CPT2: Consolidating knowledge on drug classes

Question 1

What is the mode of action of B-lactams such as penicilin?

Advantage of this mode?

Answer 1

Interferes with synthesis of bacterial cell wall peptidoglycan

via Inhibition of transpeptidation enzyme that cross links peptide chains attached to peptidoglycan

This results in weak cell wall and osmotic lysis

• Advantage of this mode of action – they do not kill any cells in the body

Question 2

What are clinical uses of penicillins?

Answer 2

They are effective against gram positive and negative bacteria. Some have a more predominant Gram positve or negative affect depending on the indivual penicillin and specific chains

Clinical use:

• -septicaemia
• -pneumonia
• -meningitis
• -UTI
• -sinusitis
• -bone & joint infections
• -skin & soft tissue infections (e.g. cellulitis, “diabetic foot”)

Question 3

Pharmacokinetics

Answer 3

Pharmacokinetics/routes of admin.

• Benzylpenicillin - not absorbed from gut - given im/iv
• Penicillin V – given orally
• Widely distributed into body fluids - breast milk, across placenta
• elimination mostly renal & occurs rapidly

Question 4

Unwanted effects of penicillins

Answer 4

Unwanted effects:

• Relatively free from direct toxic effects due to selectivity of action on bacterial cells
• Main unwanted effect of penicillin = HYPERSENSITIVITY
• Skin rashes & fever common
• Acute anaphylactic shock

Question 5

Penicilin:

1. Cautions
2. Contra-indications
3. drug interactions

Answer 5

Cautions

• history of allergy, renal impairment

Contraindications

• penicillin hypersensitivity

Drug interactions

• very few
• broad spectrum penicillins may ↑INR if patient on warfarin

Question 6

How does resitance to penicillins develop?

What can be used to avoid this?

Answer 6

Resistance developed due to:

• Production of betalactamases
  
  • These are enzymes which breakdown B-lactam ring in penicillin structure
    
    • Betalactamase inhibitor - Clavulanic acid (Augmentin®/Timentin®)
      
      • Clavulanic acid contains a beta-lactam ring in its structure that binds in an irreversible fashion to beta-lactamases, preventing them from inactivating certain beta-lactam antibiotics, with efficacy in treating susceptible gram-positive and gram-negative infections.
    • Betalactamase-resistant penicillin e.g. flucloxacillin
      
      • Flucloxacillin has an acyl side chain attached to the β-lactam ring, which prevents access of β-lactamase to the ring and makes the drug resistant to inactivation by the enzyme.
• A decrease in permeability of outer membrane occurs in G-ve organisms

Question 7

Indications for cephalsporins?

Answer 7

Broad spectrum AB which are effective against Gram positive and Gram negative bacteria

Clinical uses:

• Septicaemia
• Pneumonia
• Meningitis
• Biliary-tract infections
• UTIs
• Peritonitis

Question 8

Mechanism of action of cephalsporins

Answer 8

Attach to penicillin binding proteins/ transpeptidase enzyme, inhibiting cross-linking of peptide chains. This to interrupt cell wall biosynthesis, leading to weakened cell wall, osmotic lysis and cell death

Question 9

Pharmacokinetics and routes of administration of cephalsporins

Answer 9

The pharmacology of the cephalosporins is similar to that of the penicillin’s.

• Mostly IV/ IM delivery, some oral
• All distribute well in body fluids e.g. breast milk and cross the placenta.
• Cephalosporins penetrate the cerebrospinal fluid poorly unless the meninges are inflamed; cefotaxime and ceftriaxone are suitable cephalosporins for infections of the CNS (e.g. meningitis).
• Excreted renally

Question 10

Cephalsporin:

1. Unwanted side effects
2. Cautions
3. Contraindications

Answer 10

Unwanted side effects

• Hypersensitivity
• Allergies

Cautions: Renal impairment, history of allergies to penicillin and cephalosporins

Contraindicated: Hypersensitivity to cephalosporins

Question 11

Cephalsporin drug interactions

Answer 11

Drug interactions:

• Cephalosporins may increase the chance of bleeding if you’re taking blood-thinning medications (anticoagulants) such as heparin and warfarin.
• Aminoglycosides increase risk of nephrotoxicity

Question 12

Aminoglycoside indications

Answer 12

Active against some Gram positive and many Gram-negative bacteria. Used for aerobic bacteria NOT anaerobic bacteria.

