DD - Adverse drug reactions / poisoning

A - controlled studies show no risk. fetal harm is small. e.g. potassium chloride

B- no evidence of risk in humans.

C- risk cannot be ruled out. animal studies show adverse effect or no studies available

D - positive evidence of human fetal risk.

X- contraindicated in pregnancy. e.g. triazolam/flurazepam/temazepam, accutane (isotretinoin)

-extension effects - dose related and predictable
-side effects - dose dependent and predictable
-idiosyncratic reactions - unpredictable
-drug allergy - unpredictable, independent

arise from an extension of the therapeutic effect.

mechanism based.

e.g. insult to lower blood glucose cuases hypoglycemia

10%

elevated drug concentrations (due to reduced elimination rates or protein-bound drug displacement) leading to toxicity
OR
causes decreases in plasma concentratoins (via more rapid drug elimination or decreased drug absorption) leading to levels below therapeutic effectiveness.

phamcologic or physiolgoic enhancement
or antagonism of drug action

-elderly
-pts in high risk clinical situations (dependent on drug treatment, acute illness, unstable disease)
-pts with renal/hepatic disease
-pts with multiple preswcribing physicians

-absorption
-distribution
-metabolism
-excretion

means they need to be monitored carefully in plasma

insulin and warfarin

-anticoagulants
-antiseizure
-antiarrhythmics
-aminoglycoside Ab
-cancer chemotherapeutics
-HIV agents
-immunosupressants (cyclosporine
-neuromuscular blocking agents
-digoxin
-insulin

decreases in motility --> lower peak plasma drug levels

increases in absorption less important

physiochemical inactivatoin via changes in pH or formation of insoluble complexes reduces bioavailability

protein bindingdisplacement interactions.

competitive binding increases free drug

cellular distribution interactions

inducers (increase metaboilc rate) causing subtherapeutic levels

inhibitors (decreased metaboilc rate) causing increased toxic levels of drug

most interactions occur via CYP

most in KIDNEYS
change in GFR (glomerular filtration rate)
change in tubular secretion
change in urine pH

-antagonistic effects
-synergisitc or additive therapeutic efects
-synergistic or additive side effects
-indirect pharmacodynamic effect

when 2 drugs mixed in same IV fluid
chemical inactivation or precipitation via pH changes or alteration of vehicle

supportive care

-cardiopulmonary support and protection of airway
-assess electrolytes, acid-base balance and fluids
-CNS precautions
-renal function (direct drug toxicity and indirect hypotension renal failure)

study of absorption, distribution and elimination of toxic parent compounds and metaboic products that aids in predictino of amt of toxin that reaches site or injury and the resulting damage.

-absorption (bioavailability F)
-volume of distribution (Vd)
-clearance (metabolism/excretion)
-half-life

large amt of ingested drug may slow tablet dissolution

alter GI emptying

injure GI tract --> altered absorption --> delayed peak effect

important to know contribution of kidney and liver to elimiantion fo toxin to plan treatment strategy

the published values are for therapeutic doses

half life may be PROLONGED in toxic overdoses due to saturation of the elimination mechanisms

pharmacokinetic
-prevent / decrease absorption
-inhibit toxication (prevent conversion to toxic species)
-enhance metabolism (detox)
-increase elimination of toxin (decrease rate out)

pharmacodynamic
-antidotes

-emesis (ipecac, apomorphine)

-gastric lavage

-chemical adsorption. activated charcoal

local irritation and CNS stimulation of chemoreceptor zone

effective orally but must be given BEFORE charcoal

emesis after 15-30 minute lag, repeat after 20 minutes

not recommended in children, rarely used at all

dopamine agonist, produces emesis by stimulation of chemoreceptor zone
respiratory depressnat, toxic in children

contraindications
-comatose patient (lack of gag reflex --> risk of aspiration)
-ingestion of corrosive poisons (strong acids or alkalis)
-ingestion of CNS stimulatn such as strychnine (risk of seizures)
ingestion of petroleum distillate (risk of pneumonitis)
pregnancy category C

most rapid and complete method of emptying stomach

lavage + emesis removes only about 30% of most oral poisons

-washing of stomach contents with saline and removal via nasogastric tube
-best within 60 minutes of poison ingestion

binds drug in gut to limit absorption
-effective without prior gastric emptying and can reduce eliminatino half lives of drugs that have been given IV
(back diffusion of drug from blood with ion-trapping in the stomach)

decrease time of toxin in GI tract (via osmotic laxative effect)
indicated if toxin ingestion is > 60 min

