Principles in Management of the Poisoned Patient

1
Principles in Management of the Poisoned Patient

• Toxicokinetics vs Toxicodynamics
• The term "toxicokinetics" denotes the absorption,
  distribution, excretion, and metabolism of
  toxins, toxic doses of therapeutic agents, and
  their metabolites.
• The term "toxicodynamics" is used to denote the
  injurious effects of these substances on vital
  function.
• Volume of Distribution
• The volume of distribution (Vd) is defined as the
  apparent volume into which a substance is
  distributed
• Vd is increased by increased tissue binding,
  decreased plasma binding and increased lipid
  solubility.
• Drug with high Vd ?extensive tissue distribution
  
• A large Vd implies that the drug is not readily
  accessible to measures aimed at purifying the
  blood, such as hemodialysis.
• Examples of drugs with large Vd (gt 5 L/kg)
  include antidepressants, antipsychotics,
  antimalarials, narcotics, propranolol, and
  verapamil. Drugs with relatively small volumes of
  distribution (lt 1 L/kg) include salicylate,
  phenobarbital, lithium, valproic acid, warfarin,
  and phenytoin

2
Antidotes, Definition and Types

• An antidote is a substance which can counteract a
  form of poisoning

• Types of Antidotes
• chemical antidotes combine with the poison to
  create a harmless compound. For example,
  neutralization of acids by weak alkalis, e.g.,
  (HCl ? NaHCO3)
• Physical antidotes prevent the absorption of the
  poison e.g., activated charcoal
• Pharmacological antidotes counteract the effects
  of a poison by producing the opposite
  pharmacological effects, e.g., ACHE inhibitors?
  atropine

3
Some anatomic and neurotransmitter features of
autonomic and somatic motor nerves
N.B. Parasympathetic ganglia are not shown
because most are in or near the wall of the organ
innervated
4
Cholinergic Transmission

• After release from the presynaptic terminal, ACh
  molecules may bind to and activate an ACh
  receptor (cholinoceptor).
• Eventually (and usually very rapidly), all of the
  ACh released will diffuse within range of an
  acetylcholinesterase (AChE) molecule.
• AChE very efficiently splits ACh into choline and
  acetate, neither of which has significant
  transmitter effect, and thereby terminates the
  action of the transmitter.
• Most cholinergic synapses are richly supplied
  with AChE the half-life of ACh in the synapse is
  therefore very short. AChE is also found in other
  tissues, eg, red blood cells.
• Another cholinesterase with a lower specificity
  for ACh, butyrylcholinesterase pseudocholinestera
  se, is found in blood plasma, liver, glia, and
  many other tissues

5
Parasympathetic Nervous System, Receptors for
acetylcholine (cholinoceptors)

• Nicotinic receptors, nAChRs (the nicotinic
  actions of ACh are those that can be reproduced
  by the injection of nicotine)
• At neuromuscular junctions of skeletal muscle
  (muscle type)
• Postsynaptic
• Excitatory (increases Na permeability)
• Agonists ACh, carbachol (CCh), suxamethonium
• Stimulate skeletal muscle (contraction)
• Antagonists tubocurarine, hexamethonium
• On postganglionic neurons in the autonomic
  ganglia (ganglion type)
• Postsynaptic
• Excitatory (increases Na permeability)
• Agonists Ach, CCh, nicotine
• Stimulate all autonomic ganglia
• Antagonists mecamylamine, trimetaphan

6
Parasympathetic Nervous System, Nicotinic
Receptors for acetylcholine

• On some central nervous system neurons (CNS type)
• Pre- and postsynaptic
• Excitatory (increases Na permeability)
• Agonists nicotine, ACh
• Pre- and postsynaptic stimulation of many brain
  regions
• Antagonists methylaconitine, mecamylamine
• On adrenal medulla
• Ach stimulates secretion of adrenaline from
  adrenal medulla

7
Parasympathetic Nervous System, Muscarinic
Receptors for acetylcholine

• Muscarinic receptors, mAChRs (the muscarinic
  actions of ACh are those that can be reproduced
  by the injection of muscarine)
• Location mAChRs are located
• in tissues innervated by postganglionic
  parasympathetic neurons such as
• On smooth muscle
• On cardiac muscle
• On gland cells
• See next table for details.
• in postganglionic sympathetic neurons to sweat
  glands
• In the central nervous system

