Drug vs Poison: Reaching the Target

What Separates the Drug From the Poison?

• A true drug reaches its intended target. Six factors are needed to achieve this
• Drug must dissolve in the stomach
• Drug must be absorbed from the gut
• Drug must survive the liver and the body's attempts to destroy it
• Drug must not affect other parts of the body
• Enough of the drug must reach the brain and get through the protective barrier around the brain
• The drug must bind to target
• A compound failing to reach its target can become a harmful poison.

Selectivity and Bone Loss Drugs

• Certain drugs meant to treat bone loss, are toxic
• These bone loss drugs mimic chemicals so they concentrate in bone, improving function.
• In 2003, efforts were made to find drugs that were less toxic, to generate millions of dollars, but were found to cause suicidal thoughts
• The solution is to modify the drug so it cannot reach the brain.
• A Montreal company first solved toxicity issues after 10 years of trying to resolve it.
• The principle of selective toxicity was demonstrated here.
• Restricting a drug’s access to certain areas makes it a drug rather than a poison

Imodium, Ventolin, and Botox: Examples of Selective Drugs

• Imodium can eliminate communities, as an addictive narcotic
• Imodium does not leave the gut, and therefore isn't as damaging to lives and the community
• Ventolin switches on a system controlled by adrenaline
• If Ventolin activates the system, the heart is not affected in a bad way, it is therefore selectively not a poison
• Botox, one of the most toxic substances known, is used for cosmetic purposes only
• There is enough Botox in a small vial to kill everyone in a big city, however it is still injected into the skin in tiny Quantities

The Importance of Selectivity

• Selectivity is the most important attribute that separates the drug from the poison
• Bleach would not be able to get to bacteria without selectivity
• Adalimumab is used for arthritis
• Apixaban is an anticoagulant.
• Lenalidomide and Nivolumab are used for Cancer
• Pembrolizumab is used for Cancer
• Etanercept is used for Arthritis
• Trastuzumab is used for Cancer

Aspirin and Targeted Action

• It is amazing that a simple structure is a chemical that takes away headache
• Out of 20,000 different proteins in the human body, it only targets cyclooxygenase

Common Drugs and Simplicity

• Most widely prescribed drugs are off-patent, generic, inexpensive, old, and reasonably effective
• Hydrocodone and Levothyroxine are common examples.
• Simvastatin, Rosuvastatin, and Amlodipine are further examples of prevalent medications
• Salbutamol, metformin, and chlorothiazide also fit the criteria

Antibiotics

• Antibiotics target bacteria
• Selectivity is the targeting attribute
• Permeability is the ability to easily pass through or be penetrated

Tuberculosis

• Tuberculosis is a disease, but some drugs can treat it
• Antibiotics do not cure every diseases; they do help to control them

Historical Perspective on Infectious Diseases

• The cold, damp Northern climate equals death from respiratory infections
• Hot, Southern climate equals death from gut infections
• USA Major causes of death at the start of the 20th century were pneumonia, TB, and diarrhea
• The USA major causes of death at the end of the 20th century were heart disease, cancer, and stroke
• 1993 infectious diseases accounted for 1.2% of deaths in the developed world
• 1993 infectious diseases accounted for 41.5% of deaths in developing world
• Infections used to kill or make life miserable such as cholera, TB, dysentery, plague, typhoid, typhus, syphilis, leprosy, diphtheria, pneumonia, post-surgery infections, gangrenous wounds, burns, child-birth and even simple cuts and grazes
• Antibiotics has won the war on Infectious diseases

Issues in the Fight Against Illnesses

• Imagine if the slightest cut could kill, imagine surgery was impossible, if the illnesses were not sorted soon, then this might be the reality in the near future
• "Without an effective global effort, drug resistance could claim 10 million lives each year by 2050"– Review on Antimicrobial Resistance, an initiative supported by the U.K. government and the Wellcome Trust in 2015
• Tuberculosis killed more than 1 billion people in the last 200 years
• Tuberculosis By the start of 20th century had killed 1 in 7 of all the humans who had ever lived

Tuberculosis (TB) Statistics and Drug Resistance

• Up to 1/3 of the world’s population may be infected with TB
• 10 million people develop TB each year, and around 50% would die without treatment
• About 1.8 million deaths occurred in 2017
• With drug sensitive TB, it Requires 6 months of treatment, with a cure rate of 85%
• For Multi-drug resistant TB (2017: 580,000 new cases), it requires 18 months of treatment, a cure rate of 48%, and 14,000 pills and injections
• For Extensively drug resistant TB (2017: 50,000 cases), the cure rate is 34% (much less in some studies)

