Clinical pharmacology and renal disease Flashcards
what does low clearance of a drug mean?
high systemic exposure (and vice versa)
Adverse events often related to over-exposure
very often total clearance is only renal a function of:
(i) Glomerular filtration
(ii) Tubular secretion
(iii) Reabsorption
what is filtration of a drug dependent on?
Drug must be in plasma (and free)
(Depends on Vd and protein binding)
Kidney perfusion
Health of kidney – specifically glomerulus
ClGF = fu x GFR
No secretion/reabsorption – this is total renal clearance
Creatine (and inulin) – measure GFR
Size and charge affect filtration
where does active renal secretion mainly occur?
Mainly occurs in proximal tubule
Weak acid/base; Nucleoside; P-glycoprotein transporters
Can clear drugs too large to filter
Again depends on blood flow; free drug
Saturable
β-lactam antibiotics; frusemide; ranitidine; ribavirin; verapamil
If renal clearance > GFR: secretion
passive tubular reabsorption?
Lipid solubility
Concentration gradient
Dehydration (highly concentrated urine = highly concentrated drug)!
Depends on urine flow rate
But also pH
Back to ion trapping again!
Urinary alkalisation can be used to increase clearance of weak acids
(Aspirin)
Vd influences [plasma]
Drug cleared from plasma
Redistributes from other tissues
(Compartments)
Shift from peripheral compartments to plasma
[Plasma] maintained (declines slowly)
Drugs with high Vd have longer elimination half-life
Half-life = 0.693 x (Vd/Clearance)
Some drugs are given as a single dose
Most are not
how is drug dosage kept at a steady state?
Peaks and troughs (think ‘safety’)
Can take a while to get to steady state
(4-5 half-lives)
Vd used to calculate loading dose
LD = (Cp x Vd)/F
MD rate = (Cp x Cl)/F
what is nephrotoxicity, how can drugs lead to it?
Polypharmacy
Synergistic effect: examples
Worse if already renally impaired
Existing renal disease
Age
Other illness:
Patients often volume depleted, dehydrated, hypotensive
Need to be aware of drugs that are (potentially) nephrotoxic
…and of combinations that might cause problems
Need to understand importance of measuring GFR (risk factor)
Know which drugs can be used safely with low GFR
Recognise drugs with narrow TI
Realise importance of reducing loading/maintenance doses…
…increasing dosing interval
Importance of TDM
who is most at risk for nephrotoxicity?
Who is most at risk? Old; very young; polypharmacy; co-morbidities (diabetes, CHF, intravascular volume depletion); ethnicity
Usually involves specific, accurate, precise and timely determinations of drugs (or metabolites) in biological samples collected at appropriate times (eg steady state)
Can employ the measurement of a biological parameter as a surrogate or end-point marker of effect (eg INR)
Consideration of ‘normal range’ and ‘exposure target’
Appropriate adjustment of dose… for as long as necessary
what need to be considered when prescribing in renal impairment?
Risk/benefit ratio
Severity of toxicity and possible adverse effects
Availability of TDM
Do:
Use drugs with a wide therapeutic range
Consider changing to a drug that isn’t renally excreted
Reduce the dose of the drug
Reduce the dosing frequency
what is the relationship between GFR and total drug clearance?
what is acute kidney injury?
Clinical syndrome
Often multiple contributory factors
Pre-renal (reduced cardiac output; hypovolaemia; drugs that affect BP and blood volume)
Intra-renal (direct drug effects; vascular; inflammatory)
Post-renal (structural obstruction; inc intratubular pressure; decreased GFR)
Pre-renal most common (NICE CKS)
what are common causes of AKI?
Acute tubular necrosis
Common cause of AKI
Death of tubular epithelial cells
Glomerulonephritis
Collection of conditions
Glomerular damage
Inflammatory
Interstitial nephritis
Inflammatory: tubulointerstitial space
how do drugs exert nephrotoxic effects?
what drugs cause acute tubular necrosis?
Drugs: Aminoglycoside antibiotics; amphotericin B; cisplatin; statins/cyclosporin; colistimethate; foscarnet; radiocontrast agents (rare)
what drugs cause acute interstitial nephritis?
Drugs: penicillins; cephalosporin; cocaine; omeprazole; herbal medicines
what drgs cause glomerulonephritis?
Thrombotic microangiopathy: cyclosporin; tacrolimus; chemotherapeutic agents; thienopyridines; 19 oestrogen-containing oral contraceptives
what drugs lead to post renal?
Drug-associated obstruction of urine outflow due to crystal formation can occur at several sites within the tubules or the ureters
Outside the ureters due to retroperitoneal fibrosis caused by agents such as methysergide
Acyclovir, Indinavir
Sulfonamides
Triamterene
Methotrexate
Vitamin C in large doses (due to oxalate crystals)
describe nephrotic syndrome vs nephritic syndrome?
describe nephrotic syndrome?
The nephrotic syndrome is due to glomerular dysfunction and marked by heavy proteinuria
Hypoalbuminaemia
ADME – reduced drug binding – higher effective drug dose
Drugs implicated include DMARDs like gold and penicillinamine
NSAIDs
interferon
captopril
what is the epidemoiology for AKI?
20% of hospital admissions due to AKI are drug related
Most occur in the community
AKI affects:
7% of hospitalized patients
20-30% of critically ill patients
Aminoglycoside antibiotics (severe gram-negative sepsis) cause nephrotoxicity in 10% to 20% of therapeutic courses
Mechanism: proximal tubular injury leading to cell necrosis
Main cause of AKI in secondary care
what are NSAIDS?
NSAIDs widely used in primary and secondary care
Commonly bought OTC
7% of reported cases of AKI; 35% of drug-induced AKI in the general population
Two forms of AKI
Haemodynamically mediated
Immune mediated (acute interstitial nephritis)
summary?
Drugs frequently induce renal disease
Asymptomatic increase in urea and creatinine
Fluid and electrolyte abnormalities
Acute tubular necrosis; acute and chronic interstitial nephritis
AKI due to ATN is the most common and is due to aminoglycosides
Avoid nephrotoxic drugs: volume depleted/hypotensive patients with pre-existing renal disease; patients receiving other nephrotoxic agents
Most common in:
Elderly; sick; polypharmacy