8
Muscarinic Autonomic Effects of Acetylcholine

• Eye (iris sphincter muscle)
  Contraction (miosis)
• Eye (ciliary muscle)
  Contraction (for near vision)
• SA node
  Bradycardia
• Atrium
  Reduced contractility
• AV node
  Reduced conduction velocity
• Arteriole
  Dilation (via nitric oxide)
• Bronchial muscle
  Muscle Contraction
• Bronchial secretion Increase
• GIT (motility)
  Increase
• GIT (secretion) Increase
• GIT (sphincters) Relaxation
• Gallbladder
  Contraction
• Urinary bladder (detrusor)
  Contraction
• Urinary bladder (trigone, sphincter)
  Relaxation
• Penis
  Erection (but not ejaculation)
• Sweat glands
  Secretion (sympathetic cholinergic!)
• Salivary glands
  Secretion
• Lacrimal glands
  Secretion
• Nasopharyngeal glands
  Secretion

9
Parasympathetic Nervous System,
Summary of Intervention Mechanisms

• Cholinergic neurotransmission can be modified at
  several sites, including
• a) Precursor transport blockade, e.g.,
  hemicholinium
• b) Choline acetyltransferase inhibition, no
  clinical example
• c) Promote transmitter release, e.g., choline,
  black widow spider venom (latrotoxin)
• d) Prevent transmitter release, e.g., botulinum
  toxin
• e) Storage, e.g., vesamicol prevents ACh storage
• f) Cholinesterase inhibition, e.g.,
  physostigmine, neostigmine
• g) Receptors agonists (chlinomimetic drugs) and
  antagonists (anticholinergic drugs)

latrotoxin
10
Muscarinic Agonists (, Cholinomimetics,
Parasympathomimetics)

• Acetylcholine itself is rarely used clinically
  because of its rapid hydrolysis following oral
  ingestion and rapid metabolism following i.v.
  administration.
• Fortunately, a number of congeners with
  resistance to hydrolysis (methacholine,
  carbachol, and bethanechol) have become
  available.
• There are also several other naturally occurring
  muscarinic agonists such as muscarine and
  pilocarpine.
• Bethanechol is used (rarely) to treat
  gastroparesis, because it stimulates GI motility
  and secretion, but at a cost of some cramping
  abdominal discomfort. In addition, it may cause
  hypotension and bradycardia. Bethanechol is also
  widely used to treat urinary retention. This
  agent also occasionally is used to stimulate
  salivary gland secretion in patients with
  xerostomia (dry mouth, nasal passages, and
  throat)
• In rare cases, high doses of bethanechol have
  seemed to cause myocardial ischemia in patients
  with a predisposition to coronary artery spasm
• Pilocarpine is more commonly used than
  bethanechol to induce salivation, and also for
  various purposes in ophthalmology. It is widely
  used to treat open-angle glaucoma, topically.
  Pilocarpine possesses the expected side effect
  profile, including increased sweating, asthma
  worsening, nausea, hypotension, and bradycardia
  (slow heart rate).

11
Antichloinergic drugs

• Nonselective Muscarinic Antagonists
• The classical muscarinic antagonists are derived
  from plants and are nonselective competitive
  antagonists. Atropa belladonna contains atropine.
  Hyoscyamus niger contains primarily scopolamine
  and hyoscine.
• Clinically, atropine is used for raising heart
  rate during situations where vagal activity is
  pronounced (for example, vasovagal syncope). It
  is also used for dilating the pupils. Its most
  widespread current use is in pre-anesthetic
  preparation of patients in this situation,
  atropine reduces respiratory tract secretions and
  thus facilitates intubation.
• Ipratropium (nonselective) is used by inhalation
  as a bronchodilator
• Cyclopentolate and tropicamide (both are
  nonselective also) are developed for ophthalmic
  use and administered as eye drops
• Oxybutinin and tolterodine are new drugs
  developed for urinary incontinence

12
Antichloinergic drugs

• Side effects of muscarinic antagonists include
• constipation,
• xerostomia (dry mouth),
• hypohidrosis (decreased sweating),
• mydriasis (dilated pupils),
• urinary retention,
• precipitation of glaucoma,
• decreased lacrimation,
• tachycardia,
• and decreased respiratory secretions

• Selective Muscarinic Antagonists
• Pirenzepine shows selectivity for the M1
  muscarinic receptor.
• Because of the importance of this receptor in
  mediating gastric acid release, M1 antagonists
  such as pirenzepine help patients with ulcer
  disease or gastric acid hypersecretion.

