CLINICAL PHARMACOLOGY in CRITICAL CARE

Pharmacology and Therapeutic Dept.,Clinical-Pharmacology Division,Faculty Of Medicine,Gadjah Mada University.*LSD

*CRITICAL : pertaining to or of the nature of a crisis; in danger of death; in sufficient quantity as to constitute a turning point, as a critical mass or as critical concentration.CRITICAL ILLNESSES : often associated with Circulatory, Respiratory, Hepatic and/or Renal dysfunction which may alter the pharmacokineticsand/or pharmacodynamic of drugs.

(Benowitz, N.L.,et al 1997)

*CRITICAL ILLNESSES( ICU / ICCU ) Dysfunction of VITAL ORGANSADVERSE DRUG REACTIONSDRUG INTERACTIONSACUTE INTOXICATIONSPOSTOPERATIONSHOCKOTHERS

*CRITICAL ILLNESSoften associated :

CIRCULATORY ( Hemodynamics ) RESPIRATORY HEPATIC and/or RENAL DYSFUNCTIONMULTIORGAN FAILURESEVERE INFECTION may altered :

PHARMACOKINETICS (PK) and/or

PHARMADYNAMICS (PD)

*CRITICAL ILLNESSES

DECISIONS ABOUT ROUTE OF ADMINSTRATION and DOSES of the medicine;

- physiological status of the patients - pharmacokinetics and pharmacodynamics characteristics of the medicine

- how the two interact each other

*PHARMACOKINETICSABSORPTIONDISTRIBUTIONMETABOLISMELIMINATION /EXCRETIONPHARMACEUTICIN SITETHE BODYIN SITETHE BODY

*The Effects of Critical Illness on Drug Pharmacokinetics Pathophysiological condition Effects on drug kinetiks (example):Depressed gut absorptive capacityDrug absorption altered by enteral feedingIncreased total body water

Hypoalbuminaemia

Hepatic dysfunction

Decreased hepatic perfusionRenal dysfunctionDecreased drug absortion (eg: digoxin)Reduced availability of drug (eg:phenytoin) Higher loading dose (eg: gentamicin) Longer half-life ((eg: vancomycin)

Increased drug-free fraction (eg. phenytoin)Delayed drug metabolism, (eg:benzodiazepine)Decreased drug clearance (eg.: lidocain)Decreased drug clearence (eg :aminoglycoside, digoxin)

*PK & PDIn EMERGENCY / CRITICAL CARE : - DOSAGE - ROUTES OF DRUG ADMINISTRATION - DRUGS INTERACTIONarialIf not appropriate :

NEW PROBLEM

*arythmiastamponadeValvular dysfunc.Myocard.failr.haemorrhagehypertensionCIRCULATORY FAILUREInadequate cardiac outputAuto regulation, redistribution of blood flow.Slow distributionof drug to tissuesGreater %age of COto well perfusedorgansShunting of renal blood from corticalto juxtamedullarynephronDecreased bloodflow to kidneyDecreasedtblood flowto liverHigher initial drugconcentration inbloodDecreased GFR,increased tubular reabsorp.,decreased tubular secretionImpaired hepatocellularfunctionHigher initial drugconcentration in wellperfused tissues(brain, heart)Dcreased drugexcretionDecreased clearance ofhighly extracted drugsDecreased clearance of poorlyextracted drugsPHARMACOKINETIC CONSEQUENCES OF CIRCULATORY FAILURE

*CIRCULATORY FILUREALTERED FLUID BALANCEHEPATIC FAILURERENAL FAILUREACUTE PULMONARY INSUFFICIENCYINFECTIONS / FEVERBURNS / MULTIPLE ORGAN FAILUREACID-BASED DISTURBANCESDRUG INTERACTIONS (in critical ill patients)Pharmcokinetics : absorption; distribution; metabolism; excretion.Pharmacodynmics : responses of tissues/organs

*CRITICAL CARE MANAGEMENT (general principles)Preservation of Cardiovascular, Respiratory and Metabolic function.

- Physiological monitoring : vital signs, CNS, ECG, intra-arterial catheters (unstable BP), blood gas analysis, electrolytes, EEG, etc. - Preservation of Cardiovascular Function : fluid & electrolytes, myocardium ( by streptokinase or t-PA, tissue-type plasminogen activator in acute attack

*2. Fluid therapy.

Objective : to replete intravascular volume.

Condition : haemorrhage, vomiting, diarrhoe, excessive diuresis, inadequate fluid intake and redistribution of fluid out of the vascular space intravascular volume depletion hypotension inadequate organ perfusion.

Target : clinical sign of inadequate perfusion no longer evident or CVP (central venous pressure) 12 15 mmH2O especially brain. Until BP reached adequate organ perfusion.

Fluid replacement : isotonic solution (normal saline, R.Lactate,etc), colloid ( albumin, dextran, plasma expander ) or blood component.

*33. Cerebral proctection. Metabolic demands of the brain : maintain adequate blood flow, adequate oxygen, and glucose. Controlled the fever, seizure, etc.

4. Anti-infective Therapy. Critical ill patients have a high risk of infection because impaired host defence and multiple invasive procedures ( oxygen canule, endotracheal tube, nasogastric tube, urinary catheter, iv catheter etc. )

5. Prophylaxis Gastric Stress Erosions and Ulcers gastrointestinal bleeding. Prophylactic : H2 blocker ) cimetidine, ranitidin, sucralfate, etc.