-sorbitol
-magnesium citrate/sulfate
-sodium solfate
-polethylene glycol

osmotic cathartic given together to prevent briquet formation

osmotic cathartic (decrease time of toxin in GI tract)
avoid in renal disease or poisonings with nephrotoxic agents

osmotic cathartic (decrease time of toxin in GI tract.
avoid use of sodium containing cathartics in CHF or hypertension (systemic absorption --> fluid overload)

methanol/ehtylene glycol

methanol metabolized --> formic acid (retinal damage & blindness)

ethylene glycol metaboilzed --> oxalic acid (insoluble crystals in kidney - acute kidney failure)

treatment - correction of metabolic acidosis with NaHCO3, removal of parent compounds and metabolites with
hemodialysis, and suppression of production of production of toxic metabolites by inhibiting the rate limiting enzyme (alcohol dehydrogenase) with ethanol (competitive inhibitor) or fomepizole (specific inhibitor of alcohol dehydrogenase)

substrate and a competitive inhibitor of alcochol dehydrogenase

specific inhibitor of alcohol dehydrogenase

-acetaminophen
-cyanide

toxic single dose > 10-20 g will saturate phase II metabolic pathways leading to increased formation of phase I hepatotoxic metabolite
AND
deplete glutathione stores availble for detoxification

hepatocellular injury

cyanide binds ferric ions in cytochrome oxidase

inhibits:
cellular respiration
cytotoxic hypoxia
lactic acidosis

-gastric lavage
-supportive theray
-N-acetylcysteine (precursor for glutathione synthesis and nucleophile to capture the electrophilic heatotoxic metabolite)

hydroxocobalimin (vitamin b12 precursor that binds cyanide to make cyanocobalamin)

-extracorporeal removal
-enahnced metabolism
-enhanced renal excretion
-chelation of heavy metals

method to enhance elimination

-hemodialisis/peritoneal dialysis (blood pumped through filter)

-hemoperfusion (bloodpumped through column of adsorbent material)

blood pumped through filter

-effective for toxins with small Vd
-toxins should have low protein binding capacity
-helps in correction of fluid and electrolyte imbalance

no because hemodialysis useful for toxins with small Vd

blood pumped through column of adsorbent material.
-useful for high MW toxins with poor water solubility
-risks: bleeding (removal of platelets) and electrolyte distubances

method to enhance elimination

-induction of cytochrome p450 is NOT REALISTIC due to delay (1-3 days for onset of action)
-enhancement of detoxificatoin metaboilc pathways with N-acetylcysteine in acetaminophen toxicity and thiocyanate in cyanide poisoning
-inhibition of metabolism to block formation of toxic metabolistes (e.g. inhibition of alcohold dehydrogenase in methanol or ethylene glycol toxicity)

enhances detoxification of metabolic pathways in acetaminophen toxicity

enhances detox metabolic pathways in cyanide poisoning

method of enhancment of elimination in toxic
-forced diuresis
-block reabsorption from kidney
-block active reabsorption

normal saline plushigh efficacy diuretics (furosemide)
-small effect with danger of fluid overload (worsens pulmonary function)
-protects kidney (beneficial effect)

prevention of passive reabsorption via alteration of urinary pH and ion trapping
-make urine more basic (with NaHCO3) then trap weak acids like aspirin
-make urine more acidic(with NH4Cl or ascorbic acid) then trap weak bases

-enhances elimination of toxins (increase renal excretion) and inactivate toxin (decreases ability to interact with and damage target tissue)

heavy metals coordinate covalent bonds with protein side chain nucleophiles

enzyme inhibition

AND

alteration of membrane structure

give chelating agent to complex with free metal ions.
this promotes dissociation of metals from intracellular macromolecules.

-dimercaprol
-penicillamine
-succimer

chelating agents
-treats mercury poisoning
-treats lead poisoning (Ca-Na2-EDTA)

better at preventing binding to sulfhydryl groups than reactivating them.

treat Cu++ toxicity (Wilsons disease)

treats mercury and lead poisoning
rheumatoid arthritis (uncertain mechanism) and cystinuria)

treat children with elevated blood lead levels

mercury poisoning

useful to metals more tightly bound than Ca++

treats lead intoxification

not useful for mercury toxicity

mercury toxicity

treats acute iron intoxication, chronic iron overload, possible use for Al+++chelation in dialysis patients

N-acetylcysteine

naloxone

flumazenil

pralidoxime/atropine

pralidoxime/atropine

digoxin Fab (digibind)

protamine

vitamin K analogs

ethanol, 4-methylpyrazole

deferoxamine

dimercaprol

succimer, Ca(Na)2EDTA

penicillamine

hydroxcobalimin

oxygen

methylene blue