Pharmacology therapy inacute poisoning

Prof.Dr.Aznan Lelo,PhD,SpFK

Dr.Datten Bangun MSc,SpFK1

Dept.Farmakologi & Therapeutika

Fak. Kedokteran

U S U

1

"All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.“

Paracelsus (1493-1541)

General Management History:

• Applies to ANY episode of Poisoning

= WHAT

= HOW MUCH (Ideally mg/Kg)

= WHEN

= ELSE (Including Alcohol)

= WHY

= Use Paramedics, friends, relatives, anyone!!

General Management -1

• A (Airway)

• B (Breathing)

• C (Circulation)

• D (Disability-AVPU/ Glasgow Coma Scale)

• DEFG ( Don’t ever forget the Glucose)

• GET A SET OF BASIC OBSERVATIONS

General Management -2

Use all your senses, search for the cluesLOOK -Track Marks

- Pupil SizeFEEL - Temperature, SweatingSMELL - Alcohol

Specific Management Options-1

. DECREASING DRUG ABSORPTION

– Gastric Lavage

– Absorbants

Specific Management Options -2INCREASING DRUG ELIMINATIONINCREASING DRUG ELIMINATION

- Alkaline Diuresis (Aspirin)- Haemodialysis (Aspirin)

Specific Management Options - 3

ANTAGONISING THE EFFECTS OF THE POISON:- Desferrioxamine ----- (Iron)- Naloxone ---------------- (Opioid)- N- Acetylcysteine------ (Paracetamol)

TREATMENT OF ACUTE POISONING

• Treat the patient, not the poison", promptly

• Supportive therapy essential

• Maintain respiration and circulation –• Maintain respiration and circulation –primary

• Judge progress of intoxication by: Measuring and charting vital signs and

reflexes

PREVENTION OF ABSORPTION OF POISON

• Decontamination from skin surface

• Emesis: indicated after oral ingestion of most chemicals; – must consider time since chemical ingested

• Contraindications:• Contraindications:• ingestion of corrosives such as strong acid or

alkali;

• if patient is comatose or delirious;

• if patient has ingested a CNS stimulant or is convulsing;

• if patient has ingested a petroleum distillate

PREVENTION OF ABSORPTION OF

POISON

Induce emesis in the following ways: • mechanically by stroking posterior pharynx;

• use of syrup of ipecac, 1 oz followed by one glass of water;

• use of apomorphine parenterally• use of apomorphine parenterally

Gastric lavage: insert tube into stomach and wash

stomach with water or ½ normal saline to remove unabsorbed poison

Contraindications:= should not be attempted with young children,

= are the same as for emesis except that the procedure

PREVENTION OF ABSORPTION OF

POISON

• Chemical Adsorption1 activated charcoal will adsorb many poisons thus

preventing their absorption

2 do not use simultaneously with ipecac if poison is excreted into bile in active formexcreted into bile in active form

adsorbent in intestines may interrupt enterohepatic circulation

PurgationUsed for ingestion of enteric coated tablets when time after ingestion is longer than one hour Use saline cathartics such as sodium or magnesium sulfate

PREVENTION OF ABSORPTION OF POISON

Chemical Inactivation

• Not generally done, particularly for acids or bases or inhalation exposure

• For ocular and dermal exposure as well as burns on skin; treat with copious watercopious water

Decreasing passive resorption:= from nephron lumen------Diuresis= Cathartics= Peritoneal dialysis = Hemodialysis = Hemoperfusion

Antagonism of the absorbed poison

• If poisoning is due to agonist acting at receptors for which specific antagonist is available; antagonist may be available

• Drugs that stimulate antagonistic

• If poisoning is due to agonist acting at receptors for which specific antagonist is available; antagonist may be available

• Drugs that stimulate antagonistic • Drugs that stimulate antagonistic

physiologic mechanisms may of little

clinical value; titration difficult

• Use of antibodies

• Drugs that stimulate antagonistic

physiologic mechanisms may of little

clinical value; titration difficult

• Use of antibodies

Acute poisoning,a dynamic process

possible death

Worsening

possible sequelae

Timet 0

recoveryfree interval

24 to 72 h

exposureexposure

Prehospital emergency care

• Decreasing the ‘free medical interval’

– Diagnosis or approximation of diagnosis

– Evaluation of severity, recognition of risk

factorsfactors

– Supportive treatment

– Specific treatment? antidotes?

