History of Drug Use and Development

History of Drug Use and Development

• Useful drugs like opium were discovered over 2000 years ago
• Clinically useful drugs were predominantly developed in the past 250 years
• Modern pharmacology has been shaped by discoveries by ancient civilizations, the role of poisons, and the influence of religion
• Healers in ancient Greece, Egypt, and China have influenced modern pharmacology

Discoveries in Ancient Civilizations

• In ancient Greece in 380 BCE, Theophrastus wrote a textbook on therapeutics that included opium from opium poppy.
• In 1803, a German pharmacist isolated morphine crystals from opium, discovering their pain-relieving effects.
• Opium contains 10% morphine and 0.5% codeine, relieving extreme pain.
• Ancient Egyptians recorded history on papyri, including a textbook of drug use for medical students about purgatives, such as senna, which is still used today.
• Ancient China was the site of the earliest recorded drug experiments, where the Emperor classified drugs by taste.
• Ma huang was used for coughs and fevers
• Ephedrine has been isolated from ma huang to treat asthma, and a derivative is used as a decongestant.

Poisons in Ancient Times

• Poisons were used in ancient times leading to the development of current drugs like curare which was a plant-derived poison used to paralyze animals during hunts by indigenous Amazonians
• Curare is now used in surgery as an anesthetic for muscle relaxation
• Ergot, a poisonous fungus on rye, caused epidemics 250 years ago

Influence of Religion

• Healers acted as physicians and priests, using plants with toxic substances to alter consciousness for communication with a god

Definition of a Drug

• A drug is any non-nutritive substance received by a biological system affecting the organism's biological function; includes chemicals and herbal agents.
• Example: Caffeine as a non-nutritive substance used to stay awake
• About 25% of drugs are derived from plants and may be purified or modified

Drugs Targeting Different Diseases and Systems

• Brain signaling is altered by drugs like LSD and psychedelic derivatives treat mental illnesses, anxiety, and depression.
• In the 1900s Paul Ehrlich created arsenic complexes to bind to parasites, and the 1930s saw the introduction of sulfa drugs as antibacterial compounds.
• In the 1940s, penicillin was introduced (Alexander Phelinin) to treat gram-positive bacterial diseases.
• In the 1950s, streptomycin was introduced to combat tuberculosis and gram-negative diseases
• Penicillin resistance limits its use today, but some derivatives are still effective.

Drug Development and Trials

• Drug development involves basic research, preclinical studies, clinical trials, Health Canada review & manufacturing, and post-market surveillance
• Basic drug research identifies a target for drug action
• The first step in drug development to study the target's molecular, cellular, and organ-level effects which are receptors involved in pain relief
• Promising compounds become lead compounds, which then undergo detailed safety and efficacy studies

Preclinical and Clinical Studies

• Preclinical studies on drugs range from molecular and cellular studies to tissue and whole animal studies.
• Pharmacology studies establish the drug's mechanism of action.
• Toxicology studies find potential risks such as acute toxicity, chronic toxicity, and effects on reproduction, carcinogenicity, and mutagenicity which can be expensive and take years
• Manufacturers need to submit proof of safety and efficacy in animals, provide the methodology for human clinical trials, and obtain approval from scientists

Clinical Trial Phases

• Clinical trials are studies done on humans and involve Phase 1, Phase 2, and Phase 3. Most drugs do not pass all 3 phases.
• Phase 1 determines a drug's absorption, distribution, elimination, and adverse effects on healthy volunteers while observing doses for tolerability.
• Phase 2 looks to determine drug effectiveness in treating the condition by testing on a limited number of patients (100-500) and observing drug safety.
• Phase 3 is randomized controlled trials which get a drug licensed and marketed
• Phase 3 studies involve large, diverse groups to compare the drug’s safety and effectiveness compared to no treatment and can take months to years and can cost upwards of $50 million.

