DOSES AND DRUG INTERACTIONS OF PENICILLINS

DOSES OF PENICILLINS:

Most commonly used penicillins have the following doses:

* BENZYL PENICILLIN:

By intramuscular or slow intravenous injection or by infusion:

2.4-4.8 g daily in divided doses

* PHENOXYMETHYL PENICILLIN:

By oral route:

500 mg every 6 hours up to 1g every 6 hours in severe infections.

* AMOXICILLIN:

By mouth:

250mg every 8 hours, doubled in severe infections.

* AMPICILLIN:

By mouth:

0.25g-1g every 6 hours, at least 30 minutes before food.

DRUG INTERACTIONS OF PENICILLINS:

* ALLOPURINOL:

Increased risk of rash when amoxicillin and ampicillin are given with allopurinol.

* ANTIBACTERIALS:

Absorption of phenoxy methyl penicillin is reduced by neomycin.

* CYTOTOXICS:

Penicillins reduce excretion of methotrexate (increased risk of toxicity).

* MUSCLE RELAXANTS:

Piperacillin enhances effects of non depolarising muscle relaxants and suxamethonium.

* PROBENECID:

Excretion of penicillins is reduced by probenecid.

* SULFINPYRAZONE:

Excretion of penicillins is reduced by sulfinpyrazone.

USES AND ADVERSE EFFECTS OF PENICILLINS

USES OF PENICILLINS:

These are used to treat the following infections:

(1) Urinary tract infections.

(2) Septicemia.

(3) Meningitis.

(4) Intra-abdominal infection.

(5) Gonorrhea

(6) Syphilis

(7) Pneumonia.

(8) Respiratory infections.

(9) Ear, nose and throat infections.

(10) Skin and soft tissues infections.

ADVERSE REACTIONS:

(1) Hypersensitivity.

(2) Diarrhea.

(3) Nephritis.

(4) Neurotoxicity.

(5) Hematologic toxicities.

(6) Cation toxicities.

PHARMACOKINETICS AND RESISTANCE OF PENICILLINS

PHARMACOKINETICS OF PENICILLINS:

(1) ADMINISTRATION:

The route of administration is determined by the stability of drug to gastric acid and by the severity of infection.

(a) ROUTES OF ADMINISTRATION:

Ticarcillin, carbenicillin and piperacillin and the combinations of ampicillin with sulbactam, ticarcillin and clavulanic acid and piperacillin with tazobactam must be administered intravenously or intramuscularly.

INTRAVENOUS ADMINISTRATION

INTRAMUSCULAR ADMINISTRATION

Penicillin V, amoxicillin and carbenicillin are only available as oral preparations.

ORAL ADMINISTRATION

(b) Depot forms:

Procaine Penicillin G and benzathine Penicillin G are administered intramuscularly and serve as depot forms. They are slowly absorbed into the circulation.

(2) ABSORPTION:

Most of the penicillins are incompletely absorbed after oral adminstration and they reach the intestine in sufficient amounts to affect the compsition of intestinal flora. However, amoxicillin is completely absorbed. Absorption of all the penicillinase- resistant penicillins is decreased by food in the stomach, because gastric emptying time is lengthened and the drugs are destroyed in an acidic environment. Therefore, they must be administered thirty to sixty minutes before meals. Other penicillins are less affected by food.

(3) DISTRIBUTION:

All penicillins cross the placental barrier but none has been shown to be teratogenic. However, peneteration into bone and cerbebrospinal fluid is insufficient for therapy unless these sites are inflammed. However, distribution through out the body is good.

(4) METABOLISM:

Metabolism of penicillins is insignificant, but metabolism of Penicillin G has been shown to occur in patients with impaired renal function.

(5) EXCRETION:

The primary route of excretion is tubular secretory systemof kidney as well as by glomerular filtration. Nafcillin is eliminated primarily through biliary route. Penicillins are also excreted into breast milk and into saliva.

GLOMERULAR FILTRATION

RESISTANCE OF PENICILLINS:

Natural resistance to penicillins occur in organisms that either lack a peptidoglycan cell wall or have cell walls that are impermeable to the drugs. Acquired resistance to the penicillins by plasmid transfer has become a significant clinical problem because an organism may become resistant to several antibiotics at the same time due to the acqiurement of plasmid that encodes resistance to multiple agents. Multiplication of such an organism will lead to increased dissemination of resistance genes. By obtaining a resistance plasmid, bacteria may acquire one or more of the following properties:

(1) Beta lactamase activity.

