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Drugs
Any substance received by a.biological system that is not received for nutritive purposes and which influences the biological function of the organism. Means that chemicals, biological agents and herbal products are all drugs.
When were the majority of clinically useful drugs developed?
Over the past 250 years.
Pharmaology
The science of drugs, including their uses, effects and mechanisms of action.
Key historical influences that have shaped modern pharmacology
The many discoveries made by ancient civilizations
The role of poisons in history.
The influence of religion.
Ancient Civilizations
Healers existed in a number of ancient cultures including Ancient Greece, Ancient Egypt and Ancient China.
Ancient Greece: Threophastus
Threophrastus, a pupil of Aristotle wrote a textbook on therapeutics that included opium.
Opium is obtained from the opium poppy.
Ancient Greece: Serturner
A pharmacist working in Germany in 1803. Isolated crystals of morphine in opium and tested the pure substance. Discovered it could relieve pain.
What does opium contain
Morphine, codeine
Morphine
Opium contains approximately 10% morphine. Coined from Morpheus.
Codeine
Contains 0.5% codeine.
Ancient Egypt
recorded on documents called papyri.
q
Ebers papyrus
1550 BCE: Intended to be a textbook of drug use for medical students.
The papyrus contained mainy true observations on the use of drugs, especially purgatives.
Senna- still used today
Ancient China
Earliest recorded drug experiments come from China in the year 2700 BCE. Shen Nung used to classify drugs according to taste.
Ma Huang was classified as a medium drug. Widely used for coughs, influenza and fevers.
Ephedrine has been isolated from Ma Huang. Used to treat asthma. Can be used as a decongestant.
Poisons: Curare
Plant-derived drug. Historically used by indigenous people in regions of the Amazon.
Curare: Use of a poison
Indigenous peoples of the Amazon dipped their arrows in curare for hunting. Acted upon voluntary muscles causing paralysis.
Curare: Use as a drug
Used by Indigenous People inspired allopathic medicine. Eventually used by anesthetics during surgery. Small doses could relieve muscles. The structure has since been modified to make it safer.
Ergot
A poisonous fungus that grows on the heads of rye.
Ground together with rye in the middle ages, finding its way into bread. Caused terrible epidemics, killing as many as 20 000 people in Russia.
Ergot: Effects of Poisoning; Nervous System
Once it enters the body, ergot targets the nervous system. Results in symptoms such as mental frenzy, hallucinations and convulsions.
Ergot: Effects of Poisoning; Cariovascular System
Ergot poisoning can cause constrictions of blood vessels leading to fingers, toes and limbs becoming starved of their blood supply.
Ergot: Effects of Poisoning; Reproductive System
Can cause violent contractions of the uterus.
Some midwives recognized that small amounts of ergot could be useful in hastening labour. Used as early as the 16th century.
Physicians in the 1800s used ergot to expedite lingering labour. Could result in death.
Ergot: Use as a drug
Ergotamine and ergonovine are the two compounds derived from ergot with pharmocological uses.
Ergotamine
Is useful in the treatment of migraines.
Ergotamine constricts the blood vessels preventing the pulsation of arterial blood vessels that carry blood to the head.
Ergonovine
Once used to hasten birth. Force of uterine contractions may be too strong and parent may be injured by too rapid delivery of the child.
Can be used to arrest uterine bleeding.
The Influence of Religion
Traditional healers acted as both physicians and priests. This results in therapy being heavily influenced on both religion and magic.
Plants containing intoxicating substances were used by traditional healers to alter their state of consciousness and facilitate communication with their gods.
Peyote
A cactus used in Mexico to achieve a mystical state, linked to spiritual and ritualistic use.
Contains a potent substance mescaline, which causes hallucinations, a feeling of well-being and distortion of perception, similar to LSD.
Zinc Oxide
Used in ancient times, considered of great importance to therapies.
Found in a number of topical creams such as rash creams and calamine lotion.
Roman Shipping Vessel
Sunk off the coast of Tuscany around 120 BCE. Excavated in the 1980s and 90s, uncovering ancient roman medical tablets sealed in tin containers.
Analysis of the medical tablets revealed a number of zinc compounds, iron oxide, besswax, pine resin and other plant derived material.
About 25 % of the drugs used today are...
derived from plant sources, with the active substances being purified and then modified to be either more effective or less toxic.
Drugs acting on the brain: discovery
Albert Hofmann worked for a Swiss pharmaceutical firm was involved in trying to synthesize improved pharmaceutical products using ergot.
Synthesized LSD, similar in structure to ergotamine and ergonovine.
Drugs Acting on the Brain
Alter the normal chemical signalling in the brain.
LSD
Lysergic Acid Diethylamide.
Classified as a controlled substance in the 1970s.
