Neurotoxicology

Neurotoxicity: An adverse change in the structure or function of the central

and/or peripheral nervous system following exposure to a chemical, physical,
or biological agent1

Adverse Effect: Alterations from baseline or normal conditions that diminish

an organisms ability to survive, reproduce, or adapt to the environment 1

Guidelines for Neurotoxicity Risk Assessment

Federal Register, 63(93):26926-26954, 1998
http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=12479

Patterns of Neurotoxic Injury

Neuronopathy: Death of entire neuron

Astrocyte proliferation
Axonopathy: Axon degenerates
Neuronal chromatolysis
Nissl substance and nucleus to periphery
Myelinopathy: Injury to Schwann or
Oligodendrocytes

Adapted From: Anthony et al., Casarett & Doull, 2001

Toxic Pathway(s)
Loss of ion gradients mitochondrial uncoupling
Altered lipid metabolism
Metabolic disruption
Altered glutamine metabolism
?

Metabolic inhibitors
DNA/Protein synthesis/function
Oxidative stress
Excitotoxicity
?

Membrane turnover
Inhibition of NTE
?

Neurofilament X-linking
Axonal transport
Lack of cell constituents
Ion chelation
?
4

Signs of Peripheral/Central Neuropathies

Biochemical

Neurofilament accumulations
Changes in axonal transport
Altered myelin
Altered ion gradients

Physiological
Decreased amplitudes of nerve action
potentials
Decreased nerve conduction velocity
Denervation potentials in muscles
Alterations in somatosensory evoked
potentials

Behavioral
Parasthesias
Increased reaction time
Vibrotactile abnormalities
Paralysis

Pathological
Neuronal / Axonal degeneration
Changes in myelin

Normal Receptor-Ligand Interaction

1
2

Cell
Membrane

Ligand
Receptor

Outside Cell
Inside Cell

Ligand binds to receptor

Signal Protein

3
Positive Response

Inactivation of Receptor by Toxicant

1
2

Toxicant
inactivates
receptor

No Response

Toxicant

Competition For Receptor

Ligand

1
2

Toxicant
out competes
normal ligand

Toxicant

Ligand cannot bind

receptor

No Response

Classical Culprits
Heavy Metals: Hg, Pb, As
Industrial: solvents CC4, pesticides
Biological: bacterial/botulinum, venoms,
plant poisons

Prescription Drugs

Antibiotics
Cardiac drugs
Gastrointestinal agents
Respiratory agents
Psychiatric drugs
Anti-inflammatory
Vitamins/Misc

paresthesia
An abnormal sensation, such as
of burning, pricking, tickling,
or tingling.

Antibiotics

Penicillins
Aminoglycosides
Antifungals
Anti-TB
Anti-viral
Misc

Antibiotics
Penicillins: IV doses = seizure, jerking
Aminoglycosides: *mycins
Neomycin, kanamycin, streptomycin,
gentamycin, tobramycin, amikacin
All cause damage to 8th cranial nerve and
hearing apparatus 8-25% irreversible
neuromuscular blockade (curare-like) pot
fatal in surgery (give neostigmine to reverse
resp paralysis)

Antibiotics
Antifungals: eg. Amphotericin B (systemic)
About 7% incidence of mild parethesias,
dizziness, seizure, dysphagia, weakness
Potential resp paralysis thats worse with
renal impairment

Antibiotics
Antituberculins:
Isoniazid binds pyroxidine and causes
excess vitamin secretion. Polyneuropathy
Paresthesias, pain, temp, touch discrimination,
weakness, seizures, (psychosis, seizures, headache,
depression are rare)
TX: give pyroxidine (50 mg/d).
If OD, give anticonvulsants as well

Rifamycin (same), Ethambutol (optic neuritis)

Antibiotics
Antivirals: HIV
Acyclovir (IV) to tx varicella zoster, herpes
simplex seizure, hallucin, coma. Rare PO
side-effects
Amantadine to tx influenza & mild parkinsons
(anti-Ach & anti-DA actions). SEs =
confusion, halluc, delirium, seizure, toxic if
kidney problems

Antibiotics
Miscellaneous
UTI drugs
Sulfonamides, pyrimethamine, trimethoprim. Can
cause tinnitis, headache, fatigue, acute psychosis
Nitrofurantion distal subacute polyneuropathy
(numbness, weakness, areflexia).
Chloraphenicol = confusion, delirium, optic n.,
ototoxicity. Also inhibis phenytoin & phenobarb (anticonv) metabolism and causes problems indirectly
Tetracycline = ICP (headache, papilledema)
Erythromycin = least toxic, but interferes with
carbamazepine (anticonvulsant) metabolism.

