Module 1 Section 1 And 2 History And Drug Development

Question 1

Central Nervous System (CNS)

Answer 1

The portion of the nervous system comprised of the brain and spinal cord

Question 2

Drugs definition

Answer 2

Any substance received by a biological system that is not received for nutritive purposes and which influences the biological functions of the organism. This broad definition means that chemicals, biological agents and herbal products are all considered drugs

Question 3

Pharmacology definition

Answer 3

The science of drugs, including their uses, effects, and mechanisms of actions

Question 4

Early written records from blank and blank provide a glimpse of the ancient traditions of drug use

Answer 4

China and Egypt

Question 5

When were drugs discovered

Answer 5

A few useful drugs like opium were discovered 2000 years ago but the majority of clinically useful drugs were developed over the past 250 years with the advent of experimental biological science like pharmacology

Question 6

List several key influences that have shaped modern pharmacology

Answer 6

1. The many discoveries made by ancient civilizations
2. The role of poisons in history
3. The influence of religion

Question 7

How did ancient civilization discoveries shape modern pharmacology?

Answer 7

Although pharmacology only a few years old, healers existed historically in traditional cultures of ancient times

Ancient Greece: in 380 B.C.E Theophrastus, a pupil of aristotle, wrote a textbook on therapeutics including opium (obtained from opium poppy (palaver somniferum)). Serturner, a pharmacist working in Germany in 1803 isolated crystals of morphine from opium and tested on himself and the three companions, discovering its pain relieving capabilities
Opium found to contain 2 important substances: morphine and codeine

Ancient Egypt: recorded on documents called papyri
-a papyri, the beers papyrus dating 1550 B.C.E was intended to be textbook of drug use for medical students
-contains many true observations of drugs like purgatives which cause bowel movements
-one drug recommended for use was senna which still available today

Ancient China: earliest drug experiment in 2700 B.C.E.
-emperor Shen Nung classified drugs according to taste
-ex. Drug Ma Huang classified as a “medium drug”. Widely used for coughs, influenza and fevers in Chinese medicine in past
-now ephedrine isolated from Ma Huang and used to treat asthma, and derivation of ephedrine is used as a decongestant.

Question 8

Morphine

Answer 8

-opium contain approximately 10% morphine
-serturner named from Morpheus meaning god of dreams
-able to relieve pain in great intensity unlike aspirin (acetylsalicylic acid) and Tylenol (acetaminophen) which only relieve moderate pain
-commonly used today

Question 9

Codeine

Answer 9

-opium contains 0.5% codeine
-widely used for pain relief and a constituent of Tylenol-3, a prescription drug in Canada

Question 10

How did the influence of poison effect modern pharmacology

Answer 10

-discovery of positions resulted in discovery and development of drugs still used today.
“All substances are poisons. There are none which is not a poison. The right dose differentiates a poison and remedy”-Paracelsus, 16th century Swiss physician
Exs.

Curare
-a plant-derived drug
-historically used by indigenous peoples in various regions of amazon rainforest in South America
Use as poison:dipped arrows in to use as poision for hunting. Acted upon voluntary muscles of the animal, causing paralysis and eventually death by respiratory paralysis.
Use as drug:inspired allopathic medicine and eventually curare used by anesthetists during surgery. Giving small dose=muscle relaxation=facilitating surgeons work. Still used today, has been modified to make safer

Ergot
-poisonous fungus that grows on the heads of rye, particularly during wet seasons
-in Middle Ages, ergot grounded together with rye, finding its way into bread
-resulted in terrible epidemics
-250 years ago one of these epidemics killed 20,000 people in one region of Russia
Effects of poisoning: nervous system (once enter body, target nervous system. Results in symptoms like mental frenzy, hallucinations and convulsions), cardiovascular system (can cause constriction of blood vessels leading to fingers, toes, and limbs being starved of their blood supply, and a resulting burning sensation. Overtime limps become black and die and may fall off), reproductive system (cause violent contractions of uterus. Early as 16th century midwives recongnized small amounts of ergot could be useful in hastening labour. In 1800s physicians used ergot to expedite lingering labour but if used incorrectly, may cause death)
Use as a drug: 2 compounds derived from ergot have pharmacological use
Ergotamine: treats migraines (one theory says migraines caused by pulsation of arterial blood vessels that carry blood to head so ergotamine constricts blood vessels, reducing amplitude of pulsation.
Ergonovine: once used to hasten birth but not now as force of uterine contractions may be too strong and parent may be injured by too rapid delivery of child. Can be used to arrest uterine bleeding after childbirth.

