Pharmacology and Critical Illness
OVERVIEW
- critical illness changes many aspects of pharmacodynamics and pharmacokinetics
- In simple terms, pharmacodynamics is “how the drug effects the body” and pharmacokinetics is “how the body handles the drug”
- changes also occur in obesity, pregnancy, old age and the very young which may each coexist with critical illness
- extracorporeal devices (e.g. ECMO and RRT) also have important effects on pharmacodynamics and pharmacokinetics
- critically ill patients are more likely to experience ‘polypharmacy’, increasing the likelihood of drug interactions
PHARMACODYNAMICS IN CRITICAL ILLNESS
- effects can be therapeutic and toxic
- close relationship with pharmacokinetics
- drug effect decreased from: increased Vd, impaired tissue blood flow
- drug effect may be increased from: failure to excrete
Systems effects
- cardiovascular: more susceptible to cardiotoxicity because of myocardial dysfunction
- renal: more susceptible to impairment because of dehydration and impaired renal blood flow
- nervous system: more susceptible to cerebral toxicity because of encephalopathy
- haematological system: more susceptible to anti-coagulation c/o sepsis and DIC, also increased risk of DVT -> require prophylaxis
PHARMACOKINETICS IN CRITICAL ILLNESS
Absorption
- unpredictable oral bioavailablity due to ileus and diarrhoea
- Delayed GI absorption:
- decreased gastric emptying rate
- prolonged gut transit time (e.g. ileus)
- altered gastric pH
- decreased blood flow to the gut
- decreased venous flow from the gut
- intestinal wall oedema
- Impaired absorption:
- Accelerated gut transit time due to diarrhoea or prokinetics
- Bacterial overgrowth
- Brush border loss due to ischaemia
- Continuous feeds results in poor absorption of drugs that interact with feeds (e.g. phenytoin, thyroxine)
- slower IM absorption due to impaired peripheral blood flow
Distribution
- Vd commonly increased by increased total body water (e.g. capillary leak syndrome and fluid resuscitation)
- may result in underdosing of drugs
- Decreased plasma proteins
- decreased protein binding leads to increased free drug allowing increased clearance (at least transiently)
Metabolism
- decreased hepatic metabolism
- decreased hepatic blood flow
- cytokine-induced effects
- hepatic injury
- hypothermia leading to diminished enzyme function
- hepatic enzyme inhibition by other drugs
- increased metabolism in the liver
- increased metabolic rate due to fever
- enzyme activation by other drugs
- decreased spontaneous degradation
- hypothermia
- decreased tissue metabolism
- decreased tissue blood flow
- hypothermia
- decreased plasma metabolism
- deficiency of serum enzymes responsible for drug removal occurs with severe hepatic dysfunction
Elimination
- decreased clearance in the urine (variably resotred by RRT)
- decreased renal blood flow
- decreased glomerular filtration rate
- poor tubular function, decreased active transport
- acute renal injury eg. ATN
- decreased clearance in the urine
- augmented renal clearance occurs in some sub-populations (e.g. young multi-trauma)
- decreased biliary clearance
- biliary stasis
- decreased gut transit leading to recirculation
References and Links
CCC Pharmacology Series
Respiratory: Bosentan, Delivery of B2 Agonists in Intubated Patients, Nitric Oxide, Oxygen, Prostacyclin, Sildenafil
Cardiovascular: Adenosine, Adrenaline (Epinephrine), Amiodarone, Classification of Vasoactive drugs, Clevidipine, Digoxin, Dobutamine, Dopamine, Levosimendan, Levosimendan vs Dobutamine, Milrinone, Noradrenaline, Phenylephrine, Sodium Nitroprusside (SNiP), Sotalol, Vasopressin
Neurological: Dexmedetomidine, Ketamine, Levetiracetam, Lignocaine, Lithium, Midazolam, Physostigmine, Propofol, Sodium Valproate, Sugammadex, Thiopentone
Endocrine: Desmopressin, Glucagon Therapy, Medications and Thyroid Function
Gastrointestinal: Octreotide, Omeprazole, Ranitidine, Sucralfate, Terlipressin
Genitourinary: Furosemide, Mannitol, Spironolactone
Haematological: Activated Protein C, Alteplase, Aprotinin, Aspirin, Clopidogrel, Dipyridamole, DOACs, Factor VIIa, Heparin, LMW Heparin, Protamine, Prothrombinex, Tenecteplase, Tirofiban, Tranexamic Acid (TXA), Warfarin
Antimicrobial: Antimicrobial Dosing and Kill Characteristics, Benzylpenicillin, Ceftriaxone, Ciprofloxacin, Co-trimoxazole / Bactrim, Fluconazole, Gentamicin, Imipenem, Linezolid, Meropenem, Piperacillin-Tazobactam, Rifampicin, Vancomycin
Analgesic: Alfentanil, Celecoxib, COX II Inhibitors, Ketamine, Lignocaine, Morphine, NSAIDs, Opioids, Paracetamol (Acetaminophen), Paracetamol in Critical Illness, Tramadol
Miscellaneous: Activated Charcoal, Adverse Drug Reactions, Alkali Therapies, Drug Absorption in Critical Illness, Drug Infusion Doses, Epidural Complications, Epidural vs Opioids in Rib Fractures, Magnesium, Methylene Blue, Pharmacology and Critical Illness, PK and Obesity, PK and ECMO, Sodium Bicarbonate Use, Statins in Critical Illness, Therapeutic Drug Monitoring, Weights in Pharmacology
Toxicology: Digibind, Flumazenil, Glucagon Therapy, Intralipid, N-Acetylcysteine, Naloxone, Propofol Infusion Syndrome
Journal articles
- Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient – Concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev. 2014 Jul 15. pii: S0169-409X(14)00147-1. doi: 10.1016/j.addr.2014.07.006. [Epub ahead of print] Review. PubMed PMID: 25038549. [Free Full Text]
- Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med. 2009 Mar;37(3):840-51; quiz 859. doi: 10.1097/CCM.0b013e3181961bff. Review. PubMed PMID: 19237886.
- Roberts JA, Abdul-Aziz MH, Lipman J. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. The Lancet. Infectious diseases. 14(6):498-509. 2014. [pubmed] [free full text]
FOAM and web resources
- ICN — Pharmacokinetics in the Critically Ill by Jeff Lipman at smaccGOLD (2014)
Critical Care
Compendium
Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.
After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.
He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE. He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.
His one great achievement is being the father of three amazing children.
On Twitter, he is @precordialthump.
| INTENSIVE | RAGE | Resuscitology | SMACC
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Excited to see a couple of Jason Roberts’ (@jasonroberts_pk) papers included here – he’s the guru of ICU pharmacy when it comes to antimicrobial dosing, in all sorts of circumstances. Have previously used papers of his to guide dosing/timing for a patient on TPE.