Clinical pharmacology Flashcards
What might build up in the blood as a result of impaired renal function?
Active drug
Toxic or active metabolites
Which well known drug has a high therapeutic index and low toxicity?
Benzylpenicillin
Which well known drugs have a narrow therapeutic index and have the potential to cause toxicity and/or death?
Gentamicin - may cause renal or ototoxicity (ear)
Digoxin - risk of arrhythmias, nausea or death
Lithium - risk of renal toxicity and death
Tacrolimus - risk of renal and CNS toxicity
What factors create worry in regards to patients in hospital?
They are often: Sick Volume depleted Hypotensive Prescribed a large number of potentially renotoxic agents
All factors interact to bring on renal impairment or worsen pre existing renal impairment / toxicity
What damage can drugs cause to the urinary system?
Drugs can cause acute renal injury, intra-renal obstruction, interstitial nephritis, nephrotic syndrome, and acid-base and fluid electrolytes disorders.
List some changes in renal excretion that will automatically change drug pharmacokinetics or pharmacodynamics
Changes in passive tubular reabsorption or active tubular secretion (due to disease age or drug therapy)
Where are all drugs and their metabolites filtered?
At the glomerulus
If renal impairment means prolongation of half life what care must be taken
Must take care when using drugs with a low therapeutic index in the presence of renal impairment
In a patient with reduced GFR what must you do? (3)
REDUCE DOSAGE
Increase dose interval
TDM Monitor blood levels for toxic drugs like gentamicin, lithium, digoxin, vancomycin
How does renal disease alter the actions of drugs on the brain?
The BBB becomes permeable and the brain becomes more sensitive to tranquillisers, sedatives and opiates
If a patient’s circulatory volume is decreased, which agents may they be more sensitive to?
Antihypertensive agents like ACE inhibitors or alpha-blockers
What are some dramatic changes in pharmacokinetics that can be caused by renal impairment
Increased t1/2 (half life)
Build up of drug or metabolites
Decrease in protein binding. So more free drug available
What are some alterations in pharmacodynamics that can be caused by renal impairment
Increased sensitivity to pharmacological action
Increased sensitivity to toxicity and ADRs
Increased sensitivity to the toxic effects of combined therapy - synergism
What is therapeutic index?
The Therapeutic Index is used to compare the therapeutically effective dose to the toxic dose of a drug.
The larger the therapeutic index (TI), the safer the drug is.
Look
We need to know:
The drugs which may be used safely when eGFR ↓
and which drugs have a narrow therapeutic index
We need to realise the importance of:
Reducing loading dose and maintenance dose
and increasing the dosing interval
The importance of TDM, and monitoring renal function and blood pressure during the course of treatment
Look
Ideally if a patient suffers from renal impairment we should use drugs which:
have a high therapeutic index and
are metabolised by the liver with the production of non-toxic metabolites
How can drug induced renal disease come about?
Any drug in the blood will eventually reach the kidneys.
If the drug is primarily cleared by the kidney, it will be increasingly concentrated as it is moves from the glomerulus and along the renal tubules.
The concentrated drug exposes the kidney tissue to far greater drug concentration per surface area
But drug induced renal damage is usually preventable
Drug induced renal toxicity can cause four major syndromes - what are they?
Acute renal failure
Nephrotic syndrome
Renal tubular dysfunction
with potassium wasting
Chronic renal failure
Acute renal failure
A sudden deterioration in renal function which results in a rapid rise in creatinine
Often elderly patients who are sick, have a poor fluid intake, who are on multiple medications and who are not being monitored aggressively.
Classification of acute renal failure
Pre-renal - prevents bloodflow to the kidneys - reduced GFR
Renal or intrinsic - affecting kidney itself
Post-renal or obstructive - urinary flow obsturction etc
Pre-renal drug induced renal disease
Water and electrolyte abnormalities - diuretics, laxatives, lithium, NSAIDs
Increased catabolism - Steroids, tertracyclines
Vascular occlusion - Oestrogens/ OCP
What are the 3 types of intrinsic acute renal failure?
Acute tubular necrosis
Acute interstitial nephritis
Thrombotic microangiopathy
Which drugs can cause acute tubular necrosis?
aminoglycoside antibiotics,
amphotericin B,
cisplatin (causes renal failure in up to 25% of patients after a single dose), radiocontrast agents
Statin drugs given in combination with immunosuppressive agents such as cyclosporin
Which drugs can cause acute interstitial nephritis
Penicillins
Cephalosporins
Cocaine
NSAIDs
Chinese herbs
What can thrombotic microangiopathy cause?
Severe acute renal failure
Pathologic hallmark is thrombi in the microvasculature of many organs
Changes in the kidney include afferent arteriolar and glomerular thrombosis
Main drugs causing thrombotic microangiopathy?
19 estrogen-containing oral contraceptives
Cocaine
Which agent can cause damage due to retroperitoneal fibrosis of the ureters? (ie outside the ureters)
Methysergide
Drugs implicated in crystal formation
Acyclovir, indinavir
Sulfonamides
Methotrexate
Main drug causing nephrotic syndrome
NSAIDs
NSAID-induced renal syndromes
Acute renal failure,
Nephrotic syndrome,
Hypertension,
Hyperkalemia,
Papillary necrosis
What is the most common type of NSAID-induced acute renal failure?
Decreased synthesis of renal vasodilator prostaglandins - leads to reduced renal blood flow and reduced glomerular filtration
NSAID-induced acute allergic interstitial nephritis
Idiosyncratic reaction
Particularly to the propionic acid derivatives (ibuprofen, naproxen, and fenoprofen),
Associated with nephrotic syndrome in about 90% of cases
Aminoglycoside-induced renal injury
Aminoglycoside antibiotics, used in severe gram-negative sepsis, cause nephrotoxicity in 10% to 20% of therapeutic courses.
Mechanism is proximal tubular injury leading to cell necrosis.
Summary
Drugs frequently induce renal disease:
Asymptomatic increase in urea and creatinine
Fluid and electrolyte abnormalities
Acute tubular necrosis - death of tubular cells
Acute and chronic interstitial nephritis
Acute renal failure due to Acute tubular necrosis is the most common and is due to aminoglycosides.
Avoid nephrotoxic drugs in volume deplete or hypotensive patients with pre-existing renal disease.
Avoid nephrotoxic drugs in patients receiving other nephrotoxic agents
Most common in:
- Elderly
- Sick
- Multiple medications
How do we avoid problems with patients that have hypertension and renal disease
Use drugs which are totally metabolised by the liver or elsewhere in the body e.g ACEIs
Use reduced dose of the drug with longer dosing periods. i.e. atenolol 25mg/day or on alternate days.
ACEIs are commonly recommended however they can produce severe acute renal dysfunction.
Direct vasodilators can produce profound hypotension and salt and water retention
Thiazides/thiazide-type diuretics may precipitate gout