– Prevention of early complications

– Orientation (Hospital, ICU)

• As early as possible

Antidotes drugs• Atropine

• Beta-blockers

• Calcium gluconate

• Dicobalt edetate

• Digoxin antibodies

• Ethanol

• Glucagon

Methylene blueNaloxoneOxygenPhentolaminePhysostigminePrenalterolProtamin sulphate• Glucagon

• Glucose

• Hydroxocobalamin

• Isoprenaline

• 4-methylpyrazole

Protamin sulphateSodium nitriteSodium nitroprussideSodium thiosulfate

Questions?

• Is the antidote effective?

• Is the antidote needed within one hour?

• How many patients should a facility prepare for …?

• What amount of the antidote is needed to • What amount of the antidote is needed to treat a 70-Kg patient?

Dinegara kita:=antidotum apa yang tersedia?= di RS kita,antidotum apa yg harus ada?

Dinegara lain bagaimana?

Toxidromes

• Patterns of signs and symptoms

• Useful to help in diagnosis and • Useful to help in diagnosis and treatment of unknown poisons

• Opium– Fluid obtained

from the poppy plant

• Opiate– a substance

derived from opium

DEFINITIONS

OPIOID

Papaver Somniferum“Poppy Plant”

opium• Opioid

– substance with morphine-like actions, but not derived directly from the poppy plant

Opiate or opioid tend to be used interchangeably.

In the class of opioid/opiate substances, all of the following can be prescribed legally

except for heroin.

• Heroin*

• Morphine

• Oxycodone– OxyContin– Percodan– Percocet• Codeine

• Methadone

– Percocet

• Hydrocodone– Vicodin

• Fentanyl• Hydromorphone

– Dilaudid

OPIATE INTOXICATION�MOST COMMON

� Miosis (small pupils; except with Demerol use which causes paralysis of the ciliary body and pupils dilate)

� Nodding

� Hypotension (low blood pressure)� Hypotension (low blood pressure)

� Depressed respiration

� Bradycardia (slow heart rhythm)

� Euphoria

� Floating feeling

Classic triad seen in opioid OD:=Miosis,respiratory depression,coma

Rescue breathing

Many agencies teach mouth to mouth

Treatment in opioid OD:

How about Oxygen?

Naloxone (Narcan)

• Opioid antagonist which reverses opioid related sedation and respiratory depression and may cause withdrawal

• Displaces opioids from the receptors, then • Displaces opioids from the receptors, then occupies the receptor for 30-90 minutes

• No psychoactive effects

• Over the counter in Italy

• Routinely used by EMS

Administration of naloxone:

• Inject into muscle but subcutaneous and intravenous are also effective

• Acts in 2-8 minutes

• If no response in 2-5 minutes repeat

• Lasts 30-90 minutes

Injectable Inexpensive- $0.25- 1.00 / dose

Well-documented effectiveness Requires injection

Naloxone preparations

IntranasalMore expensive $6-9.00 per doseLess well-documentedEasier to use

Sympathomimetics / Stimulants

• Agitation/delusions/paranoia

• Fight/Flight response

• Tachycardia

• Hypertension

Toxidromes

• Hypertension

• Arrhythmias

• Dilated pupils

• Seizures

• Hyperpyrexia

Common causes• Cocaine

• Amphetamines

• Decongestants

• Ecstasy

Treatment:until now:- benzodiazepine,or hypothermia

How about β-adrenergic blockers?---���� it opposes only β-,not α-adrenergic

Anticholinergic• Tachycardia

• Arrhythmias

• Pupils: mid-point or dilated / divergent

• Confusion / drowsiness / coma

• Seizures

• Dry flushed skin

Toxidromes

• Dry flushed skin

• Urine retention

• Hypertonia, Hyper-reflexia, Myotonic jerks

Anticholinergic signs -Hot as a hare-Blind as a bat-Dry as a bone-Red as a beet -Mad as a hatter

Common causes

• Antidepressants-Tricyclics

• Antihistamines

• Atropine

• Antipsychotics

• Antispasmodics• Antispasmodics

Treatment for atropin intoxication:= physostigmine

Serotonin Syndrome

• Similar to anticholinergic syndrome

– loss of consciousness: uncommon

– sweating and tremor: common

• Agitation

• Delirium

• Hypertonia / myoclonus

• Tachycardia

• Tachypnoea

Common Causes

= SSRIs= MAOIs (Hyperpyrexia / Hypertensive crisis)

