S11: antimicrobials & anticoagulants Flashcards
Describe the three types of antibiotic resistance
Multi-drug resistant: non-susceptibility to at least one agent in three or more antimicrobial categories
Extensively-drug resistant: non-susceptibility to at least one agent in all but two or fewer antimicrobial categories
Pan-drug resistant: non-susceptibility to all agents in all antimicrobial categories
Outline antimicrobial stewardship
Appropriate use of antimicrobials
Optical clinical outcomes
Minimize toxicity and other adverse events
Reduce the costs of healthcare for infections
Limit the selection for antimicrobial resistant strains
List interventions for antimicrobial stewardship
Persuasive – education, consensus, audit
Restrictive – prior authorisation, automatic stop orders
Structural – computerised records, rapid lab tests, expert systems
Describe the mechanism of action of beta-lactam antibiotics
Interfere with the synthesis of the bacterial cell wall peptidoglycan
Generally bactericidal
1) Antibiotic binds to penicillin-binding protein on bacteria
2) Inhibits the transpeptidation enzyme (links peptidoglycan chains to form rigid cell walls)
3) Disruption of bacterial cell wall structure
List types of beta-lactam antibiotics
Penicillins
Cephalosporins
Carbapenems
Describe co-amoxiclav and the role of clavulanic acid
Clavulanic acid = beta-lactamase inhibitor
Beta-lactamase = enzyme used by certain bacteria to break down beta-lactam antibiotic molecular structure
Clavulanic acid is commonly combined with amoxicillin to overcome these issue
List indications for Penicillins
Bacterial meningitis Bone and joint infections Skin and soft tissue infections Otitis media Pneumonia UTIs STIs
List examples of cephalosporins
Cefalexin
Ceftriaxone
List indications for cephalosporins
Septicaemia Pneumonia Meningitis Biliary tract infections UTIs (especially in pregnancy or in patients unresponsive to other drugs) Sinusitis
List antibacterials affecting bacterial protein synthesis
Tetracyclines
Macrolides
Nitrofurans
Describe tetracyclines, giving examples
Following intake into susceptible organisms by active transport, tetracyclines act by inhibiting protein synthesis -> bind to bacterial ribosomes, preventing binding of tRNA to it, thus preventing the initiation of protein synthesis
Examples: doxycycline
Bacteriostatic
List indications and warnings for tetracyclines
Respiratory tract infections Acne Chlamydia Lyme disease Warning: shouldn’t be given to children <12 years, pregnant & breastfeeding women -> causes staining of developing teeth
Describe macrolides, giving examples
Inhibit bacterial protein synthesis by an effect on ribosomal translocation
Bactericidal/bacteriostatic
Examples: clarithromycin, azithromycin
Antimicrobial spectrum very similar to penicillin, also active against atypical respiratory pathogens
Describe the mechanism of action of nitrofurans
Works by being reduced to multiple reactive intermediates by nitrofuran reductase inside the bacterial cell
These intermediates then attack ribosomal and DNA proteins within the bacteria, as well as inhibit the citric acid cycle
Why is nitrofurantoin one of the first-line agents in treating UTIs?