Phase 3 Steps

• Enrollment requires carefully defined criteria and using a target population.
• Treatment allocation needs to be double blind, minimizing bias. Results are measured and compared objectively to determine the treatment's effectiveness
• Health Canada will approve the drug if it is effective and the toxicity is acceptable

Drug Nomenclature and Bioequivalence

• Manufacturers create a drug name (generic) and brand name
• Chemical names are too complex leading to generic names, and manufacturers apply for brand-name patents, which gives the company 20 years to market it
• Factoring in preclinical development time, patents are around 10 years
• Two drugs are bioequivalent if their generic and brand names contain the same active ingredient and give similar blood levels
• Comparing blood levels of the original and new drug being administered to healthy volunteers determines Bioequivalence.
• Phase 4 is done because administrations may be missed or not discovered in phase 3, thus post-release surveillance occurs

Drug Action

• Considerations for a drug's action: drug targets, drug response, efficacy, potency, and therapeutic range
• Drug targets should only act with one target in the body, usually receptors.
• Receptors are located on the inside or outside of a cell that have a regulatory or functional role in the organism which are bound to and activated by endogenous ligands like hormones or neurotransmitters.
• Some drugs, like antacids, act with biological systems and not receptors by neutralizing stomach acid through acid-base neutralization
• Most drugs either mimic or block the action of the natural ligand at the receptor.
• Agonists stimulate the receptor
• Antagonists block the receptor

Drug Response

• Generally, the intensity of the drug effects is called dose-response relationship
• A dose threshold means a number of receptors need to be activated for a response
• A small increase in dose leads to a large increase in response until the maximum effect is reached, and increasing the dose has no further effect
• Drug effect is on the y-axis and has a max of 100
• The dose is on the x axis
• The dose is proportional to response and small increases in dose lead to large increases in response in the therapeutic range
• ED50 is the dose that will result in 50% response and the curve will hit a plateau and max effect
• Efficacy describes a drug's ability to produce a response
• Potency: dose is required to produce a response of magnitude (50%) and the drug is more potent you have to take less of it

Therapeutic Range

• Therapy aims to give a dose that keeps the blood concentration above a minimum for the desired response, and below an unacceptable toxicity
• Wider therapeutic range means safer drug

Pharmacokinetics

• Pharmacokinetics is the movement of a drug into, through, and out of the body.
• Three routes of administration: topical, enteral, and parenteral
• Topical routes are applied directly to the skin
• Enteral routes go through the GI tract through mouth, rectum, or under the tongue/cheek.
• Parenteral routes bypass the GI tract through, intravenous intramuscular and subcutaneous

ADME - Absorption, Distribution, Metabolism, Excretion

• After administration four factors determine drug concentration in the blood: absorption, distribution, metabolism, and excretion (ADME).
• Topical administration includes application to skin, through the skin, or by inhalation to treat mild to moderate skin conditions like acne.
• Transdermal drug delivery involves skin absorption for systemic effects which is convenient because it bypasses stomach enzymes, the liver, and intestines. Also, steady drug supplies are delivered for days, but it’s expensive.
• Rapid absorption happens through inhalation which is used for local and systemic effects. Quantities of drugs are small avoiding toxicity. Requires proper patient use.
• Enteral routes enter blood through the GI tract. When absorbed, the drug is delivered to the liver, which decreases the amount of active drug that is left to enter the general circulation which is called the first pass effect
  • The mouth is a common, least expensive and most convenient administration route but can have variable absorption due to differences in intestinal motility and disease
  • The rectum is for systematic or local effects, circumvents vomiting/digestive enzymes, but absorption can be slow due to limited rectum medications
  • Sublingual & buccal routes bypass digestive enzymes

Parenteral Administration

• Intravenous (IV) drugs have immediate effects that are used for poorly absorbed substances and have the highest risk for drug reactions because its irreversible and requires trained personnel and preparation.
• Intramuscular (IM) injections are delivered deep into muscle.
• Subcutaneous (SC) injections are administered into the skin's deepest layer allowing for adjustments to preparations that control the timing of release from the injection site
• Not all of the administered drug enters the blood in other words, the bioavailability differs
• Bioavailability is the dose fraction that reaches the blood in an active form
• IV is the fastest administration route and the drug goes straight into the bloodstream and has one hundred percent bioavailability.
• Second fastest= Sublingual because it absorbs into blood vessels under the tongue.
• Slowest/most common administration route is Oral, which goes through the stomach (followed by GL tract in small intestine) where a portion of the drug is metabolized/excreted