13
Cholinesterase Inhibitors

• The muscarinic and nicotinic agonists mimic
  acetylcholine effect by stimulating the relevant
  receptors themselves.
• Another way of accomplishing the same thing is to
  reduce the destruction of ACh following its
  release.
• This is achieved by cholinesterase inhibitors,
  which are also called the anticholinesterases.
• They mimic the effect of combined muscarinic and
  nicotinic agonists.
• Cholinergic neurotransmission is especially
  important in insects, and it was discovered many
  years ago that anticholinesterases could be
  effective insecticides, by overwhelming the
  cholinergic circuits (see War Gases below)
• By inhibiting acetylcholinesterase and
  pseudocholinesterase, these drugs allow ACh to
  build up at its receptors. Thus, they result in
  enhancement of both muscarinic and nicotinic
  agonist effect.

14
Cholinesterase Inhibitors, Reversible

• "Reversible" cholinesterase inhibitors are
  generally short-acting. They bind AChE
  reversibly. They include physostigmine that
  enters the CNS, and neostigmine and edrophonium
  that do not.
• Physostigmine enters the CNS and can cause
  restlessness, apprehension, and hypertension in
  addition to the effects more typical of
  muscarinic and nicotinic agonists.
• Neostigmine is a quaternary amine (tends to be
  charged) and enters the CNS poorly its effects
  are therefore almost exclusively those of
  muscarinic and nicotinic stimulation. It is used
  to stimulate motor activity of the small
  intestine and colon, as in certain types of
  non-obstructive paralytic ileus. It is useful in
  treating atony of the detrusor muscle of the
  urinary bladder, in myasthenia gravis, and
  sometimes in glaucoma.
• Some patients encounter muscarinic side effects
  due to the inhibition of peripheral
  cholinesterase by physostigmine.
• The most common of these side effects are nausea,
  pallor, sweating and bradycardia. Concomitant use
  of anticholinergic drugs which are quaternary
  amines (e.g., glycopyrrolate or methscopolamine
  and which therefore do not cross the blood-brain
  barrier) are recommended to prevent the
  peripheral side effects of physostigmine.
• Edrophonium (Tensilon) is a quaternary amine
  widely used as a clinical test for myasthenia
  gravis.
• If this disorder is present, edrophonium will
  markedly increase strength. It often causes some
  cramping, but this only lasts a few minutes.
• Ambenonium and pyridostigmine are sometimes also
  used to treat myasthenia.

15
Cholinesterase Inhibitors, Irreversible

• Long-acting or "irreversible" cholinesterase
  inhibitors (organophosphates) are especially used
  as insecticides. Cholinesterase inhibitors
  enhance cholinergic transmission at all
  cholinergic sites, both nicotinic and muscarinic.
  This makes them useful as poisons.
• They bind AChE irreversibly. Example
  organophosphates (e.g., phosphorothionates)
• Many phosphorothionates, including parathion and
  malathion undergo enzymatic oxidation that can
  greatly enhance anticholinesterase activity. The
  reaction involves the substitution of oxygen for
  sulphur. Thus, parathion is oxidized to the more
  potent and more water-soluble paraoxon.
• Differences in the hydrolytic and oxidative
  metabolism in different organisms accounts for
  the remarkable selectivity of malathion.
• In mammals, the hydrolytic process in the
  presence of carboxyesterase leads to
  inactivation. This normally occurs quite rapidly,
  whereas oxidation leading to activation is slow.
• In insects, the opposite is usually the case, and
  those agents are very potent insecticides.

16
Insecticide Poisoning

• Causes and symptoms
• Exposure to insecticides can occur by ingestion,
  inhalation, or exposure to skin or eyes.
• The chemicals are absorbed through the skin,
  lungs, and gastrointestinal tract and then widely
  distributed in tissues.
• Symptoms cover a broad spectrum and affect
  several organ systems
• Gastrointestinal nausea, vomiting, cramps,
  excess salivation, and loss of bowel movement
  control
• Lungs increases in bronchial mucous secretions,
  coughing, wheezing, difficulty breathing, and
  water collection in the lungs (this can progress
  to breathing cessation)
• Skin sweating
• Eyes blurred vision, smaller sized pupil, and
  increased tearing
• Heart slowed heart rate, block of the electrical
  conduction responsible of heartbeat, and lowered
  blood pressure
• Urinary system urinary frequency and lack of
  control
• Central nervous system convulsions, confusion,
  paralysis, and coma