Up to 50% of an oral dose nitrofurantoin is excreted in the urine in unchanged form
Allows nitrofurantoin to concentrate within urine, leading to more effective levels within the bladder than in other tissue compartments
Describe quinolones, giving examples
Inhibit topoisomerase II, the enzyme that produces a negative supercoil in DNA & thus permits transcription or replication
Common examples: ciprofloxacin
Good cover of gram negative organisms, as well as atypical organisms & gram positives
List indications and side effects of quinolones
Indications: complicated UTIs, pseudomonas aeruginosa, gonorrhoea
Side effects: tendinitis +/- rupture, aortic dissection, CNS effects
List antibacterial agents that interfere with folate synthesis or action
Sulfonamides
Trimethoprim
Describe trimethoprim
Folate antagonist: reversible inhibitor of dihydrofolate reductase, which is responsible for the production of tetrahydrofolic acid -> necessary for biosynthesis of bacterial nucleic acids & proteins
Binds with much stronger affinity to bacterial dihydrofolate reductase than human
Bacteriostatic/bactericidal
Indications: UTIs (careful when prescribing to reproductive age females)
Describe metronidazole
Exact mechanism of action has not been established
It is thought anaerobes and protozoa metabolise metronidazole, making it active in blocking nucleic acid synthesis
Has disulfiram-like action, so patients must avoid using alcohol when on the antibiotic
List types of antivirals
Aciclovir (DNA polymerase inhibitors)
Oseltamivir (neuraminidase inhibitors)
Describe aciclovir
Predominately activated in infected cells, as the viral enzyme thymidine kinase is more effective at phosphorylating it, thus activating it
Fully phosphorylated form then inhibits viral DNA polymerase
Indications: herpes simplex virus (genital herpes, encephalitis), varicella zoster (chicken pox, shingles)
Describe aciclovir in herpes simplex virus
NICE guidelines do not recommend routine prescribing of oral antivirals for healthy people with herpes labialis, more lenient when dealing with immunocompromised patients
Genital herpes: episodic antiviral treatment if attacks are infrequent (<6/year), suppressive antiviral treatment if attacks are more frequent (>6/year)/causing psychological distress/affecting the person’s social life
Describe CYP450 enzymes
Present in most tissues of the body, but predominantly the liver
Essential for the metabolism of many medications and hormones
Most significant: CYP3A4 & CYP2D6
Describe CYP450 inhibitors and inducers
Inhibitors block the metabolic activity of one or more CYP450 enzymes
- Means the drugs usually broken down by the inhibited enzyme will be metabolised at a slower rate, essentially leading to an ‘overdose’
Inducers increase the enzyme synthesis of one or more CYP450 enzymes
- Means more enzyme, therefore the drugs broken down by said enzyme break down quicker, leading to below therapeutic levels in the blood
Give examples of CYP450 inhibitors & inducers
1) Warfarin metabolised by CYP2C9, metronidazole is a CYP2C9 inhibitor; inhibiting this enzyme will slow down the metabolism of warfarin, therefore allowing higher circulating conc. of warfarin to persist
2) Verapamil and simvastatin both metabolised by CYP3A4, macrolides inhibit CYP3A4; leads to overdosing of verapamil and simvastatin
Describe enterohepatic circulation and relationship with oral antibiotics
Begins with drug absorption across the intestine into portal circulation, followed by uptake into hepatocytes
Drug or conjugated metabolites are secreted into bile & returned to the intestine, where drug can be reabsorbed into circulation
Oral antibiotics – can eliminate gut flora, thus lessen/prevent EHR
-important interaction with oral contraceptives -> lower rates of EHR, lower blood concentrations of oestrogen/progesterone = increased risk of becoming pregnant
Describe haemostasis and thrombosis
Limits bleeding following injury – adhesion and activation of platelets and fibrin formation
Thrombosis: pathological haemostasis
Venous and intracardiac thrombosis driven largely by coagulation cascade & fibrin, arterial thrombus mainly platelet rich
Describe heparins
Produced naturally in mast cells and vascular endothelium
Unfractionated heparins are large
Low molecular weight heparins
Inhibit coagulation in vitro and in vivo -> enhance antithrombin III activity
Describe mechanism of action of unfractionated heparin
Typically i.v. bolus and infusion, s.c. for prophylaxis with low bioavailability
Binding to antithrombin causing conformational change & increased activity of ATIII
To catalyse inhibition of thrombin, heparin needs to simultaneously bind ATIII & IIa
Xa inhibition only needs ATIII binding
Describe low molecular weight heparins
Almost always s.c., bioavailability > 90%, longer half life
More predictable dose response as dose not bind to endothelial cells, plasma proteins & macrophages
Don’t inactivate thrombin, inhibition of Xa specifically by enhancing ATIII activity
Fondaparinux – synthetic pentasaccharide selectively inhibits Xa by enhancing ATIII
List examples of low molecular heparins
Dalteparin
Enoxaparin
Describe pharmacokinetics of heparins
Large negatively charged molecules – poor GI absorption
Given parenterally – i.v. or s.c.