Question 11

How did the influence of religion effect modern pharmacology

Answer 11

-in ancient societies traditional healers acted as physicians and priests, causing therapy to be heavily influenced by religion and magic
-most countries had plants containing intoxicating substances used by traditional healers in order to alter state of consciousness and facilitate communication with their gods
Ex. Peyote drug
-used in Mexico
-used to achieve mystical state, which linked to spiritual and ritualistic use
-contains potent substance mescaline, which cause hallucinations, feeling of well-being and distortion of perception similar to LSD (Lysergic acid diethylamide. A potent hallucinogenic that acts on the brain).

Question 12

Ancient Rome medicine

Answer 12

-zinc oxide considered great importance in therapies
-Roman shipping vessel sunk off coast of Tuscany around 120 B.C.E.
-in 1980 and 90 ruins of shipwreck excavated
-analysis of medical tablets revealed number of zinc compounds in addition to iron oxide, starch, beeswax, pine resin, and other plant-derived materials
-eye wash medicine?
-today zinc oxide found in number of topical creams today including diaper rash creams and calamine lotion

Question 13

About blank percent of the drugs used today are derived from plant sources with the active substances being purified and then potentially modified to either be more efficient or less toxic

Answer 13

25%

Question 14

Drug discovery of the 19th century

Answer 14

-heralded the era of chemical synthesis and most drug discovered or introduced into therapy were small molecules obtained by chemical synthesis in laboratory

2 major categories of drugs discovered throughout history
1. Drugs acting on the brain
-drugs that alter the normal chemical signalling in the brain
-ex. LSD or lysergic acid diethylamide which most potent hallucinogenic drug
LSD synthesized in 1943 by Albert Hofmann who worked for Swiss pharmaceutical firm
was involved in trying to synthesize improved pharmaceutical products based on components of ergot
LSD similar in chemical structure to ergotamine and ergonovine
Psychedelic effects of LSD supported idea certain mental illnesses might be due to production of potent substances in brain that could produce psychic disturbance.
Research into potential therapeutic effects of LSD stopped around 1970s as classified as controlled substance
-recently, some evidence indicate derivatives of psychedelic compounds like LSD might be effective in treating certain mental illnesses like depression, anxiety, addiction

2. Drugs acting against infectious diseases
   1900s: organoasrenicals
   Paul ehrlich designed complexes of arsenic and organic molecules (called organoarsenicals) which selectively bound to parasites. This idea applied to other infectious diseases and led to dramatic cure for syphilis (bacterial infection transmitted sexually through direct contact with syphilis sore. Syphilis is easy to cure when diagnosed and treated in early stages) in early 20th century
   1930s: Sulfa drugs
   Gerhard domagk introduced sulfa drugs in 1930s in Germany. These were first successful synthetic drugs for treatment of bacterial diseases and now termed antibacterial compounds (antibiotics refers specifically to chemical structure produced by microorganisms and not synthetic compounds)
   1940s: penicillin
   Alexander Fleming discovered first antibiotic, penicillin. Introduced into modern medicine occurred during Second World War. Major use was therapy of gram-positive (bacterial with thick cell wall and no outer membrane) bacterial diseases like diphtheria and staphylococcus
   1950s:streptomycin
   Selman Waksman discovered a different kind of antibiotic, streptomycin. Turning point in treatment of tuberculosis and gram negative (bacterial with thin cell walls and outer membrane) bacterial diseases like cholera and E. Coli

Question 15

Infectious diseases

Answer 15

Any disease caused by an organism, such as bacteria viruses, fungi, or parasites. The introduction of drugs to combat infectious disease was a major milestone in drug development

Question 16

Explain antibacterial compounds verse antibiotics

Answer 16

antibacterial compounds refer to synthetic compounds
antibiotics refers specifically to chemical structure produced by microorganisms and not synthetic compounds

Question 17

What are the 5 major steps to drug development

Answer 17

-basic research and drug discovery
-preclinical trials
-clinical trials
-Health Canada review and manufacturing
-post-market surveillance and phase IV clinical trials
*refer to good notes for nice summary photo

Question 18

Steps 1 to drug development
Drug Discovery: Basic Research and Discovery of Target

Answer 18

Step 1: identification of the target
-could be a receptor that when activated, causes relief of pain
-once a compound that binds well to target is identified, will be studied to determine its pharmacological effects at the molecular, cellular, organ, and whole animal level

Step 2: studying the target
-if compound shows promise in initial studies, it is identified as a lead compound and enters more detailed studies for safety and efficacy (maximum pharmacological response that can be produced)
-in ex. Of developing new drug to relieve pain, effect of the drug on pain would be studied

Question 19

Step 2:Preclinical studies
Is the drug safe and effective?

