BOOK (Finals) - Toxic mechanisms

• GABA_A receptors

• glutamate

• N-methyl-D-aspartate (NMDA)

• serotonin (5-HT₃)

CNS depressant effects of ethanol are primarily mediated by stimulation of inhibitory _____ and other neurotransmitters (3)

• hypoglycaemia

• ketoacidosis

• gluconeogeonesis

• fatty acid oxidation

In ethanol, metabolic effects include ______ and _____, resulting from impaired ______ and ______

• hyperlactataemia

• lactate

• pyruvate

• NADH:NAD⁺

In ethanol, ethylene glycol, _____ occurs due to impaired conversion of _____ to _____ following an increase in the ______ ratio.

• cardiovascular depression

• vasodilatation

Ethanol causes direct, dose-dependent ______ and ______

• glycolic

• oxalic acid

• high anion-gap metabolic acidosis (HAGMA)

In ethylene glycol, the more significant toxic effects are due to accumulation of _____ and _____ metabolites, resulting in a severe, progressive ______

• acute oliguric renal failure

• calcium oxalate crystal

• renal tubules

In ethylene glycol, _______ occurs secondary to _____ deposition in _____ and the nephrotoxic effects of glycolic acid.

• myocardium

• brain

• skeletal muscle

• hypocalcaemia

• cardiac dysrhythmia

• seizures

In ethylene glycol, calcium oxalate deposition can also occur in other tissues such as _____, _____, _____, resulting in _____ with a risk of _____ and ______

ketonaemia without acidosis

characteristic feature of isopropanol intoxication

isopropanol

Unlike other alcohols, _____ does not cause a severe, progresssive HAGMA

isopropanol

alcohol that is a gastrointestinal irritant and also causes dose-dependent cardiovascular depression

mitochondrial cytochrome oxidase

In methanol, hyperlactataemia is secondary to inhibition of _____ and impaired conversion of lactate to pyruvate following an increase in the NADH:NAD* ratio.

• retina

• optic

• blindness

In methanol, direct toxic effects on the _____ and _____ nerve lead to _____

• encephalopathy

• subcortical white matter haemorrhages

• symmetrical necrosis

• basal ganglia & thalamus

In the brain, characteristic features of methanol ______ include _______ and ________ of highly metabolically active structures such as the _______ and ______

Diethylene glycol

consists of two ethylene glycol molecules linked by a stable ether bond, and free ethylene glycol is not liberated

• alcohol dehydrogenase (ADH)

• aldehyde dehydrogenase (ALDH)

• 2-hydroxyethoxyacetic acid (HEAA)

• diglycolic acid (DGA),

Diethylene glycol is sequentially metabolised by ______ and ______ to the metabolites ______ and ______ which cause renal and neurological toxicity

• Ethylene glycol monobutyl ether (EGBE)

• Ethylene glycol monoethyl ether (EGME)

have stable ether linkages, preventing the formation of ethylene glycol (2)

• propylene glycol

• lactic acid

cardiovascular and CNS effects of _____ appear to be a direct toxic action, and metabolism of the molecule results in production of ______

Amisulpride

• atypical antipsychotic (benzamide derivative)

• highly selective dopamine antagonist (binds to D₂ and D₂ receptors)

• minimal affinity for other receptors

ephedrine

Amphetamine is structurally related to ______ (a phenylethylamine)

Amphetamines

enhance the release of multiple neurotransmitters and block their reuptake

• monoamine oxidase

• noradrenergic, dopaminergic and serotonergic

• dopaminergic

In amphetamines, inhibition of ______ also occurs, leading to enhanced central and peripheral ______, ______, ______ stimulation. Permanent destruction of ______ neuropathways also occurs

MDMA (3,4-Methylenedioxymethamphetamine - Ecstasy)

at recreational doses, ______ can induce the syndrome of inappropriate antidiuretic hormone secretion (SIADH), leading to profound hyponatraemia, seizures and coma

• angiotensin-converting enzyme

• angiotensin II

ACE inhibitors reversibly inhibit ______, preventing conversion of angiotensin I to _____, a potent vasoconstrictor