6. Pulmonary embolism : cause by prolonged immobility, tissue injury and/or activation of coagulation. DVT present 58% in majot and large trauma (hip & knee replacement) If thrombotic risk very high : prophylaxis use LMWH (low molecular weight heparin) like enoxaparin.

*7. AVOIDING ; DRUG-INDUCED COMPLICATION.

- multiple pharmacotherapy / polypharmacy interaction.

- to minimise : a. consider the effects of the presence of organ dysfunction on pharmacokinetics and adjust initial drug doses; b. Set specific end-point for therapy (where possible); c. monitor drug concentration if possible; d. monitor patients for early evidence or toxicity; e. Review medication record in total on a regular basis to detect possible adverse drug interactions.

*SPECIFIC CRITICAL CARE CONDITIONSSHOCK

ANAPHYLAXIS

ACUTE RESPIRATORY FAILURE

ARDS (acute respiratory distress syndromes)

BRAIN INJURY

6.DISORDERS OF BLEEDINGS(HAEMORRHAGY;HEMATEMESIS; MELENA;HEMOPTOE)

7. HEART PROBLEMS ( AMI, etc)

*ANAPHYLAXIS.

The leading cause : drugs; foods; insect stings; extracts of allergens increased vascular permeability loss of plasma depletion of intravascular volume & tissue oedema.

Treatment : - antagonising the effects of chemical mediators; - preventing further release of mediator; - minimising exposure to the inciting agent.

Pharmacotherapy : - adrenaline - 2-adrenoceptor agonist (salbutamol, orciprenalin) - antihistamines - corticosteroids - vasopressors ( noradrenaline, methoxamine)

*ACUTE RESPIRATORY FAILURE.

May as complication of: chronic obstructive lung disease ARDS severe pulmonary infection diaphragmatic muscular weakness / paralysis massive obesity CNS dysfunction (due brain injury; drug over dose) Clinical : somnolence; confusion; disorientation / coma; depressed respiration; and cyanosis.Laboratory : arterial bllod gas analysis : hypoxaemia; CO retention.

Therapy : - low flow oxygen by nasal canule or mask; - higher oxygen concentration via ETT; - bronchodilators (inhaled 2-agonist); - corticosteroids (asthma; COPD); - specific therapy to the cause.

*ACUTE RESPIRATORY DISTRESS SYNDROME / ARDS( = non-cardiogenic pulmonary oedema ) Cause ARDS : sepsis; trauma; shock; burns; aspiration pneumonia; drug overdose; inhalation of toxic substance; oxygen toxicity and fat emboli.

Pulmonary oedema : injury to pulmonary capillary endothelial cells and to the epithelial cells that line the alveolus and provide the tightest barrier to fluid and protein movement fluid leaks into alveoli. Treatment of ARDS : - oxygenation by mechanical ventilation PO2 70 80 mmHg. - PEEP (positive end-expiratory pressure) or CPAP (continous positive airway pressure). - haemodynamic monitoring by fluid therapy - drug : no specific treatment, depend the condition. Usually diuretic or vasodilators, vasopressor (dopamine). - specific treatment for complicating illness.

*BRAIN INJURY

Head traumaCerebrovascular diseaseInfectionAnoxia (carbon monoxide poisoning)Global ischaemia (severe shock, post cardiac arrest)

Clinical sign : cerebral edema increased intracranial pressure > 15 mmHg (by space-occupying lesion: tumor,haematom abscess)

Treatment : cerebral edema - osmotic agent (mannitol and glycerol) - corticosteroid (for suppressing inflammation and decreasing capillary permeability) - barbiturates (reduction cerebral metabolic activity) common use in Reyes syndrome.

*INTRACRANIAL HYPERTENSION (1)

MANAGEMENT: - monitoring: neurological status intracranial pressure intra-arterial pressure (intracranial pressure < 40 50 mmHg poor prognosis).

- maintain & normalizing metabolic function (oxygenation and blood glucose concentration).

- adequate venous drainage (position 30 degree head-up tilt).

*INTRACRANIAL HYPERTENSION (2)

- surgical decompression

- hyperventilation but PaCO2 not reduce below 20 mmHg ( target value : 25 mmHg ) - anti-edema therapy : 20 % manitol or 10 % glycerol frusemid ( a diuretic ) high dose corticosteroid ( suppressing inflammation )

*COMPLICATION OF DRUG INTOXICATIONDRUG-INDUCED COMADRUG-INDUCED AGITATED DELIRIUMDRUG-INDUCED SEIZURESDRUG-INDUCED HYPERTHERMIADRUG-INDUCED HYPERTENSIONDRUG-INDUCED ASPIRATION PNEUMONIADRUG-INDUCED PULMONARY OEDEMADRUG-INDUCED ARRHYTHMIAS

*MONITORING & EVALUATE;

-> THE FUNCTION OF VITAL ORGANS : brain, heart, lungs, kidney, GIT, etc

-> DO IT PERIODICALLY : by test function/physiological, laboratory, electromedic, radiologic -> In INTENSIVE CARE UNIT (ICU; ICCU)

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