Drug Passage

• Once a drug enters the body it goes through 4 stages
• First process is absorption: movement of a drug from its administration site into the blood which requires crossing a biological membrane
• Distribution is the movement of a drug from the blood to the site of action and other tissues
• Most drugs reach all tissues/organs
• Rate of drug distribution depends on blood flow
• Free drug in the bloodstream can go to the therapeutic site of action, to tissue reservoirs, or cause adverse effects. The drug could also be bound to protein (no therapeutic effect)
• Metabolism is the conversion of a drug to a different chemical compound
• Products of metabolism are metabolites which are usually devoid of pharmacological action
• To be eliminated from the kidneys in the urine, a drug must be water-soluble
• Most metabolism occurs in the liver
• Metabolism/biotransformation occurs sequentially in 2 phases
• Phase 1 prepares the drug by adding or unmasking a functional group
• Phase 2 adds a large, water-soluble molecule
• P450 enzymes are in the liver
• Drug excretion moves the drug and its metabolites out of the body
• The drug and its metabolites are eliminated by kidneys in urine
• Lipid Soluble drugs can be reabsorbed or eliminated by lungs. Drug Misuse can be detected in saliva
• The recommended dose is the amount causing the desired effect, but people react differently, so it needs to be adjusted

Drug Toxicity and Interactions

• An adverse drug effect is unintended - Extension: too much drug in blood (overdose) - Unrelated effects include nausea - Allergic reaction - Withdrawal and addiction - Teratogenesis develops fetus problems - Biotransformation metabolite can bind to tissue and cause tissue damage
• Rare toxic reactions may appear only after prolonged use and cannot be detected in animals etc
• Toxicity/therapeutic index is TD50/ED50
• A safe drug has a higher therapeutic index
• TD50: dose toxic in 50% of population or ED50%: dose effective in 50%
• A drug-drug interaction occurs when one drug changes the effects of another -A drug during absorption can increase intestinal movement and decrease the contact of a 2nd drug decreasing absorption -A drug during metabolism can block the inactivation of a 2nd drug increasing blood levels
• Lastly drug excretion can facilitate 2nd drug excretion to decrease blood effects
• Drug-food interference is food interfering with drugs
• Example: high tyramine is in cheeses and is capable of raising blood pressure broken down during MAO
• MAO inhibitors are antidepressants which intensifies tyramine effects. Grapefruit alters absorption

Central Nervous System Aspects

• The cerebral cortex is the largest part of the brain, rich in neurons and involved with sensory and motor coordination, intelligence, memory, and consciousness etc
• The limbic system integrates memory, emotion, and reward and contains the dopamine reward center associated with misuse
• Neurons generate electrical signals
• New neurons are generated through neurogenesis to reshape neuroplasticity
• Neurons are made up of dendrites, the axon, and a cell body with cytoplasm containing neurotransmitters which are secreted and are a complex branching pattern that accepts incoming data through the dendritic membrane
• The Axon is a sinlge fiber that carries the impulse away electrically
• The synapse is the junction between two neurons
• Synaptic transmission is where neurotransmitters are used to activate the next neuron
• The synapse is a target site for drugs by either enhancing effect or stopping transmission

Neurotransmitters

• Glutamate is primary excitatory neurotransmitter in CNS important involved in learning and acts on family of glutamatergic receptors
• Serotonergic system hyperactivity is involved in anxiety/depression while CNS stimulants can increase serotonin neurotransmitters at synsape
• Dopamine is involved controlling hormonal systems, motor coordination, and reward while Norepinephrine can bind receptor types but activation leads to excitation
• Acetylcholine produces an excitatory response with nicotine and muscarinic receptors that can be stimulated while the drugs block action of receptors create amnesia for Alzehmers
• GABA is inhibitory neurotransmitter
• CNS depressants enhancs GABA
• 3 types of opioid peptides exist: enkephalins, endorphins and dynorphins which are all varying in kappa, mu, and deltareceptors