• aldosterone

• hyperkalaemia

Angiotensin II has endocrine effects and its inhibition leads to a reduction in circulating _____, which can result in ______

• vascular

• tissue

ARBs cause same effects as ACEi by their action at _____ and _____ receptors

anticoagulant rodenticides (superwarfarins)

• agents inhibit hepatic vitamin K-dependent production of clotting factors

• prolonged elimination half-lives

• II

• VII

• IX

• X

anticoagulant rodenticides (superwarfarins) inhibit these clotting factors (4)

• greater affinity for vitamin K, 2,3-epoxide reductase

• disruption of vitamin K cycle

• hepatic accumulation

3 mechanisms of anticoagulant rodenticides (superwarfarins)

anticonvulsants

these agents exert anticonvulsant effect by inhibiting excitatory neurotransmission or enhancing GABA activity

Gabapentin

• structural analogue of GABA

• exerts its effect by blockade of voltage-gated calcium channels in the CNS

Topiramate

has multiple pharmacological effects, including inhibition of carbonic anhydrase enzymes

Oxcarbazepine

structurally similar to carbamazepine, is much less toxic in overdose

non-sedating antihistamines

• mildly lipophilic

• less able to cross BBB

• selective, competitive, reversible inhibitors of peripheral H₁ receptors

• lower affinity for central H₁, muscarinic (M₁), a1-adrenergic and serotonergic (5-HT) receptors

arsenic

• enters cells by active transport or passive diffusion

• binds to sulfhydryl (-SH) groups

• substitutes for phosphate in ATP

• disruption of multiple cellular enzymatic pathways

• uncoupling of mitochondrial oxidative phosphorylation

• impaired cellular respiration

arsenic toxicity results from (3)

• bladder

• lung

In arsenic, inhibition of DNA replication and repair, particularly in chronic exposure, results in an increased risk of ____ and ____ malignancy

Arsine gas

can cause rapid onset of severe haemolysis by generation of reactive oxygen species within erythrocytes

baclofen

• synthetic analogue of GABA

• agonist at spinal GABA_b receptors, inhibiting the release of excitatory neurotransmitters

• crosses the blood-brain barrier

• increasing doses lead to sedation or coma.

• paradoxical excitatory

• intrathecal

In baclofen, _____ features such as delirium and seizures can occur and a withdrawal syndrome is recognised with abrupt cessation, particularly with _____ therapy

barbiturates

• cause CNS depression by enhancing the inhibitory effects of gammaaminobutyric acid (GABA)-mediated neurotransmission

• bind to the GABA_A receptor complex and increase the duration of chloride channel opening

• antagonise the effect of the excitatory neurotransmitter glutamate in the CNS

• medullar cardiorespiratory centres

• hypothalamic autonomic nuclei

• hypothermla peripheral vasodilatation

• direct myocardial depression

• respiratory arrest

In barbiturates, inhibition of _____ and _____ results in _____, _____, and ______

benzodiazepines

• act by enhancing gamma-aminobutyric acid (GABA)-mediated neurotransmission

• bind to GABA_A receptor complex and increase frequency of chloride channel opening

• zolpidem

• zopiclone

2 non BZD sedative-hypnotics that act at GABA_A receptor complex

benzotropine

• synthetic drug containing active tropine component of atropine and diphenylmethyl portion of diphenhydramine

• anticholinergic and antihistamine activity

• enhances dopaminergic effects by inhibiting dopamine re-uptake

beta blockers

agents that are competitive antagonists at b₁ and b₂ receptors

• decreased intracellular cAMP

• catecholamines

In beta blockers, excessive beta-adrenergic blockades leads to ______ concentration and resultant blunting of the chronotropic, inotropic, and metabolic effects of ______

Buproprion

noradrenaline and dopamine reuptake inhibitor with a structure similar to amphetamines

electricl discharge

predominant mechanism of injury in button batteries

• hydroxide

• negative

• alkaline

• liquefaction

• necrosis

• 2

In button batteries, ____ ions are generated at ____ pole of the battery, causing localized ____ corrosive injury with tissue ____ and ____ with ___ hours of lodgement