Question 13

Mechanism of action

Answer 13

Mechanism:

• Inhibition of protein synthesis
• Binds to 30s ribosomal subunit and causes a misreading of genetic code

Streptomycin: Binding blocks formation of 30S initiation complex needed to start protein synthesis

Spectinomycin: Inhibits elongation phase. Inhibits normal translocation (movement) of ribosome along mRNA molecule.

Gentamycin, Tobramycin, neomycin: Elongation stopped by preventing binding of elongation factor (EF-G) to ribosome.

Question 14

Route of administration and pharmacokinetics aminoglycosies

Answer 14

• Not absorbed from GUT so must be given via injections (IV/IM)
• Gentamycin most common choice
• Majority excreted by kidneys, small amount in bile
• MUST MONITOR GENTAMYCIN

Question 15

Unwanted side effects of aminoglycosides

Answer 15

Unwanted side effects:

• Nephrotoxicity
• Ototoxicity
• Skin reactions
• Tinnitus

Question 16

Aminoglycoside:

1. Cautions
2. Contraindications

Answer 16

Cautions

• Muscle weakness, renal impairment?
• Used with caution in premature infants because of their renal immaturity. Elderly, impaired renal function, diabetes, auditory vestibular dysfunctions, otitis media.
• history of otitis media, previous use of ototoxic drugs and a genetically determined high sensitivity to aminoglycoside induced ototoxicity, are other main factors which may pre-dispose the patient to toxicity.

Contra-indications

• Myasthenia Gravis
• Hypersensitivity to aminoglycoside

Question 17

Drug interactions with aminoglycosides

Answer 17

(i) Antibacterials: increased risk of nephrotoxicity with cephalosporins notably cephalothin.
(ii) Gentamicin has been known to potentiate anticoagulants such as warfarin and phenindione.
(iii) Antifungals: increased risk of nephrotoxicity with amphotericin B.
(iv) Cholinergics: antagonism of effect of neostigmine and pyridostigmine.
(v) Cyclosporin, cisplatin: increased risk of nephrotoxicity.
(vi) Cytotoxics: increased risk of nephrotoxicity and possible risk of ototoxicity with cisplatin.
(vii) Diuretics: increased risk of ototoxicity with loop diuretics.
(viii) Muscle relaxants: effect of non-depolarising muscle relaxants such as tubocurarine enhanced. Neuromuscular blockade and respiratory paralysis have been reported from administration of aminoglycosides to patients who have received curare-type muscle relaxants during anesthesia.

Question 18

Indications of macrolides

Answer 18

Used to treat Gram positive bacteria. Bactericidal e.g. erythromycin, clarithromycin

Can be alternative to penicillin

Clinical Indications:

• Campylobacter
• Enteritis
• Respiratory infections
• Legionella
• Chlamydial infection
• Non-gonococcal urethritis

1) Upper respiratory tract infections: laryngitis, pharyngitis, sinusitis, secondary infections in colds and influenza, tonsillitis, peritonsillar abscess.
2) Lower respiratory tract infections: acute and chronic bronchitis, tracheitis, pneumonia (lobar pneumonia, bronchopneumonia, primary atypical pneumonia), bronchiectasis, legionnaires disease.
3) Eye infections: blepharitis
4) Ear infections: otitis media and otitis externa, mastoiditis.
5) Oral infections: gingivitis, Vincent’s angina.
6) Skin and soft tissue infections: boils and carbuncles, abscesses, pustular acne, paronychia, impetigo, cellulitis, erysipelas.
7) Gastro-intestinal infections: staphylococcal enterocolitis, cholecytis
8) Other infections: gonorrhoea, syphilis, urethritis, osteomyelitis, lymphogranuloma venereum, diphtheria, prostatis, scarlet fever.
9) Prophylaxis: pre- and post-operative, burns, trauma, rheumatic fever.

