - can cause liver injury
• Haematological toxicity - can cause bone marrow depression
• Carinogenicity - can cause cancer
• hypersensitivity

Metronidazole: Direct effects on DNA itself

General facts

Is an alkylating agent: contains a chemical group that produces highly reactive carbonium ion intermediates. These carbonium ions react with nucleophilic substances in the cell - especially with electron donors. It forms covalent bonds with bases in the DNA. It therefore prevents replication.

• Sold under name: Flagyl
• Bactericidal

Mechanism of Action

• Diffuses across the cell membrane via passive diffusion
• Is activated through reduction by intracellular transport proteins. This only happens in anaerobic cells - it is therefore relatively safe for humans.
• The nitro group of the molecule binds to the DNA. This causes loss of helical DNA and strand breakage -- preventing synthesis.

Spectrum of activity

• Used for anaerobic infections
• Can be used for antiprotozoal
• There’s not much effect on human cells or aerobic cells

Clinical use

• Used against anaerobic cocci and bacilli infections, e.g. of wound abscess and combination therapy against helicobacter pylori.
• Used against anaerobic infections after bowel surgery
• Etc

Pharmacokinetics:

• Administration - Oral & IV
• Absorption - Rapidly absorbed after both
• Distribution - Oral bioaailability almost 100%! Goes everywhere, crosses BBB, <20% bound to plasma proteins
• Metabolism - Hepatic metabolism (30-60%)
• Excretion - Kidneys in urine, some fecal elimination

Side effects

• GIT distress; cramps & nausea
• Neurotoxicity: dizziness, vertigo, seizures, numbness
• Dermatological effects: Rashes & hives
• Steven-Johnson syndrome: rare flu-like syndromes with rashes, only found in combination with mebendazole

Drug interactions

• Acohol: causing nausea, vomiting, cramps
• Anticoagulants - prolonged prothrombin time
• Cimetidine - prologons the half life metronidazole

Resistance

• Rare, can be caused by specific resistance genes.

Fluoroquinolones: Inhibition of DNA Gyrase

General facts

DNA gyrase is an essential bacterial enzyme that unwinds the helix. It’s a type of topoisomerase.

• Most used: Ciprofloxacin
• Bactericidal

Mechanism of Action

• Inhibits topoisomerases/DNA gyrases
• This will cause permanent gaps in the DNA strands. This will cause repair by exonucleases. This will lead to breakdown of DNA and irreversible damage → death of bacteria.
• In G negative: Topoisomerase II, that normally prevents supercoiling of the DNA. Here: There’s no effect on transcription or replication
• In G positive: Topoisomerase IV, that normally relaxes supercoiled DNA

Pharmacokinetics:

• Administration - Orally, IV and Topically
• Absorption - Well absorbed from GIT (80-90%). With IV, dietary supplements containing Fe, Zn or Ca interfere with absorption.
• Distribution - Widely distributed in all tissues. Plasma binding 10-40%, Penetration of BBB is low (except ofloxacin which crosses BBB well). Can accumulate in macrophages.
• Metabolism - Hepatic metabolism
• Excretion - primarily renal - renal failure can cause toxicity. Some bile excretion.

Spectrum of activity

• Against G- organisms
• E.g. mycobacteria & legionella pneumophila
• Less active against G+ due to resistance

Clinical use:

There is a lot of different types of fluoroquinolones that have different clinical uses:

• Nalidixic acid, norfloxacin: urinary tract infections
• Ciprofloxacin: main one used, mostly against G- bacteria, e.g. chlamydia.
• Levofloxacin: used against streptococcus pneumoniae e.g.

Side effects

• GIT: Diarrhoea
• CNS effects: Headache, dizziness, confusion
• Allergic reactions: rashes, photosensiticty etc
• Reversible arthopathy: Get’s into the joints, breaking them?
• Abnormal bone & cartilage formation: you don’t give the drug to children and pregnant women

Resistance

• Altered target: there are chromosomal mutations in the bacterial genes that lowers the affinity for fluoroquinolones.
• Decrease accumulation: due to porin channels and efflux pumps.