• voltage

• duration

• oesophageal perforation

• trachea-oesophageal fistula

• aorto-oesophageal fistula

• stricutre formation

In button batteries, injury severity is directly related to ____ of battery and ____ of tissue contact. Potential complications include _____, ______, _____, and _____

• dilitiazem

• verapamil

• 2 agents that block L-type calcium channels in myocardium, resulting in slowing of cardiac conduction and decreased contractility

• block pancreatic L-type calcium channels, resulting in drug-induced insulin resistance, manifests as hyperglycaemia and elevated lactate

dihydropyridines

• block calcium channels in the peripheral vasculature, leading to smooth muscle relaxation and vasodilation

• less likely to cause severe bradycardia or decreased myocardial contractility

cannabis plant (Cannabis sativa)

• contains numerous cannabinoids

• THC is the principal psychoactive component

• acts on cannabinoid receptors in central and peripheral nervous system (CB₁) and on immune cells (CB₂)

• augments dopamine release

delta-9-tetrahydrocannabinol

THC stands for?

synthetic cannabinoid receptor agonists (SCRAs)

• greater agonist activity at cannabinoid receptors than natural THC

• structural similarities to serotonin and amphetamines

• significant sympathomimetic and serotonergic effects + hallucinogenic properties

carbamazepine

• structurally similar to TCA imipramine

• inhibits inactivated sodium channels, thus preventing propagation of action potentials

• blocks noradrenaline reuptake

• antagonist at muscarinic, nicotinic, and central N-methyl-D-aspartate and adenosine receptors

carbon monoxide (CO)

• 200 times greater affinity for hemoglobin than oxygen

• binds to intracellular molecules (myoglobin, mitochondrial cytochrome oxidase), leading to oxidative stress and mitochondrial dysfunction

• initiates endothelial oxidative injury, lipid peroxidation, and inflammatory cascade - responsible for delayed neurological sequelae

• brain

• heart

• hypoxic

In CO, organs such as the ____ and ____ with high oxygen consumption are susceptible to ____ injury

methylene chloride

industrial solvent metabolized to CO following inhalation, dermal exposure or ingestion

chloral hydrate

• direct irritant action on mucosal surfaces

• MOA is due to TCE on CNS and CVS

• decreases myocardial contractility and shortens refractory period - enhances cardiotoxicity

trichloroethanol (TCE)

toxic metabolite of chloral hydrate

• cardiac dysrhythmias

• myocardium

• catecholamines

In chloral hydrate, _____ are thought to be caused by sensitization of _____ to circulating _____

• chloroquine

• hydroxychloroquine

• 2 agents that have a narrow therapeutic index

• exerts toxicity on CNS via effects on voltage-dependent sodum channels

• hypotension

• cardiogenic shock

• cardiodepressant

• cardiac conduction

• sodium channels (QRS widening)

• potassium channels (QT prolongation + torsades de pointes)

In chloroquine and hydroxychloroquine, _____ and ____ are due to direct _____ effect. _____ abnormalities are caused by blockade of inward _____ (_____) and outward ______ (_____)

• hypokalemia

• potassium

• tissue hERG potassium

In chloroquine and hydroxychloroquine, systemic _____ is a result of intracellular re-distribution of _____ due to blockade of _____ channels

clonidine

• stimulates central pre-synaptic a₂-adrenergic receptors, causing bradycardia and hypotension by a decrease in sympathetic outflow

• increases endothelial-derived nitric oxide levels

• GABA

• endogenous B-endorphine release

In clonidine, sedation is caused by augmentation of _____ in the CNS and _____ release

clozapine

• atypical diBZD antipsychotic

• antagonist at mesolimbic dopamine (D₁ and D₂), serotinin (5-HT) and adrenergic receptors

• potent antagonist at muscarinic (M₁), histamine (H1) and GABA receptors

cocaine

• toxicity results from sympathomimetic and sodium channel blocking (local anesthetic) effect

