Module 2: Introduction to Drug Use and Development PDF

# Module 1 ## Introduction to the History of Drug Use and Development Drugs - any substance received by a biological system that is not received for nutritive purposes, and which influence the biological function of an organism - The first few useful drugs (ie. opium) was discovered over 2000 years...

# Module 1 ## Introduction to the History of Drug Use and Development Drugs - any substance received by a biological system that is not received for nutritive purposes, and which influence the biological function of an organism - The first few useful drugs (ie. opium) was discovered over 2000 years ago - Though, most clinically useful drugs have been developed over the last 250 years. ## Pharmacology - The study of drugs, including their uses, effects, and mechanisms of action ## Historical Influences that Have Shaped Modern Pharmacology: - Discoveries made by Ancient Civilizations **In 380 BCE in Ancient Greece, Theophrastus wrote a textbook on therapeutics including opium.** - Serturner (German pharmacist) isolated crystals of *morphine* from opium in 1803 - He tested the substance on him and 3 others and discovered its pain-relieving capabilities. - Opium was found to have two important substances, *morphine* and *codeine*. - Opium contains ~10% *morphine*, which is able to relieve pain of great intensity. - It contains 0.5% *codeine*, which is an ingredient in *Tylenol*. **Ancient Egyptian papyri from 1550 BCE was found to be a textbook of drug use for medical students.** - It contained true observations on drug use - It recommended the drug *senna* for bowel movements, which is an ingredient still used today. - The earliest recorded drug experiments were from China in 2700 BCE - The emperor classified drugs by taste. ## Influence of Poisons - **Curare** is a plant-derived drug that was used by the indigenous people of the Amazon as a hunting poison on the tips of their arrows. - It acted upon the voluntary muscles causing paralysis and eventually death by respiratory paralysis. - This inspired allopathic medicine to use *curare* as an anesthetic. - Small doses can be used for muscle relaxation, facilitating surgery. - Curare's structure has been modified to make it safer and is still used today. - **Ergot** is a poisonous fungus that grows on rye heads, in the Middle Ages it was ground down with the rye and cooled into bread causing epidemics to occur. - This poison effects various body systems, such as nervous, cardiovascular and reproductive. - Symptoms: mental frenzy, hallucinations, convulsions, constriction of blood vessels causing limbs to die, and violent uterine contractions. - Ergotamine and ergonovine are two compounds of ergot that have pharmacological uses. - Ergotamine is used to treat migraines. - It constricts blood vessels to the head to reduce amplitude of pulsing. - Ergonovine was once used to hasten birth but is no longer used for this as it risked maternal injury from a too rapid birth. - It can be used to stop uterine bleeding after childbirth. ## Influence of Religion - In ancient societies, healers acted as both physicians and priests. - So, therapy was heavily influenced by religion and magic. - Plants containing intoxicating substances would be used to alter the state of consciousness and facilitate communications with their Gods. - *Peyote* is an example of this in Mexico, it was used to achieve a mystical state. - Causes hallucinations, feelings of well-being and distortion of perception (similar to LSD). ## Drug Discoveries: - About 25% of drugs used today are derived from plant sources - The active substances are purified and potentially modified to become more effective or less toxic. - The 19th century heralded the era of chemical synthesis. ## Discovery of Drugs Acting on the Brain - These drugs alter the normal chemical signalling to the brain. - LSD is one of the most potent hallucinogenic drugs. - Was first synthesized by Albert Hoffman in 1943 while trying to improve pharmaceutical products based on components of ergot. - This discovery supports the idea that mental illnesses could be due to the production of substances in the brain that can produce psychic disturbance. - Some research suggests LSD may be effective in treating certain mental illnesses ## Discovery of Drugs Acting Against Infectious Disease - The introduction of drugs in fighting infectious diseases was a major milestone in the 1900s. - Paul Ehrlich designed organoarsenicals which selectively bound to parasites. - His idea was applied to other diseases and led to a cure for syphilis. - In the 1930s, Gerhard Domagk introduced Sulfa drugs which were the first synthetic drugs for the treatment of bacterial disease. - First antibacterial compound. - In the 1940s, Alexander Fleming discovered the first antibiotic *penicillin*. - In the 1950s, Selman Waksman discovered a different antibiotic *streptomycin*. - Turning point in the treatment of Tuberculosis. ## Drug Development and Drug Trials Typically, new drugs undergo a long process of development and approval. It is a well-established process that can be largely divided ino five steps: 1. Basic Research and Drug Discovery 2. Preclinical Trials 3. Clinical Trials 4. Health Canada Review and Manufacturing 5. Post Market Surveillance and Phase IV Clinical Trials ### Basic Research and Discovery of Target - **Identification of Target** - A target for a new potential drug could be a receptor that when activated causes relief of pain. - Once a compound that binds well to the target is identified it will be studied to determine its pharmacological effects at the molecular, cellular, organ, and whole animal level. - **Studying the Target** - If a compound shows promise in initial studies it is identified as a *lead compound*. - It then enters more detailed study of safety and efficacy. ### Preclinical Trials - These are conducted prior to testing the new drug in humans. - They range from molecular/cellular studies to tissue and whole animal studies. - There are two main categories of preclinical studies: *pharmacology* and *toxicology*. ### Pharmacology Studies - These determine the detailed mechanism of action of the new drug. - Ie how it lowers blood pressure. ### Toxicology Studies - Determine the potential risks or harmful effects of the drug. - Studies look at *acute toxicity*, *chronic toxicity*, and the effects on *reproductive*, *carcinogenic*, and *mutagenic* potential. - These studies are expensive and may take up to 6 years. ### Clinical Trials: Initial Steps These 3 steps are required before a drug can be tested on humans: 1. **Proof of Safety** - Pharmaceutical manufacturers must submit proof of the safety & efficacy of the drug in several animal specias to the government regulatory agency. 