Transplant immunosuppression - Calcineruin inhibitor, inhibits T cell activation Causes eye inflammation, diarrhoea, renal problems, peptic ulcers

Transplant immunosuppression (Graft rejection prophylaxis) - Blocks T-cell activation - Blocks transcription for genes that encode IL-3, 4, 5 and TNFa which are involved in early T-cell activation

Immunosuppressive - Inhibits purine synthesis - Inhibits B and T cells - Prodrug of 6-mercaptopurine Causes bone marrow depression, leucopenia, pancreatitis, thrombocytopenia, rarely causes anaemia

UTIs Antibiotic - Inhibits dihydrofolate reductase (inhibits folic acid synthesis) - Prevents conversion of DHF-THF in thymidine synthesis pathway Contraindicated in patients with blood disorders Causes diarrhoea, electrolyte imbalance, fungal overgrowth, headache, nausea and vomiting

UtIs - Inhibits the citric acid cycle and the synthesis of DNA, RNA and protein Second-line to trimethoprim

PPT 1 Flashcards by Charlotte Wickstone

Ciclosporin

Transplant immunosuppression

Calcineruin inhibitor, inhibits T cell activation

Causes eye inflammation, diarrhoea, renal problems, peptic ulcers

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Tacrolimus

Transplant immunosuppression

(Graft rejection prophylaxis)

Blocks T-cell activation
Blocks transcription for genes that encode IL-3, 4, 5 and TNFa which are involved in early T-cell activation

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Azathioprine

Immunosuppressive

Inhibits purine synthesis
Inhibits B and T cells
Prodrug of 6-mercaptopurine

Causes bone marrow depression, leucopenia, pancreatitis, thrombocytopenia, rarely causes anaemia

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Cyclophosphamide

Alkylating agent

Used to treat immune-based renal disease

Causes: agranulocytosis, alopecia, anaemia, bone marrow disorders, sperm abnormalities

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Trimethoprim

UTIs

Antibiotic

Inhibits dihydrofolate reductase (inhibits folic acid synthesis)
Prevents conversion of DHF-THF in thymidine synthesis pathway

Contraindicated in patients with blood disorders

Causes diarrhoea, electrolyte imbalance, fungal overgrowth, headache, nausea and vomiting

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Nitrofurantoin

UtIs

Inhibits the citric acid cycle and the synthesis of DNA, RNA and protein

Second-line to trimethoprim

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Co-amoxiclav

PYELONEPHRITIS

Infections due to beta-lactamase-producing strains

Clavulanic acid + amoxicillin

Clavuanic acid = beta-lactamase inhibitor

Amoxicillin = beta lactam antibiotic

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Ciprofloxacin

Second generation fluoroquinolone used for pyelonephrits

Acts on bacterial topoisomerase II (DNA gyrase) and prevents DNA supercoiling

*Can induce convulsions, especially if taken with NSAIDs (the case with all quinolones)

Also associated with tendon damage

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Gentamicin

Mainly used for serious gram - infections

Aminoglycoside, 30s inhibitor

Associated with ear and kidney damage

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What is beta lactamase?

Enzymes produced by bacteria that allow resistance to beta lactam antibioitcs

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How do beta lactam antibioitcs work?

Contain a beta-lactam ring in their molecular structure
Bacteriocidal, work by blockingthe snynthesis of the peptidoglycan layer of the bacterial cell wall
The peptidoglycan layer is needed for structual integrity, particularly in gram + organisms

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What is usually prescribed in conjunction with amoxicillin?

Clauvanic acid - beta-lactamase inhibitor thus blocking beta-lactamase degredation

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List the antibiotics with a beta lactam ring

Penicillins
Cephalosporins
Carbapanems
Monobactams

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According to kidney disease improving global outcomes (KDIGO) what are the stages of AKI?

●Stage 1 – Increase in serum creatinine to 1.5 to 1.9 times baseline, or increase in serum creatinine by ≥0.3 mg/dL (≥26.5 micromol/L), or reduction in urine output to <0.5 mL/kg per hour for 6 to 12 hours.

● Stage 2 – Increase in serum creatinine to 2.0 to 2.9 times baseline, or reduction in urine output to <0.5 mL/kg per hour for ≥12 hours.

● Stage 3 – Increase in serum creatinine to 3.0 times baseline, or increase in serum creatinine to ≥4.0 mg/dL (≥353.6 micromol/L), or reduction in urine output to <0.3 mL/kg per hour for ≥24 hours, or anuria for ≥12 hours, or the initiation of renal replacement therapy, or, in patients <18 years, decrease in eGFR to <35 mL/min per 1.73 m2.

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According to kidney disease improving global outcomes, how is AKI defined?