• sympathomimetic effects are indirect

• pre-synaptic catecholamine

• noradrenaline

• serotonin

• dopamine

• adrenaline

• adrenergic

In cocaine, blockade of ______ reuptake results in increased levels of _____, _____, _____, and ____ a the ____ receptor site

• vasospams

• endothelial fissuring

• coronary

• myocardial fast

• ventricular dysrhythmias

In cocaine, ____ and ____ can result in acute ____ syndrome. Blockade of ______ channels may result in ______

colchicine

• naturally occurring alkaloid found in autumn crocus and glory lily

• treatment of acute gout, pericarditis, and Mediterranean fever

• binds tubulin, prevents microtubule formation and inhibits mitosis and leucocyte migration into inflamed tissue (diapedesis)

corrisve agents

• causes direct chemical injury to tissues

• extent of injury determined by pH, conc. and vol.

alkaline agents

agent that causes liquefactive necrosis, resulting in deep and progressive mucosal damage

acids

agent that causes protein denaturation and coagulative necrosis

cyanide

• binds to ferric ion (Fe³⁺) of cytochrome oxidase

• inhibits oxidative metabolism, leading to lactic acidosis

• stimulates release of biogenic amines, resulting in pulmonary and coronary vasoconstriction

• triggers neurotransmitter release (NMDA) = seizures

digoxin

• inhibits membrane Na⁺-K⁺-ATPase pump, resulting in increase intracellular sodium = secondary increase in intracellular calcium via Na⁺-Ca²⁺ exchange pump

• increases serum potassium levels and enhances vagal tone

• inotropic

• cardiac ectopic beats

• dysrhthmias

• sinoatrial

• atrioventricular

In digoxin, elevated intracellular calcium results in therapeutic positive ____ effect and is responsible for enhanced automaticity causing ______ and risk of _____. Enhancement of vagal tone leads to a decrease in _____ and ____ node conduction velocities

diphenoxylate - atropine

combination synthetic opioid (agonist) and anticholinergic preparation for treatment for diarrhea

atropine

• added to discourage illicit misuse of opioid component for diarrhea treatment

• competitive antagonist of acetylcholine at muscarinic receptors

dabigatran

direct inhibitor of free and fibrin-bound thrombin, preventing conversion of fibrinogen to fibrin

• apixaban

• rivaroxaban

2 agents that directly inhibit free and clot-bound factor Xa, resulting in an anticoagulant effect by preventing conversion of prothrombin to thrombin

gamma-hydroxybutyrate (GHB)

• short-chain carboxylic acid that occurs naturally in the brain

• precursor and metabolite of GABA, also a neurotransmitter

• MOA is agonism activity at GABAB receptors, activity at GHB receptors, and dopaminergic modulation

glyphosate (glycine phosphonate)

• intracellular toxin uncoupling mitochondrial oxidative phosphorylation

• toxicity due to surfactant co-formulant (polyoxyethyleneamine)

• direct corrosive injury to mucosal surfaces when ingested

hydrocarbons

• CNS depressants

• (inhaled) disruption of lung surfactant and direct pulmonary injury, leading to chemical pneumonitis

• ventricular dysrhythmias

• myocardial sensitisation

In hydrocarbons, _____ can occur secondary to ________ to endogenous catecholamines

hydrofluoric acid

MOA of this agent - molecules penetrate the skin, soft tissues, and lipid membranes to dissociate to form hydrogen cations and fluoride anions

corrosive hydrogen ions

In HF, it causes local tissue injury and immediate pain

cytotoxic fluoride anions

In HF, ____ are responsible for delayed local effects. Reacts with cellular calcium and magnesium to form insoluble chelates (CaF₂ and MgF₂), inhibiting Na⁺-K⁺-ATPase pump and resulting in hyperkalemia

systemic fluorosis

In HF, this occurs when fluoride absorbed in the bloodstream is carried to all body organs, inducing liquefactive necrosis and cellular death. Can lead to ventricular dysrhythmias and cardiac arrest