Cholinergic

• Brady/tachycardia

• Confusion/reduced GCS

Common causes:= Organophosphates= Physostigmine= Some mushroom= Nerve gas

Toxidromes

• Confusion/reduced GCS

• Pinpoint pupils

• Seizures

• Weakness

• SLUDGE--------------�

• Pulmonary oedema

S sweating ,salivationL lacrymationU urinary frequency

urgencyD diarrhoeaG gastrointestinal discomfortE eyes pinpoint

Organophosphate

Mechanism of action

• Clinical Syndrome

• Acute Cholinergic:

– Central

– Peripheral Muscarinic

Clinical Syndrome

Respiratoryfailure

+ Death

– Peripheral Muscarinic

– Peripheral Nicotinic

• Intermediate Syndrome

• OPIDN: Delayed peripheral neuropathy

• Neurocognitive dysfunction

Signs and Symptoms of

Organophosphate poisonings

- diarhea,abdominal pain,vomitting

- blurred vision

Clinical Findings:Clinical Findings:- S alivation- L acrimation- U rination- D iarrhea- G astroenteric disorders- E yes pinpoint

CNS effects

• Malaise

• Memory loss

• Confusion

• Disorientation• Disorientation

• Delirium

• Seizures

• Respiratory centre depression or dysfunction

• Coma

ManagementThe priorities in management are :

I.General & Specific poisoning management

II.Antidotes:

= Atropin

= Oximes= Oximes

Atropine• Loading

– Doubling dose regime e.g. 2 , 4, 8, 16 mgs every 5 minutes

• Maintenance– Continuous infusion < 3mg/hr

– 10-20% of loading dose/hour

• Endpoints• Endpoints– Clear chest on auscultation with no wheeze

– Heart rate >80 beats/min

• Withdrawal– Atropine toxicity

– Clinical Improvement

What if you give too much Atropine ?

• Anticholinergic Syndrome:

– Hot as hell

– Blind as a bat

– Red as a beet

– Dry as a bone

– Mad as a hatter

• A sensitive indicator for ingestion, but poor predictor for toxicity.

• Full syndrome is rare

Paracetamol• Very common: 40% poisons admissions

• Often asymptomatic

• Can be lethal –-���� 200-300 deaths/year

Paracetamol metabolism

Metabolised by glucuronidation (60%),Sulphation (35%) and oxidation (10%)

= A minor but highly active metabolite (N-acetyl-p-benzoquinone imine = NAPQI) is usually neutralized by gluthathione,but in case of overdosis,the amount of gluthathione is not enough------- hepatotoxicity

Who are at High Risk ?

• Increased oxidation

– Chronic alcohol use

– Drugs

• Reduces glutathione stores

– Malnutrition

– Eating disorders

– Chronic liver disease

N-acetylcysteine

• Most effective within 8 hours

• Precursor for glutathione production

• Dosage:

= 150 mg/kgbw,given in bolus in 60 minutes

Treatment of Paracetamol intoxication

= 150 mg/kgbw,given in bolus in 60 minutes

in 50 or 200 ml of diluted Hidonac®

= followed by subsequent doses at slow infu-

sion,every 4 hours for at least 72 hrs

Adverse drug reaction: -urticaria,skin rash,angioedema,-bronchospasm,nausea,vomitting,fever.

SalicylateLife-threatening of salicylate poisoning:

= predominantly;- acid-base abnormalities

= CNS dysfunction

= other effects: - nephrotoxic,ototoxic= other effects: - nephrotoxic,ototoxic

= Metabolic and acid-base disturbance= Complex= Respiratory alkalosis – direct stimulation to over

breathe=Metabolic acidosis- acid, impaired normal

metabolism, production of lactic acid & excretion ofNaHCO3 thru’ the kidney

Salicylate overdose management

• Tailor treatment to symptoms

• Fluids--� IV Na+HCO3

• Reduce absorption:• Activated charcoal

• Tailor treatment to symptoms

• Fluids--� IV Na+HCO3

• Reduce absorption:• Activated charcoal• Activated charcoal

• Gastric lavage (>500 mg/kg and <1 hour)

• Increase elimination:• Urinary alkalinisation

• Cooling

• Glucose if hypoglycaemic

• Activated charcoal

• Gastric lavage (>500 mg/kg and <1 hour)

• Increase elimination:• Urinary alkalinisation

• Cooling

• Glucose if hypoglycaemic

Salicylate overdose management

• <350mg/L: oral fluids

• >350mg/L: urinary alkalinisation

• >700mg/L: haemodialysis

Severity of ingested dose:>150 mg/kg: mild>250 mg/kg: moderate>500 mg/kg: severe

PHARMACOLOGIC THERAPYFOR CIRCULATORY FAILURE

Circulatory Failure:

= the inability of the circulatory system to

adequately supply metabolic substrate to

the cells of the body.the cells of the body.