The History of Antibiotic Discovery

• In 1944, Streptomycin was discovered from soil samples, combatting TB, plague, and dysentery.
• In 1945, Cephalosporins was discovered, targeting Typhoid
• In 1947, Chloramphenicol was discovered from a Venezuela soil sample, treating Typhus
• In 1948, Oxytetracycline was discovered from a Missouri soil sample
• In 1949, Chlorotetracycline was discovered from an Indiana soil sample (near the Pfizer factory), used to combat cholera, Lyme disease, plague, and typhus
• In 1952, Vancomycin was discovered from a Borneo soil sample, becoming the "last line of defense"
• In 1957, Erythromycin was discovered from a Phillipines soil sample, targeting the skin and upper respiratory tract
• In 1958, 6-aminopenicillanic acid intermediate was discovered, giving access to semi-synthetic penicillins, treating drug-resistant infections like methicillin, amoxicillin and ampicillin
• In 1961, 7-aminocephalosporanic acid intermediate was discovered, giving access to semi-synthetic cephalosporins

How Antibiotics are Made and why

• Antibiotics Are "Drugs to us, Poisons to Bacteria" and are Natural Products and Screening
• Macrolides from a Philippine soil sample targets tuberculosis
• Tetracyclines from a Missouri soil sample attacks tuberculosis
• Vancomycin from a Borneo soil sample targets tuberculosis
• Monobactams from a New Jersey soil sample targets tuberculosis
• Streptomycin from a "heavily manured field soil" in New Jersey targets tuberculosis
• Cephalosporins from Sardinia sewage outflow targets tuberculosis
• Lincomycins from a Nebraska soil sample targets tuberculosis
• Antibiotics are difficult to make, and is hard to get the desirable traits

How Can a Drug Survive?

• To survive, drugs must be able to pass through barriers
• Selectivity isn’t too difficult, instead permeability is usually our #1 when dealing with Bacteria
• If a drug survives this journey Gram negative drugs then have two more different barriers to get through
• Tuberculosis (TB) drugs have to get through a barrier with the consistency of candle wax at room temperature

The Search for Alternatives

• Nature knows how to deal with the sorts of illnesses, it has had a billion years to work it out, but tuberculosis finds a challenge
• The problem was that some drugs were easy to find, some were difficult and then impossible

Modern Solutions

• Since it is now difficult to find conventional solutions, we have to get creative
• The aim is to identify suitable targets to screen chemical libraries against
• Selectivity should be used

Drug Discovery

• With drug Discovery, the CYP450 inhibition has a target over 50x IC50
• With Drug Discovery, it Has mutagenicity in which the Ames Target are 100 μM
• In vitro toxicity needs a target that is over 50x IC50 with a Hef greater than 23
• High potency is therapeutic
• The process also need to use selectivity to reduce potency to avoid toxicity
• Potent vs therapeutic giving, give at least a >200-fold selectivity
• Drug Discovery: in the current period, modern medication and treatment means that everything is more safe due to testing

Metabolic Functions

• The liver serves to protect us from toxic substances, it detoxifies them by metabolizing them into water soluble compounds which can be excreted via the kidneys
• The liver contains enzymes, Cytochrome P450s (CYP450s), which oxidize drugs into an inactive analogue

Bioavailability Factors and Selectivity

• Now that blood is transfused/ travelling through the body, the question of the drug itself need to be tested There need to be 50% to be considered OK
• Drugs are non-toxic
• A Normal metabolite is inactive and non-toxic
• If too much is Taken, the normal metabolic route is overwhelmed
• The Alternative metabolite is hepatotoxic and leads to permanent liver damage in case of overdose

Important Qualities

• Qualities need to be tested to ensure everything is above board
• Does it exhibit toxicity?
• To test we have to ensure that it has been tested on animals, then humans
• Then it can finally be available to the current mass market, this in turn will mean its been tested and is ready for public Use
• High selectivity is also needed
• "Cytotoxicity" is, a test for general, non-specific toxicity
• Using it only as directed can mean that there has to be limitations
• There is the need to have to be cautious
• If the test is not passed then no new drugs, even one that is going to help
• We need to be clever in the entire production process.

Therapeutic Range:

• It is also required to have a certain range
• Too little means that the medical condition wont be healed, and too little could lead to death, it has to be perfected
• Penicillin’ s therapeutic range is 100%, meaning is will work, most of the time.
• The final verdict will come through with a therapeutic window that is big enough to ensure things will be perfect.

Take Home Messages: Defining a "Drug."

• The four most important factors are that it Needs to have a. the right target b. that is has a high and right form of stability c. it has to be right and selective, not toxic d. It has to have gone through trial and error

Key Considerations for Orally-Active Drugs

• Permeability is also Needed, to ensure that something is not toxic
• The nature has had billion years of trial, but there have to be restrictions such a the CNS, Brain damage

Nature's Role and the Search for Selectivity

• The more that there are issues, the worse it will be
• If there is good and right selectivity, then all cells will respond in the desired manner.
• When finding a "cure" is the objective, there need to be certain things that help.
• The cancer cells must respond the proper way to the treatment