(2) Decreased permeability to the drug.

(3) Altered Penicillin binding Proteins.

PENICILLINS MECHANISM OF ACTION AND ANTIMICROBIAL SPECTRUM

MECHANISM OF ACTION OF PENICILLIN:

All penicillins produce their bactericidal effect by inhibition of bacterial cell wall synthesis. The mechanism of action of penicillin is as follows:

(1) PENICILLIN BINDING PROTEINS:

Penicillins inactivate numerous proteins on the bacterial cell membrane. The penicillin binding proteins are the bacterial enymes involved in the synthesis of cell wall and in the maintenance of morphologic features of bacterium. Exposure to these antibiotics can therefore not only prevent cell wall synthesis but also lead to lysis of bacteria.

(2) INHIBITION OF TRANSPEPTIDASE:

Some penicillin binding proteins catalyze formation of the cross linkages between peptidoglycan chains. Penicillins inhibit this transpeptidase catalyzed reaction, thus inhibiting the formation of cross linkages essential for cell wall integrity.

(3) PRODUCTION OF AUTOLYSINS:

Many bacteria, particularly gram positive cocci produce autolysins that pariticpate in normal remodeling of bacterial cell wall. In the presence of a penicillin, the degradative action of the autolysins proceeds in the absence of cell wall synthesis.

Thus, the antibacterial effect of the penicillin is the result of both inhibition of cell wall synthesis and destruction of existing cell wall by autolysins.

ANTIMICROBIAL SPECTRUM OF PENICILLINS:

(1) PENICILLIN G:

Penicillin G is a basis for therapy of infections caused by number of gram positive and gram negative cocci, gram positive bacilli and spirochetes.

GRAM POSITIVE AND GRAM NEGATIVE COCCI

GRAM POSITIVE BACILLI

SPIROCHETES

(2) PENICILLIN V:

Penicillin V has a spectrum similar to Penicillin G.

(3) METHICILLIN, NAFICILLIN, OXACILLIN, CLOXACILLIN AND DICLOXACILLIN:

These are penicillinase-resistant penicillins. Their use is restricted to treatment of infections caused by penicillinase-producing staphylococci.

(4) AMPLICILLIN AND AMOXICILLIN:

They have an antibacterial spectrum similar to Penicillin G but are more effective against gram negative bacilli (Escherichia coli, Haemophilus influenzae, Proteus mirabilis and Salmonella typhi). Ampicillin is the drug of choice for gram positve bacillus (Listeria monocytogenes).

ESCHERICHIA COLI

HAEMOPHILUS INFLUENZAE


SALMONELLA TYPHI

LISTERIA MONOCYTOGENES

(5) CARBENICILLIN, TICARCILLIN, PIPERACILLIN:

These are active against Pseudomonas aeruginosa, Haemophilus influenzae, Proteus mirabilis, Escherichia coli and Enterobacter species.

PSEUDOMONAS AERUGINOSA

PROTEUS MIRABILIS

ENTEROBACTER SPECIES

PENICILLINS INTRODUCTION AND CLASSIFICATION

Penicillin is a mixture of non toxic antibiotic acids especially produced by molds of the genus Penicillium and have powerful bacteriostatic effect against gram positive bacteria (staphylococci, gonococci and pneumococci). They are also bactericidal.

MOLDS OF THE GENUS PENICILLIUM

STRUCTURE OF PENICILLIN:

CLASSIFICATION:

The classification of penicillins is as follows:

(1) Amoxicillin.

(2) Ampicillin.

(3) Cloxacillin.

(4) Dicloxacillin.

(5) Carbenicillin.

(6) Methicillin.

(7) Nafcillin.

(8) Oxacillin.

(9) Penicillin G.

(10) Penicillin V.

(11) Piperacillin.

(12) Ticarcillin.

PENICILLIN G:

It is also known as benzyl penicillin. It is more active against gram negative organisms and some anaerobes. It is given parenterally. Penicillin G is indicated for treatment of infections due to susceptible organisms. Penicillin G is acid labile and should be taken on an empty stomach.

PENICILLIN V:

It is also known as Phenoxy methyl penicillin. It is less active against gram negative organisms and some anaerobes. It is given orally as it is more resistant to hydrolysis by acid gastric secretions. Penicillin V is indicated for treatment of mild to moderately severe infections. It is more stable in the presence of gastric acid so it can also be taken with meals.