Sulphonamides: Inhibition of nucleotide (folic acid) synthesis

General facts

• Folic acids is needed for synthesis of precursors of DNA & RNA in both humans and bacteria.
• Bacteria make their own from PABA (p-amino-benzoix acid)
• Humans used precursors that we take up from our diet
• We are therefore unaffected by anti-folate metabolites
• Sulphonamides have given rise to several important drugs, e.g. acetazolmide
• They are dicided into different groups, depending on if they are short-, intermediate-, or long-lasting.
• Bacteriostatic, but can be bactericidal at higher concentrations

Mechanism of Action

• The sulphonamide part of the molecule resembles PABA.
• It inhibits binding of PABA with dihydropteroate synthase → prevents the forming of dihydropteroic acid (DHF) → inhibits folic acid formation

Pharmacokinetics:

• Administration - Orally, IV, topically (used for bad burns) - can cause reactions
• Absorption - Most cross GIT, reach max concentrations in plasma 4-6hrs
• Distribution - up to 90% bound to albumin, widely distributed, crosses BBB, crosses placenta, reaches inflammatory sites
• Metabolism - acetylated and conjugated primarily in liver
• Excretion - unchanged are eliminated via glomerular filtration & secretion, can be excreted in breast milk

Spectrum of activity

• Baceteriostatic against many G+ and G- bacteria
• E.g. streptococcus and enterobacteria, chlamydia etc
• → stimulates growth of rickettsiae

Clinical use

• Only used in drug combination:
• Urinary tract infections: sulfasalazine
• GIT disorders: Sulfasalazine for IBS :O

Side effects

• GIT: Nausea, vomiting diarreah
• Nephrotoxicity - renal obstruction
• Hypersensiticity reactions - rashes, fever
• Haematological toxicity: anemia
• Kerniciterus: bilirubin induced brain dysfunction
• Hepatotoxicity: jaundice

Resistance

• Many are resistant to sulphonamides
• The resistant bacteria either: overproduce PABA, have low affinity for the DHS enzyme, adopt an alternative pathway in folate metabolism or loss of permeability to sulphonamides.
• When a bacteria becomes resistant to one sulphonamide: it becomes resistant to all :(

Disorganizers of cell membrane structure

The membrane active agents are classified into three groups:

1. Affecting membrane structure: e.g. tyrocidine and polymyxins
2. Affecting membrane permeability: e.g. valinomycin & nonactin
3. Affecting membrane associated enzyme systems

Tyrocidines & Gramicidin A

General facts

• Both contain the amino acid Ornithine which is not found in human proteins.
• Affects membrane structure

Mechanism of Action

• It acts as an ionophore on the bacterial cell wall - meaning that it facilitates ion transport over the membrane.
• It creates a sort of pore in which cl- and Na+ move through.
• This will disrupt the cell homeostasis, and therefore results in bacterial cell death.

Side effects

• Since it is not selective, it will cause toxicity in humans as well

Clinical use

• Primarly used in the treatment of infected surface wounds

Polymyxins

Mechanism of Action

• Binds to lipopolysaccharides in the bacterial membranes: thereby affecting membrane permeability.
• This leads to a displacement of Mg2+ and Ca2+ ions.
• Affects membrane structure (1)

Pharmacokinetics

• Mostly administered intramuscularly for CNS infections due to bad absorption from the gut.

Clinical use & spectrum of activity

• Selective bactericidal activity against Gram negative bacteria, especially for pseudomonas and coliforms.
• Not used that much because highly toxic

Side effects

• Highly toxic
• Causes nephrotoxicity

Inhibitors of cell way synthesis

Beta-lactams

General facts

• There are four categories of beta-lactams:

1. Penicillin
2. Cephalosporins
3. Monobactams
4. Carbapenems

• The beta-lactam has a Thiazolidine ring which is its weakness - the bacteria will break this bond which will cause resistance.