UFH – metabolism dose dependant, monitor with aPTT, used for moderate renal impairment and v. fine control
LMWH – generally no monitoring, used in most situations
List indications for heparins
Prevention of VTE
During pregnancy used as do not cross the placenta – monitored with caution
ACS – PCI and non PCI patients
What are the adverse effects, warnings, contraindications and important drug interactions of heparins?
Adverse effects: bruising, bleeding, heparin induced thrombocytopenia, hyperkalaemia, osteoporosis
Warnings, contraindications: clotting disorders, renal impairment
Important drug interactions: other antithrombotic drugs, ACEi/ARB, amiloride, spironolactone
Describe protamine sulphate
Forms inactive complex with heparin, given i.v.
Dissociates heparin from ATIII, irreversible binding
Much greater with UFH than LMWH, no effect on fondaparinux
Describe vitamin K antagonists
Inhibit activation of vitamin K dependant clotting factors
Inhibits conversion of vitamin K to active reduced form – competitive inhibition of VKOR
Delay in onset of action as circulating active clotting factors present for several days -> must be cleared and replaced with non-carboxylated forms
e.g. warfarin
List indications for warfarin
VTE – PE, DVT & secondary prevention, superficial vein thrombosis
Atrial fibrillation with high risk of stroke
Heart valve replacement bioprosthetic & some mechanical
Generally used in longer term anticoagulation compared to heparins
Describe pharmacokinetics of warfarin
Good GI absorption & taken orally
Functional CYP2C9 polymorphisms contribute to significant inter-individual variability
Racemic mixture of two enantiomers – R & S which have different potency and metabolised differently
Crosses the placenta – avoided in 1st (teratogenic) and 3rd (haemorrhage) trimesters
Response affected by CYP2C9 and others, vitamin K intake & alcohol
Describe warfarin adverse drug reactions and reversal
Bleeding – epistaxis and spontaneous retroperitoneal bleeding
Most effective antidote is vitamin K
Perioperative anticoagulation needs to be considered
Outline warfarin drug-drug interactions
Majority potentiate anticoagulant action but some decrease effects
- inhibition of hepatic metabolism especially CYP2C9: amiodarone, clopidogrel, intoxicating dose of alcohol
- reduce vitamin K by eliminating gut bacteria involved in production: cephalosporin antibiotics
- displacement of warfarin from plasma albumin: NSAIDs & drugs that decrease GI absorption of vitamin K (likely increase INR)
- acceleration of warfarin metabolism: barbiturates, phenytoin, rifampicin, St Johns Wort (likely decrease INR)
Describe warfarin use and INR
Monitoring required due to huge variation in patient response
INR 2.5 – DVT, PE & AF
INR 3.0-3.5 – recurrent DVT/PE in patients currently receiving anticoagulation
Describe DOACs
Direct Xa: inhibit both free Xa and that bound with ATIII, do not directly effect thrombin – hepatic metabolism & excreted partly by kidneys
Direct IIa: selective direct competitive thrombin inhibitor, both circulating and thrombin bound IIa
Oral administration, standard dosing & little to no direct monitoring required
List examples of DOACs
Direct Xa: apixaban, edoxaban & rivaroxaban
Direct IIa: dabigatran
What are the adverse effects, warnings, contraindications and important drug interactions of DOACs?
Adverse effects: bleeding
Warnings, contraindications: dabigatran contraindicated in low creatinine clearance (<30mL/min), others are at very low creatinine clearance (<15mL/min), avoid in pregnancy/breastfeeding
Important drug interactions: [plasma] reduced by carbamazepine, phenytoin & barbiturates, [plasma] increased by macrolides
Antidotes – andexanet and idarucizumab
Which antihypertensive drug is least likely to exacerbate hyperkalaemia observed in some patients taking heparin?
Heparin has been showed to inhibit aldosterone action so spironolactone & ramipril would increase risk of hyperkalaemia
Amlodipine