Answer 19

-conducted prior to testing new drug in humans
-range from molecular and cellular studies to tissue and whole animal studies
2 main categories
1. Pharmacology studies
-determine the detailed mechanism of action of new drug
Ex. If drug developed to treat high blood pressure, how the drug lowers blood pressure would be determined (ex does the drug dilate blood vessels?)
2. Toxicology studies
-determine the potential risks or harmful effects of the drugs
-all drugs have some toxicity at some dose in some individuals
-studies performed to look at acute toxicity, chronic toxicity and effects on reproductive, carcinogenic and mutagenic potential
-these expensive and may take 6 years to complete

Question 20

Step 3: Clinical trials

Answer 20

Initial steps:
Before testing a new drug on humans, three main steps are required before proceeding

1. Proof of safety - pharmaceutical manufacturer must submit proof of safety and efficacy of drug in several animal species to government regulatory agency in particular country concerned.
   -in Canada, this is the Health Products and Food Branch, and in USA it is the Food and Drug Administration (FDA)
2. Methodology - methodology of the proposed clinical trial in humans is required (problem solving approach?)
3. Investigation - submission evaluated by qualified scientists in regulatory agency.
   -if satisfied, permission given for highly qualified investigators, usually clinical pharmacologists, to begin investigation of drugs in humans
   -particular care is taken since animal studies will not always predict drug behaviour in humans regardless of how carefully the studies are conducted

Phase 1, 2, 3
Once initial steps complete and permission granted, manufacturer can begin clinical trials which are performed on humans
-NOTE: generally for a certain drug target, 5 to 30 compounds make it through preclinical testing and into clinical trials but many drugs fail phase 1 or phase 2 clinical trials. Usually only 1 or 2 make it into phase 3 clinical trials

Phase 1:
-carefully evaluate the absorption, distribution, elimination, and adverse effects of the new drug
-test 1 or 2 doses of the new drug to determine the tolerability of the drug
-efficacy of a drug is not assessed during this phase
-usually conducted on young healthy adults in a limited number of 20-80 people (normally around 50)

Phase 2:
-once passed phase 1 enter phase 2
-looking to determine whether drug effective in treating condition for which recommended
-limited number of people (100-500) who affected by disease for which drug designed to treat
-pay careful attention to safety of the drug

Phase 3:
-often called randomized controlled trials (RCT)
-main studies used for licensing and marketing of the drug
Number of participants- usually 1000+ of people who affected by disease to obtain information about the drug in a more diverse population
Goal- determine how safe and effective the drug is compared to no treatment (placebo) or the current recommended therapy
Duration- usually longer than phase 2 studies (months to years)
Location- conducted at centres in many cities (multi-centred) as one centre usually does not have the required number of diversity in patients
Cost- most expensive part of drug development; a phase 3 trial may cost one million to upwards of 50 million dollars

Question 21

Design of Phase 3 clinical trials

Answer 21

Phase 3 clinical trials are divided into three larger stages

1. Enrolment
   -determining enrolment prior to the study
   -people of the new drug is tested on have to be carefully defined (target population group of patients for which drug is intended for)
   Ex target population for a drug to treat hypertension (high blood pressure would be adults with a clinical diagnosis of hypertension, target population for oral contraceptive would be sexually active biological females of reproductive age

Study population is subset of the target population that meets all required criteria
2 major factors influencing who can be included in study population includes inclusion/exclusion criteria and consent

Inclusion/exclusion criteria:
-determine who is verse not eligible to participate in trial
-carefully eliminate variables other than the drug under study that may influence result while being representative of target population
Ex severity of disease carefully defined like with stages of cancer as patient with mild form of disease may see greater benefit from drug verse patient with severe form
-patients with diseases or conditions that could influence results typically excluded
-common comorbidities (One or more condition present in addition to primary condition) are often included in trials to represent target population
Ex most common comorbidity of diabetes is hypertension

Consent criteria:
-informed consent must be obtained before participant is able to participate in clinical trial
-a document written in non-scientific language outlining purpose of study, procedures that will be used and all the potential risks and benefits that may occur.
-investigators must ensure participant fully understands consent form before it is signed

-trial methodology and informed consent documents reviewed by an independent Institution Ethics Review Board to protect rights of participants
-participant can revoke consent and withdraw from study without penalty at any point

2. Treatment Allocations

Double blind design:
-allocating participants to treatment groups and conducting the trial
-most phase 3 studies conducted in double blind manner where neither investigator nor study subject is aware of treatment the study subject is assigned to
- this prevents the bias that can occur if study subject believes drug will work or investigator may be expecting positive results from drug and cause bias in results

Randomization:
-participants assigned to experimental treatment group (receiving new drug to be tested) or a control group
-to ensure groups similar, patients assigned by randomization which usually computer generated system
-ensures confounding variables (known and unknown) distributed equally between experimental and control groups
-removes any potential bias in assigning patients to groups

control:
-efficacy and safety of experimental drug has to be compared to control drug, which either a placebo or gold standard drug

3. Results

Outcome:
-to determine of the experimental treatment was more or less effective than the control, an outcomes of the trial that measures how much drug worked in each participant needs to be measured and compared
-should be measured in objective and reliable manner
For ex if trial was for a drug treating hypertension, the outcome would be blood pressure, and measuring blood pressure would ideally be done at the same time of day, by a limited number of trained study investigators and using the same technique. This strategy ensures consistency from day to day and from investigator to investigator.