Question 19

Macrolide mechanism of action

Answer 19

Binds to specific site on 50S ribosomal subunit and binding stimulates premature dissociation of peptidyl tRNA from ribosomes during protein synthesis

Question 20

Routes of action/ pharmacokinetics

Answer 20

• Excreted primarily in liver
• It is widely distributed throughout body tissues. Little metabolism occurs and only about 5% is excreted in the urine. It is excreted principally by the liver
• IV/ mouth

Question 21

Macrolide unwanted reactions

Answer 21

• Skin reactions
• Allergic reactions
• Nausea, vomiting, diarrhoea
• Jaundice
• Hepatitis

Question 22

Macrolide cautions

Answer 22

• Electrolyte disturbances (predisposition to QT interval), may aggravate myasthenia gravis, predisposition to QT interval prolongation
• Impaired hepatic impairment

Question 23

Macrolide contraindications

Answer 23

• Hypersensitivity to macrolides
• Concomitant use with astemizole, terfenadine, cisapride or pimozide.
• Erythromycin is contraindicated with ergotamine and dihydroergotamine.

Question 24

Drug interactions with macrolides

Answer 24

· Concomitant use of Erythromycin with terfenadine or astemizole is likely to result in an enhanced risk of cardiotoxicity with these drugs. The concomitant use of Erythromycin with either astemizole or terfenadine is therefore contraindicated.

· The metabolism of terfenadine and astemizole is significantly altered when either are taken concomitantly with erythromycin. Rare cases of serious cardiovascular events have been observed, including torsades de pointes, other ventricular arrhythmias and cardiac arrest. Death has been reported with the terfenadine / erythromycin combination.

· Elevated cisapride levels have been reported in patients receiving erythromycin and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and Torsades de pointes.

· Similar effects have been observed with concomitant administration of pimozide and clarithromycin, another macrolide antibiotic.

· Concurrent use of erythromycin and ergotamine or dihydroergotamine has been associated in some patients with acute ergot toxicity characterised by the rapid development of severe peripheral vasospasm and dysaesthesia.

· Increases in serum concentrations of the following drugs metabolised by the cytochrome P450 system may occur when administered concurrently with erythromycin: alfentanil, astemizole, bromocriptine, carbamazepine, cyclosporin, digoxin, dihydroergotamine, disopyramide, ergotamine, hexobarbitone, midazolam, phenytoin, quinidine, tacrolimus, terfenadine, theophylline, triazolam, valproate, and warfarin. Appropriate monitoring should be undertaken and dosage should be adjusted as necessary.

Question 26

Vancomycin:

Class of AB

Mechanism

Answer 26

• Glycopeptides

Vancomycin is a tricyclic glycopeptide antibiotic that inhibits the synthesis of the cell wall in sensitive bacteria by binding with high affinity to the D-alanyl-D-alanine terminus of cell wall precursor units. The drug is slowly bactericidal for dividing microorganisms. In addition, it impairs the permeability of the bacterial cell membrane and RNA synthesis.

Mechanism of Action: Inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminal of the growing peptide chain during cell wall synthesis, resulting in inhibition of the transpeptidase, which prevents further elongation and cross-linking of the peptidoglycan matrix (see glycopeptide pharm)

Question 27

Vancoymycin indications

Answer 27

vancomycin has bactericidal activity against aerobic and anaerobic Gram-positive bacteria including multi-resistant staphylococci. However, there are reports of Staphylococcus aureus with reduced susceptibility to glycopeptides. There are increasing reports of glycopeptide-resistant enterococci. Penetration into cerebrospinal fluid is poor.

Vancomycin is indicated in all age groups for the treatment of the following infections (see sections 4.2, 4.4 and 5.1):

• complicated skin and soft tissue infections (cSSTI)
• bone and joint infections
• community acquired pneumonia (CAP)
• hospital acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP)
• infective endocarditis

Question 28

Vancomycin:

routes of admin/ pharmacokinetics

Answer 28

• Vancomycin is administered intravenously for the treatment of systemic infections.
• Oral available
• Vancomycin diffuses readily across the placenta and is distributed into cord blood. In non-inflamed meninges, vancomycin passes the blood-brain barrier only to a low extent.
• Mostly renally excreted
• Not effected by hepatic impairment
• Vancomycin should not be administered intramuscularly due to the risk of necrosis at the site of administration.

