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 (> 5 L/kg) include antidepressants, antipsychotics, antimalarials, narcotics, propranolol, and verapamil. Drugs with relatively small volumes of distribution (< 1 L/kg) include salicylate, phenobarbital, lithium, valproic acid, warfarin, and phenytoin
Paralysis: Loss of motor function (movement) in a certain part of the body. Paralysis may be flaccid, in which muscles are weak and have little or no tone; or spastic, in which the muscles are tight
Twitching: refers to a type of involuntary muscle contraction. A twitch differs from a reflex muscle contraction in that a twitch tends to be repetitive, unwanted, lacking obvious cause, and is not considered part of the normal operation of the body.
The neuromuscular blocking drugs:
-used to produce muscle paralysis and act at the neuromuscular endplate.
The spasmolytic drugs have much milder actions and act at sites other than the muscle endplate.
The pharmacology of the neuromuscular blocking drugs is historically very complex,
and several lectures in this course were once devoted to it. This no longer seems to be
necessary in order to gain the knowledge required to use these agents appropriately.
Much of the complexity of these drugs relates to the varying characteristics of the
blockade they induced (depolarizing versus nondepolarizing), which seems simpler

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 [pseudocholinesterase], is found in blood plasma, liver, glia, and many other tissues
Motor end plate (neuromuscular junction)

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)
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
All these effects are parasympathetically mediated except sweat gland
function, which is the unique sympathetic cholinergic category, much beloved by
examination writers; these nerves are sympathetic because of their thoracolumbar origin
and cholinergic because they release acetylcholine. +

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).
Gastroparesis: nerve or muscle damage in the stomach that causes slow digestion and emptying, vomiting, nausea, or bloating. Also called delayed gastric emptying
Congeners: refers to species belonging to the same genus
Intraocular pressure is lowered within a few minutes following ocular instillation of pilocarpine. It causes contraction of the iris sphincter, which results in miosis (small pupils) and contraction of the ciliary muscle, which results in near (as opposed to distant) focus of vision.

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
Gastroparesis: nerve or muscle damage in the stomach that causes slow digestion and emptying, vomiting, nausea, or bloating. Also called delayed gastric emptying
Congeners: refers to species belonging to the same genus

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
Gastroparesis: nerve or muscle damage in the stomach that causes slow digestion and emptying, vomiting, nausea, or bloating. Also called delayed gastric emptying
Congeners: refers to species belonging to the same genus
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.
Paralysis: Loss of motor function (movement) in a certain part of the body. Paralysis may be flaccid, in which muscles are weak and have little or no tone; or spastic, in which the muscles are tight
Twitching: refers to a type of involuntary muscle contraction. A twitch differs from a reflex muscle contraction in that a twitch tends to be repetitive, unwanted, lacking obvious cause, and is not considered part of the normal operation of the body.
The neuromuscular blocking drugs:
-used to produce muscle paralysis and act at the neuromuscular endplate.
The spasmolytic drugs have much milder actions and act at sites other than the muscle endplate.
The pharmacology of the neuromuscular blocking drugs is historically very complex,
and several lectures in this course were once devoted to it. This no longer seems to be
necessary in order to gain the knowledge required to use these agents appropriately.
Much of the complexity of these drugs relates to the varying characteristics of the
blockade they induced (depolarizing versus nondepolarizing), which seems simpler

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.
Paralysis: Loss of motor function (movement) in a certain part of the body. Paralysis may be flaccid, in which muscles are weak and have little or no tone; or spastic, in which the muscles are tight
Twitching: refers to a type of involuntary muscle contraction. A twitch differs from a reflex muscle contraction in that a twitch tends to be repetitive, unwanted, lacking obvious cause, and is not considered part of the normal operation of the body.
The neuromuscular blocking drugs:
-used to produce muscle paralysis and act at the neuromuscular endplate.
The spasmolytic drugs have much milder actions and act at sites other than the muscle endplate.
The pharmacology of the neuromuscular blocking drugs is historically very complex,
and several lectures in this course were once devoted to it. This no longer seems to be
necessary in order to gain the knowledge required to use these agents appropriately.
Much of the complexity of these drugs relates to the varying characteristics of the
blockade they induced (depolarizing versus nondepolarizing), which seems simpler

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.
Paralysis: Loss of motor function (movement) in a certain part of the body. Paralysis may be flaccid, in which muscles are weak and have little or no tone; or spastic, in which the muscles are tight
Twitching: refers to a type of involuntary muscle contraction. A twitch differs from a reflex muscle contraction in that a twitch tends to be repetitive, unwanted, lacking obvious cause, and is not considered part of the normal operation of the body.
The neuromuscular blocking drugs:
-used to produce muscle paralysis and act at the neuromuscular endplate.
The spasmolytic drugs have much milder actions and act at sites other than the muscle endplate.
The pharmacology of the neuromuscular blocking drugs is historically very complex,
and several lectures in this course were once devoted to it. This no longer seems to be
necessary in order to gain the knowledge required to use these agents appropriately.
Much of the complexity of these drugs relates to the varying characteristics of the
blockade they induced (depolarizing versus nondepolarizing), which seems simpler

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
Paralysis: Loss of motor function (movement) in a certain part of the body. Paralysis may be flaccid, in which muscles are weak and have little or no tone; or spastic, in which the muscles are tight
Twitching: refers to a type of involuntary muscle contraction. A twitch differs from a reflex muscle contraction in that a twitch tends to be repetitive, unwanted, lacking obvious cause, and is not considered part of the normal operation of the body.
The neuromuscular blocking drugs:
-used to produce muscle paralysis and act at the neuromuscular endplate.
The spasmolytic drugs have much milder actions and act at sites other than the muscle endplate.
The pharmacology of the neuromuscular blocking drugs is historically very complex,
and several lectures in this course were once devoted to it. This no longer seems to be
necessary in order to gain the knowledge required to use these agents appropriately.
Much of the complexity of these drugs relates to the varying characteristics of the
blockade they induced (depolarizing versus nondepolarizing), which seems simpler