Compliance, quality of life and statistics:
-these 3 factors greatly influence the interpretation of a phase 3 clinical trail and must be considered when analyzing results

Compliance-if results of trial are to be valid, patient compliance(refers to how often the patient actually took the drug when they were suppose to) must be determined
-can be as low as 50% to 60%
-for orally administered drugs, generally participants asked to return unused drugs at each clinic visit and a a new batch of the appropriate drug handed out. Count of remaining tablets is an indication of overall compliance
-for drugs given intravenously, compliance is measured by checking that the nurse signed off on administering the drug

Quality of life-most clinical trials measure impact of the drug or treatment on quality of life of participant
-don’t always improve
-some drugs effective in treating disease but may have adverse effects or be so cumbersome to take that may not improve overall quality of life
-should be considered when determining the usefulness of a drug

Statistics-measured outcome for experimental drug must be compared to the measured outcome for the control drug using statistics
-in some clinical trials, difference between experimental drug and control drug may be as small as 2% and only proper use of statistics can determine whether the difference is real or happened by chance

*look at goodnotes for a good summary

Question 22

Placebo

Answer 22

-Latin for ‘I shall please”
-does not contain any active drug but identical in appearance, colour, taste and administration method to the active drug
-AKA fake drug
-almost everyone responds to the very act of taking a drug. Once take drug anticipate drug will ease your ailment. Ailment will somewhat ease simply cause believe it would. If sick, anxious patients, the placebo response can be as high as 40%

Question 23

Gold Standard drug

Answer 23

-drug that is accepted by medical community as the best available treatment for the specific disease at that time
-if gold standard drug available, that is what the control group receives as it is unethical to withhold treatment if one exists
-if gold standard drug not available though, a placebo is used

Question 24

Step 4: Health Canada Review

Answer 24

-at successful completion of initial phase 3 trial, the manufacturer will submit to the regulatory body a new drug application containing the detailed results of the clinical trials
-in Canada, the regulatory body is Health Canada
-results again reviewed by regulatory scientists
-if drug is deemed to be effective, and toxicity is acceptable, it will be granted approval

Question 25

Step 5: manufacturing
Generic vs brand name

Answer 25

-once regulatory agency has reviewed the new drug application, manufacturing process can begin
-manufacturers come up with drug name (generic) and a brand name for the drug

Generic vs brand name: drug’s formal chemical name is too complex for general use
-if drug undergoing development shows promise and manufacture wishes to place on market, generic name for the drug is selected
-around same time, manufacturer will apply for a patent with a brand name for the drug, which will give the company exclusive rights to market drug for 20 years
Ex. Acetaminophen is generic name and Tylenol is brand name
-20 year life of a patent begins when patent filled, usually during the preclinical development phase
-considering length of clinical trials, effective patent of a drug is in the range of 10 to 12 years
-after patent on drug expires, other manufacturers can make copies of original brand name drug and sell it under their own brand name

Bioequivalence (two drug products, generic and brand name which contain same active ingredients and give similar blood levels):
-original brand name drug and any generic versions of original drug will all contain identical active ingredients in same amount and usually same dosage form
-these regulations ensure all marked drugs are as effective as the original brand name drug and are bioequivalent
-to achieve bioequivalence, a comparative bioavailability study is conducted, which compares the blood levels after administration of both original brand name drug and the new brand name/generic drug to healthy volunteers under controlled conditions

Question 26

RCT

Answer 26

Random controlled trials are often double blind meaning neither the investigator nor the study subject is aware of the treatment the study subject is assigned to. This helps to remove bias in the study

Question 27

Part 5 cont Post-Market Survelliance (Phase 4 Clinical Trials)

Answer 27

-risks that are delayed or less frequent than 1 in 1000 administrations may be missed by phase 3 clinical trials
-surveillance of the effects of drugs is required after the drug is released for general use
-looking at adverse reaction reports for patterns to determine if making certain kids sick or reacting bad with other drugs
-if notice pattern, may order change to drug label, add new warning, or advise that certain drugs should not be taken together
-protects Canadians