Cardiac Drugs

Glycosides (tx congestive failure)

Anti-Angina drugs (chest pain, e.g. nitro)
Anti-arrhythmics ( cardiac fibrillation)
Diuretics (fight fluid)
Sympatholytics (adrenergic-blockers)
Vasodilators hypertension
Angiotensin converting enzyme inhibitors

Cardiac Drugs

Glycosides: digitalis (congestive heart)

Nausea(first,central), vomiting, visual dist
(40%, blurring, diplopia, etc.), seizure,
syncope,
CNS (15%, not cardiac)= facial neuralgia,
headache, weakness, fatigue, paresthesias,
confusion, delirium, mania, halluc.
Antiangina agents: Nitroglycerin /nitrates 15%
pts. Have intolerable headache. Also ICP,
dizziness, light-headed (hypotensive). Give
analgesic adjunct to tx headache.

Cardiac
Anti-arrhythmic ( repolarization, threshold
for ventricular fibrillation)
Quinidine (Tx fibrillation) cns symptoms 2nd
Procaine derivatives:
Lidocaine* (quick BBB penet, not oral, IV) =
excitatory, psychosis, agitation, numbness, diplopia
>tremor >resp dep, acidosis,hypoxia
Tocainide (oral) = light headed, dizzy, tremor, sweating,
blurred vision mood change
Procainamide, Bretylium, Amiodarone
Syndrome= tremor, dizziness, ataxia, falls, staggering,
walking, diff dressing (peripheral neuropathy)

Cardiac
Diuretics
1) Thiazide
Acute muscle cramps, pain, hyporeflexia,weakness,
flaccid paralysis. If cirrhosis, mental function.

2) Loop diuretic
Furosemide
Large acute doses= Deafness, paresthesias, NMusc in
anesthesia, LiCl toxicity.

3) Potassium-sparing
- Sprinolactone, triamterene
Confusion, drowsiness, weakness, dizzy, paresthesias,
headache

Cardiac
Sympatholytics/alpha & beta adrenergic blockers
(vasodilate)
Methyldopa (sedation ~5%)
Clonidine (A2-agonist), sedation, rev. dementia
Reserpine (depletes DA & induces Parkinson-like
effects, depression, appetite, etc.)
Propanolol (beta blocker, tx angina, hypertension,
arrhythmia) lassitude, insomnia, depression, psychosis
(dont give after 8 pm, or in pts with history of
psychiatric illness), impotence, MG due to nicotinic
block
Prazosin (alpha blocker) smooth muscle respnse
to NE, arterial pressure, peripheral resistance,
Effects due to hypotension: dizzy, faintness (~50%),
depression, nervousness, paresthesias, priapism,

Cardiac
Vasodilators
Hydralazine (direct) few Neuro SEs numbness
tingling
Calcium entry agents: Verapamil, nifedipine,
diltiazem
coronary vasc resistance & blood flow. TX
angina or arrhythmia
SEs are common to all 3: dizziness, light-headed,
flushing, headache fatigue, confusion, tremor,
paresthesias, insomnia, sedation, blurred vision,
weakness, nervousness
** Dont combine with beta-blockers without careful
monitoring

Cardiac
Angiotensin-Converting enzyme inhibitors
- work to keep angio levels up and
prevent hypertension.
SEs are related to hypotension: dizziness,
light-headed, vertigo. Transient and related
to dehydration, or impaired renal function

Gastrointestinal Agents
Laxatives deplete K+(electrolytes) = weak
Docusate sodium