Drugs Acting On the Brain: Contribution to Pharmacology
Discovery of LSD psychedelic effects supported the idea that certain mental illnesses may be due to the production of potent substances of the brain that produced distrubance.
Drugs Acting Against Infectious Disease
An infectious disease is any disease caused by an organism.
1900s Organoarsenicals
Paul Ehrlich: Designed complexes of arsenic and organic molecules called orsanoarsenicals which selectively bound to parasites.
Applied to other infectious diseases and led to cure for syphilis.
Syphilis
A bacterial infection transmitted sexually through direct contact with a syphilis sore. Easy to cure when diagnosed and treated early.
1930s: Sulfa Drugs
Gerhard Domagk introduced sulfa drugs in 1930s Germany.
First synthetic drug used for treatment of bacterial disease.
Now termed antibacterial compounds.
1940s: Penicillin
Alexander Fleming discovered penicilin, the first antibiotic.
Introduction to modern medicine occurred during WWII
Majorly used in gram-positive bacterial disease.
Gram-positive
Bacteria with thick cell walls and no outer membrane.
1950s: Streptomycin
Selman Waksman discovered streptomycin. Helped to treat Gram-negative bacterial diseases and tuberculosis.
Gram-negative
Bacteria with thin cell walls and an outer membrane.
Drug development process steps
Basic research and drug discovery, preclinical trials, clinical trials, Health Canada review and manufacturing, post-market surveillance and phase IV clinical trials
3-6 years
Basic research and drug discovery and preclinical trials
6-7 years
Clinical trials
-Phase 1: 10s of patients enrolled in study.
-Phase 2: 100s of patients
-Phase 3: 1000s of patients
0.5-2 years
Health Canada Review and Manufacturing
Continuous
Post-market surveillance and phase IV clinical drug trials.
Drug Discovery: Basic Research and Discovery of Target
Step 1: Identification of the Target
A target for a new potential drug could be a receptor that causes pain relief when activated.
When a compound that binds well to the target is found, it an then be studied to determine its pharmacological effects.
Drug Discovery: Basic Research and Discovery of Target
Step 2: Studying the Target
Lead compounds are compounds that show promise in the initial studies.
Enter more detailed studies for safety and efficacy.
Effficacy
The maximum pharmacological response that can be produced by a specific drug in that biological system.
Preclinical Studies
Conducted prior to testing the drug in humans. Can measure molecules/cells, tissues or whole animals studies.
Two types of clinical studies
Pharmacology studies, toxicology studies
Pharmacology studies
Determine the detailed mechanism of action of the drug.
Toxicology Studies
Determine the potential risks or harmful effects of the drug.
Can look at acute toxicity, chronic toxicity, and effects on reproductive, carcinogenic, and mutagenic potential.
Can take up to 6 years to complete.
Clinical Trials: Initial Steps
Three steps:
-proof of safety
-methodology
-investigation
Proof of safety
The pharmaceutical manufacturer must admit proof of the safety and efficacy of the drug in several animal species.
FDA is American.
Methodology
The methodology of the proposed trial is required.
Investigation
Submission is evaluated by qualified scientists in the regulatory agency. Permission given for clinical pharmacologists to begin the study in humans if satisfied.
Clinical Trials Phase 1, 2 and 3
Occur after permission is granted. Studies performed on humans.
Anywhere from 5-30 compounds may make it through preclinical testing however only one or two will make it to phase III trials,
Phase 1
Evaluate absorption, distribution, elimination and adverse effects of the new drug.
Test one or two doses of the new drug to determine tolerability.
Efficacy not assessed.
Conducted in limited number of healthy volunteers.
Phase 2
Determine whether the drug is effective at treating the condition. Limited number of people, 100-500.
Conducted in patients with the disease for which the drug is designed to treat.
Phase 3
Also called randomized control trials
Number of participants: large number, 1000s
Goal: Determine the safety and efficacy of the drug compared to the placebo/gold standard drug.
Duration: Longer than phase 2 studies
Location: Studies are conducted at centres in many cities. One centre often does not have enough diversity.
Cost: May cost one million to upwards of 50 million dollars.
Design of Phase three clinical trials
Three larger stages:
Determining enrolment prior to the study
Allocating participants to treatment groups and conducting the trial.
Monitoring and analyzing the results.
Hypertension
High blood pressure
Enrolment
The target population is the group of patients for which the drug is intended. A subset of the target population that meets all required criteria is the study population.
Inclusion in the study population is determined by both inclusion/exclusion criteria and consent influence.
Inclusion Exclusion criteria
Characteristics of the patients to be included in the study, determining who is and who is not eligible to be part of the trials.
Common comorbidities are often included.