Mechanism of Action

• Interfere with synthesis of cell wall component peptidoglycan
• It inhibits the transpeptidation enzyme which cross-links peptide chains attached to the backbone of the peptidoglycan
• Leads to a weaker cell, and therefore cell death
• Is bactericidal

Pharmacokinetics

• AD: Oral, I.V. (for some types), I.M.
• AB: Not great in GIT, food decreases absorption - should be taken on an empty stomach.
• DI: wide, no BBB (except meninges are inflamed),
• ME: metabolism can occur with impaired renal function, oxacillin metabolized in liver.
• EX: Plasma T1/2 < 2 hours, kidney

Spectrum of activity

Is dependent on which type of penicillin:

• Natural penicillin: Against non-beta-lactamase producing G+, e.g. streptococci
• Anti-staphylococcal penicillin: Active against beta-lactamase producing staphylococci
• Aminopenicillins: More active against enterococci and listeria monocytogenes
• Extended-spectrum penicillin: Great activity against G- bacteria, escp. pseudomonas species.

Clinical uses

• Are enormous, but there’s a lot of resistance.
• Examples are: pneumonia, streptococcal, meningitis, UTI’s etc

Side effects

• Hypersensiticty reactions (~10%!)
• GIT disturbances
• Nephritis
• Neurotoxicity: can provoke seizures
• Hematologic toxicity: decreased coagulation
• Some drug intereactions e.g. contraceptive pill

Cephalosporins

General facts

• Related structurally & functionally to penicillins
• Bactericidal

Spectrum of activity

• More active against gram-negative
• They have no activity against LAME - listeria, atypicals (mycoplasma&chlamydia), MRSA and Enterococci.

Pharmacokinetics

• Route of administration: Injection
• Distribution: well distributed, can cross BBB
• Elimination: kidneys

Clinical uses

• pneumonia, sepsis, UTI, meningitis etc
• Treatment of unknown bacteria
• For bacteria which are resistance to beta-lactams

Side effects

• Allergic reactions
• Cross reactivity with penicillin
• GIT disturbances
• Hematological effects (lower prothrombin)

Anti-mycobacterial drugs

Inhibition of cell wall components

Isoniazid

General facts

• Used only for tuberculosis treatment
• Bacteriostatic on resting organisms
• bactericidal for actively growing tubercle bacilli

Mechanism of action

• Inhibits the synthesis of mycolic acids, which are an essential part of mycobacterial cell wall.
• It combines with an enzyme in the mycobacteria leading to disorganization of the metabolism of the cell
• → cell death

Pharmacokinetics

• AD: orally
• AB: very bioavailable
• Distribution: is wide, crosses BBB, 20% bound to plasma proteins
• Metabolism: acetylation
• Excretion: kidneys

Side effects

• Are dose dependant:
• Allergic reactions
• Fever, vasculitis,
• CNS toxicity: memory loss, psychosis, seizures
• Peripheral neuropathy
• Hepatotoxicity

Resistance

• Is normally oxidized in the mycobacterial by catalase-peroxidase which will make it work in them. However, absences of the enzyme will lead to resistance.
• There’s also reduced penetration & over-expression of carrier proteins which leads to resistance.

Ethambutol

Mechanism of action

• Inhibits synthesis of arabinogalactan (part of the cell wall).

Spectrum of activity

• only effective against mycobacteria
• Is sometimes used as a first line anti-tuberculous drug together with isoniaxid, rifampicin and pyrazinamide

Side effects

• are uncommon
• Optic neuritis (is dose related and connected to renal failure)
• GIT dsiturbances

Resistance

• Is common if it’s used alone
• Found in mutations of arabinosyl transgerases

Inhibition of RNA synthesis

Rifampicin

General facts

• bactericidal for mycobacteria

Mechanism of Action

• Binds to beta-subunit of bacterial DNA-dependent RNA polymerase
• Creates a conformational changes that the polymerase have trouble binding to the initiation sequence of DNA
• Thereby it inhibits RNA synthesis

Clinical uses

• As a combination therapy for tuberculosis
• Used for leprosy

Side effects

• Turns urine, tears and sweat orange lol
• Rashes
• Fever
• GIT disturbances
• Jaundice
• Low platelet count

Resistance

• Mutations of RNA polymerase so rifampicin cannot bind