●Increase in serum creatinine by ≥0.3 mg/dL (≥26.5 micromol/L) within 48 hours; or

●Increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the prior seven days; or

●Urine volume <0.5 mL/kg/h for six hours

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What immediate therapy would be given to a patient presenting with AKI?

IV fluid therapy – fluid challenge = 500 mL 0.9% NaCl over fifteen minutes

Withdrawal of nephrotoxins

Withholding of hypotensive agents and diuretics

Withhold atorvastatin

What are the key actions to take when dealing with a patient with AKI?

Optimise intra-vascular fluid volume: IV fluids
Optimise BP: withold drugs that alter RAAS and any anti-hypertensives
Correct any hypovolemia
Stop drugs that worsen AKI - DAMN

Diuretics

Ace inhibitors

Metformin

NSAIDs

What is the pathophysiology of urea and creatinine increase in AKI in a patient taking diuretics ?

Reduced circulating volume due to diuretics causing reduced renal perfusion - low perfusion = lack of creatinine and urea removal thus higher levels in the blood

What are the pre-renal causes of AKI?

Hypovolemia
Decreased cardiac output
Congestive heart failure
Liver failure
NSAIDs
ACEi/ ARBs
Cyclosporine

What are the post-renal causes of AKI?

Bladder outlet obstruction
Bilateral pelvoureteral obstruction

Which drugs interfere with renal perfusion?

ACEi
ARBs
NSAIDs

In the setting of AKI, what GFR be assumed when presciring drugs metabolised and excreted by the kidney?

< 10 mL/min/1.73m2

Which drugs should be stopped or have a dose-reduction in AKI?

Fractionated heparins
Opiates
Penicillin-based antibiotics
Sulfonylurea-based hypoglycemic drugs
Aciclovir
Metformin

Which drugs aggravate hyperkalemia?

Trimethorprim
Spironolactone
Amiloride

Which drugs require close monitoring in AKI?

1. Warfarin 2. Aminoglycosides (gentamycin, tobramycin) 3. Lithium

What is the gold-standard filtration marker for measuring GFR?

Inulin - a physiologically inert substance that is freely filtered at the glomerulusand is not secreted, reabsorbed, synthesised or metabolised by the kidney. \*infrequently used because inulin is expensive and difficult to assay and requires a strict protocol

Which methods are most commonly used to measure eGFR?

- Measurement of creatinine clearance - Cockcroft-Gault equation

Which is more accurate, eGFR or Cockcroft-Gault?

Cockcroft-Gault because it adds weight into the equation

Are the majority of drugs affected by impaired renal function?

No, 80% of drugs are eliminated by hepatic metabolism - The kidneys provide the major route of elimination for water soluble drugs and water soluble metabolites

How do aminoglycosides work?

Bind to the 30s ribosomal subunit and cause: - Misreading of the mRNA codon leading to errors in amino-acid sequencing - Disruption of polysomes, reducing the efficiency of protein synthesis - Inhibition of the translocation of tRNA between A and P ribosomal binding sites

What are the adverse effects of gentamicin? (aminoglycoside)

- Damage to cochlear and vestibular apparatus - Renal damage Aminoglycosides such as gentamicin are readily taken up by renal proximal tubule cells and cochlear cells

How is gentamycin administered?

Not readily absorbed from the GI tract and is therefore given IV (sometimes IM) Highly hydrophilic and not distributed into body fat When calculatingtyhe dose for administration, excess body fat should be taken into consideration - mass without excess fat = ideal body weight Usually calculate a dose using the lower end of actual body weight

Which order kinetics does gentamicin follow?

First order kinetics - excreted unmodified by the kidneys, cleared from the blood at a rate proportional to its concentration

Describe first order kinetics

Rate of elimination is proportional to the amount of drug in the body - the higher the concentration the greater the amount of drug eliminated per unit time After a dose the level in the blood decays exponentially

What types of regimens are commonly used when prescribing gentamicin in the UK?

1. Pharmacokinetic: tailored to the patient 2. Extended interval: single daily dosing, total daily dose is given in one go, little-no tissue accumulation occurs meaning risk of toxicity is reduced, maximises bacterial kill whilst minimising toxicity AKA Hartford dosing A study in 1996 showed the two regimens are equally efficacious but extended interval gentamicin had reduced toxicity

What is a Hartford nomogram?

Used to plot gentamicin concentration

What should be remembered when taking blood to monitor gentamicin concentration?

1. Don'#t take blood from same line used to administer gentamicin 2. Take one blood sample of 10mL 6-14hrs after the start of the first infusion 3. Take the blood into a plain tube (clotted blood) 4. Document on the microbiology request form the exact time and date the infusion was set up and the exact date and time the sample was taken

In extended-interval dosing for gentamicin, what is the initial dose?

7mg/kg