Toxicologythe wrong side of the quantal response The

Toxicology-the wrong side of the quantal response Ø The study of the harmful actions of chemicals on living organisms

Toxicology includes: 1) Intentional poisonings 2) Inadvertent exposure of chemicals 3) Unintended effects of drugs

1) Intentional poisonings Q: Why is it difficult to poison someone without the poison being detected?

Q: What receptors could Joffrey’s poison be acting on?

Q: What receptors could Joffrey’s poison be acting on?

Q: What receptors could Joffrey’s poison be acting on?

Q: What receptors could Joffrey’s poison be acting on? acetylcholine parasympathetic epinephrine/ norepinephrine

Strychnine poisoning

Properties of prostaglandins (COX-1, COX-2 )

1) Intentional poisonings: a brief history Socrates: 399 BC – sentenced to kill himself by drinking hemlock Ø Antagonist of acetylcholine receptors (major receptor of nerve and muscle cells) Ø Death usually results from paralysis of respiratory muscles

1) Intentional poisonings: a brief history

1) Intentional poisonings: a brief history Inhibitors of acetylcholinesterase: Ø Novichok (March 2018 – poisoning of Sergei and Yulia Skripal) Ø VX gas (Feb 2017 – poisoning of Kim Jong-nam) Ø Sarin gas (2017 – Syria; 1995 - Tokyo subway; 1988 – Iran-Iraq war; 1950 -1970 stockpiled by both USSR and NATO) organophosphates:

Roman Emperor Claudius 54 AD- believed to have been murdered by wife with aconite from the plant monkshood. Ø Agonist of a type of sodium channel found in nerve cells. Ø Death results from heart arrythmias and failure.

Napoleon Bonaparte 1821 - Suspected to have died from arsenic poisoning Ø Europeans referred to arsenic as the “King of Poisons” because of its discreetness and potency, until test developed for its detection in 1836. Ø The Chinese used arsenic smoke in war as far back as 1000 BC Ø Has similar properties to phosphorous, and is found immediately below it in periodic table. Ø Able to compete with phosphorous and essentially act as an antagonist for a large number of enzymes.

1914 -1918: Approximately 1. 3 million casualties and 90, 000 deaths from use of chemical weapons during World War I. Ø These chemicals included chlorine, hydrogen cyanide releasing compounds, phosgene and mustard gases. http: //www. independent. co. uk/news/world-history/history-of-the-first-world-war-in-100 -moments/a-history-of-the -first-world-war-in-100 -moments-an-eye-witness-account-of-the-first-gas-attack-9294510. html

Haber process N 2 + 3 H 2 → 2 NH 3 Ø Approximately 80% of nitrogen in most individuals from industrial countries is derived from the reaction.

The first anti-cancer drugs were mustard gas derivatives Q: where does the specificity come from?

What other classes of drugs derive their therapeutic benefit through the killing of undesired cells?

1915: Alexander Flemming

Chemotherapy: drugs that derive their benefit through killing or inhibiting unwanted cells or organisms: 1. anti-cancer drugs (anti-neoplastic drugs) 2. anti-bacterial drugs (antibiotics)

Why in general is it easier to develop new anti-bacterial drugs than it is to develop novel anti-cancer drugs ?

Why in general is it easier to develop new anti-bacterial drugs than it is to develop novel anti-cancer drug ? Selective toxicity: Ø Unique cellular structures Ø Unique biochemical pathways Ø Greater dependence on a pathway than a healthy human cell Ø Growth characteristics

2) unintended toxicities Ø At least 3, 000 known chemicals. Ø Includes at least 100, 000 different industrial chemicals that are incorporated into 300, 000 consumer products marketed in US.

Carbon monoxide poisoning Ø Colorless and odorless gas formed from incomplete combustion of hydrocarbons

Carbon monoxide incidents ~ 400 deaths in US per year Q: Why is CO toxic?

CO binds hemoglobin ~ 250 x stronger than oxygen

Treatment?

Hyperbaric chamber – how does it work?