What the doctors must do?

----� act quickly to restore the blood flow to an adequate level.

How?

Not only by:

= increasing the blood pressure or

= the cardiac out put

But also:

= must achieve adequate perfusion to = must achieve adequate perfusion to all important vascular beds, …But

= must not stress the CVS or induce further injury

β- Adrenergic Receptor Agonists

- Dopamine

- Dobutamine

- Adrenaline

- Noradrenaline- Noradrenaline

Receptor Selectivity of SympatomimeticReceptor type

α1 α2 β1 β2 D1

AGENT Vasocon- Presynaptic Increases Vasodilates Low dose

stricts pe- inhibition HR,inotro- peripheral vaso dilaripheral at NA synap pic,diasto- vessels te renalvessels ses lic relaxat. Veselsvessels ses lic relaxat. Vesels

-Dopamine + ++ ++ ++-Dobutamine +/- ++ +

-Adrenaline ++ ++ ++ ++ -Noradren. ++ ++ ++

Dopamine

- Is an endogenous sympatomimetic amine

- Function as a neurotransmitter

- Is a biosynthetic precursor of adrenalin and noradrenalin.

- Activates cardiac β1-adrenergic receptor--����

= increase contractility

= increase heart rate

Unlike noradrenaline, at low doses,dopamine:

= vasodilator effect in periphery,because;

-it stimulates dopaminergic D1 receptors inrenal and mesenteric vascular beds----���� reduce afterload

At intermediate doses,dopamine:

= causes more widespread vasodilatation----

���� greater reduction in systemic vascular resistance

At higher doses,dopamine:

= activation of α1-receptors predominates---����

generalized vasoconstriction---���� increased

afterload

INDICATIONS

In low and intermediate doses;

= in cardiogenic shock

= in CHF

But now has been supplanted by

= dobutamine or

= phosphodiesterase inhibitors

Dobutamine- A synthetic sympatomimetic amine.

- The predominant overall effects is agonist at

cardiac β1-receptors ---���� modest peripheral vasodilatation via agonist action at peripheral β2- receptors

COMT rapidly metabolize dobutamine------����t½ is about 2,5 minutes

Side-effects:- cardiac arrhytmia--����supra-ventriculartachyarrhytmia, BUT less than DOPAMINE

==���� dobutamine is preferred in cardiac shock

Adrenaline (Epi)

=non-selective adrenergic agonist

= exogenously administered Epi stimulates:

- β1-,β2-,α1- and α2- receptors

- the net effects depend on the dose

= At all dose levels Epi is a potent ,β1- agonist

----���� - positive inotropic,chronotropic and lusi-----���� - positive inotropic,chronotropic and lusi-tropic (diastolis relaxation) effects

= Low dose: stimulates peripheral β2-

Higher dose: stimulate α1- ,--���� vasoconstr.

tachycardia

===���� high dose Epi is less desirable

Indication of Noradrenalin:

1.In the setting of resuscitation ofcardiac arrest

2.Non cardiovascular:= bronchospasm (via β2-mediated

bronchial relaxationbronchial relaxation= potentiation of the effect of

local anaesthesia ( via local α1-mediatedvasoconstriction

= treatment of allergic hypersensitivereactions

Phosphodiesterase Inhibitors

= Increase cardiac contractility by raising

intracellular cAMP level----���� indirectly

increase calcium intracellular

PDE-I ---����inhibit PDEPDE-I ---����inhibit PDE

cAMP intracel.

Ca++ intracel

Contractility

PDE3-Inhibitors :- Amrinone- Milrinone- Aminophylline

- Theophylline

PDE3-Inhibition: -----���� cAMP

-Contractility-HR

Inotropic +I

II. –peripheral dilatation

PDE3-I -----���� -ino-dilators