Antiemetics DA antagonists? = sedation, dystonia,

muscle spasm, Parkinson-like (tx: anticholinergics acutely)
Metoclopramide, Compazine, Phenergan (promethazine
Scopolamine (anticholinergic) transdermal is best SEs = saliva,
blur vision, sweating, urinary retention, sedation, confusion
Antidiarrheals (opioids) = sedation, resp , > Coma
Bismuth (Pepto-bismol) SEs rare
Antacids (Mg and Al) = electrolyte problems
H2 antagonists inhibit acid secretion: Tagamet/cimetidine, Zantac,
Axid, Pepcid, etc.. SEs: lethargy, confusion, depression,
hallucination, headache ** may alter warfarin or pheytoin
absorption/metabolism

Respiratory
Adrenergics = B2 mediates bronchodilation,
but early drugs werent selective
(isoproterenol, epinephrine, ephedrine).
SEs are cardiac and CNS
B2-selective = Albuterol Terbultaline (inhaled)
have fewer SEs (nausea, vomiting, headache,
tremor
Xanthines = related to caffeine (theophylline,
aminophylline. Only given to chronic pts
(constriction) SEs nausea, headache, insomnia,
nervousness, even seizure (elderly).

Psychiatric Drugs
Neuroleptics: Phenothiazines &
Haloperidol (DA antagonists). SEs=
sedation and Parkinsonian >> tardive
dsykinesias (reserpine tx). tx with levodopa
or dantrolene esp hyperthermia
Confusion in elderly(cholinergic?)
Anxiolytics/benzodiazepines e.g.
meprobamate; = drowsiness, dependence,
dry mouth, tachycardia, sedation, ataxia.

Antidepressants
Tricyclics =anticholinergic SEs:agitation,
confusion, convulsions, cardiac arrhythmia, OD
seen sometimes Physostigmine (Achase inhibitor
will reverse).
SSRIs (fluoxetine/prozac) used mostly now. SEs
nausea, dry mouth, insomnia, agitation,
nervousness, sweating dizziness, tremor, sexual
dysfunction. Not taken with MAOIs.
MAOIs SEs: fever, sweating, tachycardia,
dilted pupils, hypertension
Lithium carbonate manic depresion. SE:
confusion, intentional tremor,

Sedatives
Barbiturates to manage seizure disorders
SEs ataxia, drowsiness, sleep, nausea,
vomiting
Disulfiram to treat alcoholics
acetaldehyde overload . Encephalopathy,
flushing.

Oral contraceptives
Cerebrovascular SEs: stroke is 3-4X more
common in young women taking them.
Also involuntary movements chorea
Migraine headache

Pharmacodynamic Tolerance

Decreased responsiveness to a drug due to changes in site of

action/effector system that render it less sensitive to previously
adequate concentration of drug
Characteristics
Relatively high pharmacological specificity (homologous)
Manifestation independent of route of administration
Time course of hours, days, or weeks
Usually incomplete (i.e., surmountable)
Mechanisms
Receptor down-regulation
Decreased efficiency of receptor-effector coupling
Adaptive changes in intracellular signaling pathways

Pharmacodynamic Tolerance: Rats become progressively less

responsive to analgesic effects of morphine despite
progressively increasing brain concentrations of the drug

Blasig et al., Neuropharmacology 18: 473, 1979

Tachyphylaxis

Rapidly developed tolerance due to depletion of

response mechanism
Characteristics
Partial pharmacological specificity (heterologous)
Time course of minutes
Complete (insurmountable)
Tolerance is lost slower than it develops
Mechanism
Depletion of chemical mediator of drug action

Supersensitivity

Increased sensitivity to the actions of a drug due to

responsiveness
of site of action to same concentration of drug

increased

Postsynaptic (Denervation)
Results from reduced agonist-receptor interaction
Time course of weeks or months
Rate of reversal often faster than rate of induction
Occurs in rodents and primates, including humans
Mechanisms: receptor up-regulation, receptor-effector coupling
Presynaptic
Results from agonist interaction with site of action
Time course of days
Intermittent exposure to agonist more effective than continuous exposure
Greatest when a drug-free interval follows induction regimen
Rate of reversal often slower than rate of induction
Demonstrated in rodents but not yet in primates
Mechanisms: Unknown