Question 29

Vancoymcin:

Unwanted effects

Answer 29

• The most common adverse reactions are phlebitis, pseudo-allergic reactions and flushing of the upper body (“red-neck syndrome”) in connection with too rapid intravenous use of vancomycin.
• Lowered blood pressure
• Nephrotoxicity

Question 30

Cautions vancoymcin

Answer 30

• Systemic absorption may be enhanced in patients with inflammatory disorders of the intestinal mucosa or with Clostridioides difficile-induced pseudomembranous colitis (increased risk of adverse reactions)
• Elderly
• Renal insufficney
• Peasritatics due to renal immaturity

Question 31

Contraindications vancoymcin

Answer 31

Contraindications:

• Previous hearing loss/ otoxixity
• Hypersensitivity

Question 32

Vancomycin drug interactions

Answer 32

Other potentially nephrotoxic or ototoxic medication

Concurrent or sequential administration of vancomycin with other potentially neurotoxic or/and nephrotoxic active substances particularly gentamycin, amphotericin B, streptomycin, neomycin, kanamycin, amikacin, tobramycin, viomycin, bacitracin, polymyxin B, colistin and cisplatin may potentiate the nephrotoxicity and/or ototoxicity of vancomycin and consequently requires careful monitoring of the patient.

Because of synergic action (e.g. with gentamycin) in these cases the maximum dose of vancomycin has to be restricted to 500 mg every 8 hours.

Anaesthetics

Concurrent administration of vancomycin and anaesthetic agents has been associated with erythema, histamine like flushing and anaphylactoid reactions. This may be reduced if the vancomycin is administered over 60 minutes before anaesthetic induction.

Muscle relaxants

If vancomycin is administered during or directly after surgery, the effect (neuromuscular blockade) of muscle relaxants (such as succinylcholine) concurrently used can be enhanced and prolonged.

Question 33

Vancoymycin monitoring

Answer 33

Recommended for TDM to reduce chance of renal toxicity

Therapeutic trough (minimum) vancomycin blood levels should normally be 10-20 mg/l, depending on the site of infection and susceptibility of the pathogen. Trough values of 15-20 mg/l are usually recommended by clinical laboratories to better cover susceptible-classified pathogens with MIC ≥1 mg/L

Question 34

What is co-trimoxazole made off?

Indications

Answer 34

Sulfamethoxazole and trimethoprim

Co-Trimoxazole tablets are indicated in children (>12 to <18 years old) and adults (>18 years old) for the treatment of the following infections when owing to sensitive organisms (see section 5.1):

• Treatment and prevention of Pneumocystis jirovecii pneumonitis or “PJP”.
• Treatment and prophylaxis of toxoplasmosis.
• Treatment of nocardiosis.

The following infections may be treated with Co-Trimoxazole where there is bacterial evidence of sensitivity to Co-Trimoxazole and good reason to prefer the combination of antibiotics in Co-Trimoxazole to a single antibiotic:

• Acute uncomplicated urinary tract infection.
• Acute otitis media.
• Acute exacerbation of chronic bronchitis.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Question 35

Co-trimoxazole pharmacokinetics and route of admin

Answer 35

Route of administration/ pharmacokinetics:

• Tablet, Oral suspension, Solution for infusion
• 50% protein bound
• Renal excretion primarily

Question 36

Unwantes side effects

Co-trimoxazole

Answer 36

Unwanted side effects:

Co-trimoxazole is associated with rare but serious side effects. Discontinue immediately if blood disorders (including leucopenia, thrombocytopenia, megaloblastic anaemia, eosinophilia) or rash (including Stevens-Johnson syndrome or toxic epidermal necrolysis) develop.

Question 37

Co-trimoxazole:

Cautions

Contraindications

Answer 37

Cautions:

Asthma; avoid in blood disorders (unless under specialist supervision); avoid in infants under 6 weeks (except for treatment or prophylaxis of pneumocystis pneumonia) because of the risk of kernicterus; elderly (increased risk of serious side-effects) (in adults); G6PD deficiency (risk of haemolytic anaemia); maintain adequate fluid intake; predisposition to folate deficiency; predisposition to hyperkalaemia

Contraindications:

Avoid if eGFR less than 15 mL/minute/1.73 m² and if plasma-sulfamethoxazole concentration cannot be monitored.