Comorbidities
One or more conditions present in addition to the primary condition,
Treatment Allocation
Double blind design, randomization, control
Double blind design
Neither the investigator nor the study subject is aware of the treatment the study subject is assigned to. Bias can occur if a study subject believes the drug will work or an investigator may expect positive results.
Randomization
Patients assigned to either a treatment group or a control group. Assigned using a process known as randomization. Helps to ensure the confounding variables (known and unknown) are distributed equally between both groups and removes bias from assigning patients.
Control
Either a placebo or a gold standard drug. Used to compare the actual efficacy of the experimental drug.
Placebo
Does not contain an active drug but is administered the same as the experimental drug. The placebo response can be as high as 40% since people expect themselves to feel better.
Gold standard
The drug accepted by the medical community as the best available treatment for the specific disease at that time. The control group will receive this if available as it is unethical to withhold treatment.
Health Canada Review
The manufacturer will submit a new drug application containing the detailed results of the clinical trials. The drug is reviews by regulatory scientists and can then be granted approval.
Manufacturing: Generic and Brand name
A drug's formal chemical name is too complex for common use. A generic name for the drug is selected while at the same time, the manufacturer will apply for a patent with a brand name for the drug, which will give the company rights to market the drug.
What must any generic versions of the original drug contain?
Identical active ingredients in the same amount and form
Bioequivalent
The same active ingredients are contained in two drug products which give similar blood levels.
Post-Market Surveillance
Risks that are delayed or less frequent than 1/1000 administrations may be missed in phase three clinical trials. Surveillance of the effects of the drugs is required after the drug is released for general use. (Figures out how they're reacting or affecting certain groups)
What factors must one look at to see the effects of drugs on the body?
Drug targets
Drug response
Efficacy and potency
Therapeutic range.
Receptors
A molecule or complex of molecules on the outside/inside of a cell that has a regulatory or functional role in the organism.
Many of the same receptors may exist on a single cell and many of the same cell types exist in an organism.
Opioid receptors cause pain relief when activated. If activated in the gastrointestinal tract then constipation occurs.
How else may drugs interact other than receptors?
Drugs may not interact via receptors, but through a chemical reaction (antacids neutralize stomach acid) or physical chemical forces
Cholestyramine
Cholestyramine is a drug used to lower cholesterol. It works by chemically binding to bile acids in the gastrointestinal tract, preventing their reabsorption and increasing the elimination of bile salts used to make cholesterol.
Ligand
A molecule that binds to a receptor.
How does a drug cause a response
Drugs mimic the action of the endogenous ligand at the receptor.
Agonists
Drugs that bind to and stimulate a receptor.
Antagonists
Drugs that bind to but block the response at a receptor.
Dose-response relationship
Intensity of the pharmacological effects produced by the drug increases in proportion to the dose.
Marijuana
Refers specifically to cannabis product obtained from dried plants.
Subjects experiencing a "social marijuana high"...
Subjects experiencing a "social marijuana high" accumulated significantly more speedometer errors than under control conditions. No differences in accelerator, brake, signal, steering and total errors.
Subjects intoxicated from alcohol accumulated significantly more...
accelerator, brake, signal, speedometer, and total errors than under normal conditions, but no significant difference in steering errors.
What was the findings of driving high or drunk?
Impairment in simulated driving does not seem to be a function of increased marijuana dosage or inexperience with the drug.
Problems with the cannabis v. alcohol study
The intensity of the effects of cannabis increase in proportion to the dose. Large doses of cannabis do impair motor performance.
Dose Response Relationships: Low Doses
Very little response is observed, not many receptors being activated.
Dose Response Relationships: Threshold
As the dose increases, more receptors are activated until the desired response is seen. A certain number of receptors are needed for an effect.
Dose Response Relationships: Therapeutic doses
After the threshold, a small increase in dose results in a large increase in response.
Dose Response Relationships: Maximal Effect
Once the maximal effect is reached, continuing to increase the amount of drug will have no further increase in therapeutic response.
ED50
Effective dose fifty. The dose at which % response is 50%.
Efficacy
The maximum pharmacological response that can be produced by a specific drug in that biological system.
Potency
The dose of a drug that is required to produce a response of a certain magnitude, usually 50% of the maximal response for that drug.
Therapeutic Range
Drugs are administered to achieve a therapeutic effect.
The aim of therapy is to give a dose that keeps the blood concentration above the minimum concentration to produce a desirable response while keeping it below the concentration that produces a toxic response.
Pharmacokinetics
Refers to the movement of a drug into, through and out the body.
Processes Involved in Pharmacokinetics
Administration of a drug can happen through three routes: topical, enteral and parenteral.
Four key processes occur after administration: absorption, distribution, metabolism and excretion (ADME).