Question 38

Drug interactions

co-trimoxazole

Answer 38

Drug interactions:

Zidovudine: in some situations, concomitant treatment with zidovudine may increase the risk of haematological adverse reactions to co-trimoxazole. If concomitant treatment is necessary, consideration should be given to monitoring of haematological parameters.

Cyclosporin: reversible deterioration in renal function has been observed in patients treated with co-trimoxazole and ciclosporin following renal transplantation.

Rifampicin: concurrent use of rifampicin and Co-Trimoxazole results in a shortening of the plasma half-life of trimethoprim after a period of about one week. This is not thought to be of clinical significance.

When trimethoprim is administered simultaneously with drugs that form cations at physiological pH, and are also partly excreted by active renal secretion (e.g. procainamide, amantadine), there is the possibility of competitive inhibition of this process which may lead to an increase in plasma concentration of one or both of the drugs.

Diuretics (thiazides): in elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.

Pyrimethamine: occasional reports suggest that patients receiving pyrimethamine as malarial prophylaxis at doses in excess of 25 mg weekly may develop megaloblastic anaemia should co-trimoxazole be prescribed concurrently.

Warfarin: co-trimoxazole has been shown to potentiate the anticoagulant activity of warfarin via stereo-selective inhibition of its metabolism. Sulfamethoxazole may displace warfarin from plasma-albumin protein-binding sites in vitro. Careful control of the anticoagulant therapy during treatment with Co-Trimoxazole is advisable.

Phenytoin: co-trimoxazole prolongs the half-life of phenytoin and if co-administered the prescriber should be alert for excessive phenytoin effect. Close monitoring of the patient’s condition and serum phenytoin levels is advisable.

Digoxin: concomitant use of trimethoprim with digoxin has been shown to increase plasma digoxin levels in a proportion of elderly patients.

Methotrexate: co-trimoxazole may increase the free plasma levels of methotrexate. If Co-Trimoxazole is considered appropriate therapy in patients receiving other anti-folate drugs such as methotrexate, a folate supplement should be considered (see section 4.4).

Trimethoprim interferes with assays for serum methotrexate when dihydrofolate reductase from Lactobacillus casei is used in the assay. No interference occurs if methotrexate is measured by radioimmuno assay.

Lamivudine: administration of trimethoprim/sulfamethoxazole 160 mg/800 mg (co-trimoxazole) causes a 40% increase in lamivudine exposure because of the trimethoprim component. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole.

Interaction with sulphonylurea hypoglycaemic agents is uncommon but potentiation has been reported.

Hyperkalaemia: caution should be exercised in patients taking any other drugs that can cause hyperkalaemia, for example ACE inhibitors, angiotensin receptor blockers and potassium-sparing diuretics such as spironolactone. Concomitant use of trimethoprim-sulfamethoxazole (co-trimoxazole) may result in clinically relevant hyperkalaemia.

Repaglinide: trimethoprim may increase the exposure of repaglinide which may result in hypoglycaemia.

Folinic acid: folinic acid supplementation has been shown to interfere with the antimicrobial efficacy of trimethoprim-sulfamethoxazole. This has been observed in Pneumocystis jirovecii pneumonia prophylaxis and treatment.

Contraceptives: oral contraceptive failures have been reported with antibiotics. The mechanism of this effect has not been elucidated. Women on treatment with antibiotics should temporarily use a barrier method in addition to the oral contraceptive, or choose another method of contraception.

Azathioprine: There are conflicting clinical reports of interactions between azathioprine and trimethoprim-sulfamethoxazole, resulting in serious haematological abnormalities.

Question 39

Mechanism of action of trimethoprim

Mechanism of action of sulfamethoxazole

Answer 39

• Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF). THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis.
• Sulfamethoxazole competitively inhibits dihydropteroate synthase, the enzyme responsible for bacterial conversion of PABA to dihydrofolic acid. Inhibition of this pathway prevents the synthesis of tetrahydrofolate and, ultimately, the synthesis of bacterial purines and DNA, resulting in a bacteriostatic effect.