2. **Methodology** - Of the proposed clinical trial is humans is required. 3. **Investigation** - Submission is evaluated by the regulatory agency. If satisfied, permission will be given. - Submission is looked over really well because animal tests can be very different than humans. **Note:** For a certain drug target, anywhere from 5-30 compounds make it into clinical trials, though many will fall in Phase 1 or 2, and only one or two usually make it to Phase 3 clinical trials. **Phase 1:** - Carefully evaluate the absorption, distribution, elimination, and adverse effects of the new drug. - They test one or two doses of the new drug to determine the tolerance of the drug. - Efficacy is not tested. - Conducted in 20-80 healthy volunteers. **Phase 2:** - Looking to determine whether the drug is effective in treating the condition. - Looking to determine whether the drug is effective in treating the condition. - They pay close attention to the safety of the drug. **Phase 3:** - Often called *randomized control trials*. - The main studies used for the licensing + marketing of the drug. - They test the drug in a more diverse population (usually 1000+ ppl) - Goal to determine how safe & effective the drug is compared to no drug (placebo) and/or the current recommended therapy. - Usually take longer than Phase 2 studies (months to years). - These are the most expensive part of drug development - Can cost 1-50 million dollars ### Design of Phase 3 Trials **Enrolment** - The people the new drug is tested on have to be carefully defined - The *target population* is the group of patients whom the dug is intended. - **Study Population** is the subset of the target population that meets all the required criteria. - Two things influence who can be included in the study population: - *Inclusion/Exclusion Criteria* - Define characteristics of the patients to be included in the study. - Eliminate any other potential variables that may influence results. - Common comorbidities are often included in the trials to be representative of the target population. - *Consent* - This is reviewed before hand. - Informed consent must be obtained before one can participate. - Includes a doc written in non-scientific language that outlines everything. - Investigators must ensure participants understand everything before consent is given. - Consent can be revoked at any time. **Treatment Allocation** - **Double Blind Design** - where neither the investigator + participant is aware of the treatment the participant is assigned. - Helps eliminate bias. - Patients are assigned to the experimental treatment group or the control group *randomly*. - Usually uses a computer-generated system. - The *control* can either be a *placebo* or *golden standard drug*. - Golden standard is used before placebo if available (for ethical reasons). **Results** - The outcome of the trial measures how much the drug worked in each patient. - This needs to be measured + compared in an objective & reliable manner. - Three factors must be considered when analyzing results: - **Compliance** - patient compliance must be determined for the results to be valid (compliance can be as low as 50-60%). - **Quality of Life** - some drugs may be effective but cause such sever side effects that they may not improve overall quality of life. - **Statistics** - measured outcomes from the experimental and control drugs must be compared to determine if the difference is real or by chance. ### Health Canada Review - After a successful initial Phase 3 trials, the manufacturer submits a new drug application with results to the regulatory body (Health Canada). - They then review it and if it is deemed effective and the toxicology is acceptable, it will be granted approval. ### Manufacturing - A *generic name* for the drug is selected as the chemical name is too complex (*acetaminophen*). - Around the same time, they apply for a *patent* for a *brand name* (*Tylenol*) - The patent lasts 20 years. When it expires, other manufacturers can make copies of the drug and sell it under their own brand name. - The copy is under strict regulations to contain the identical active ingredient, dosage, etc. - This is called *bioequivalence*. - Two drug products which contain the same active ingredient(s) and give similar blood levels. - Tested through comparative bioavailability. ### Post-Market Surveillance (Phase IV Clinical Trials) - Delayed or less frequent risks may be missed in the Phase 3 trials, so the effects are surveyed after the drug is released for general use. ## Drug Action ### Drug Targets - **Receptors** - a molecule or complex of molecules located on the outside or inside of a cell that has a regulatory role in the organism. - Thousands of the same receptors are normally bound to or activated by *endogenous ligands*. - The location of the receptors determines where the drug will act and whether the interaction is beneficial or detrimental. - Common: Opioid receptors in the brain cause pain relief but opioid receptors in the gastrointestinal tract cause constipation. - **Other Drug Targets** - some drugs interact nonspecifically with the biological system and not via receptors. - Chemical Reactions - Antacids neutralize stomach acid through simple acid-base neutralization reactions. - Physical Chemical Forces - Cholestyramine works by chemically binding to bile acids in the GI tract, preventing reabsorption and increasing the elimination of bile salts. ### Drugs and Receptors - Most drugs mimic or block the effect of the endogenous ligand. - **Agonists** - stimulate receptors (molecular/chemical mimic). - **Antagonists** - block receptors (molecularly different blocks). ### Drug Response - **Dose-response relationship** - generally the intensity of the pharmacological effects produced by a drug increases proportionally to the dose. - Fundamental concept in pharmacology. - **Low doses:** very little response observed. - Not many receptors are being activated. - **Threshold:** more and more receptors are activated until threshold is met and the desired response is seen. - **Therapeutic doses:** after threshold, small increases in dosage cause a large increase in response. - **Maximal effect:** increase in response is not indefinite, once maximal effect is reached, increasing the dosage will have no additional effects. - **Dose-response curve** - The dose of the drug is proportional to the response. - *ED50* - Cannot adjust the maximum pharmacological effect that can be produced by a specific drug in a biological system (efficacy). - Clinically more important. - *Potency* - the dose of a drug required produce a response of a certain magnitude (usually 50% of the maximal). - The more potent the drug, the less you need. - Drug A (10mg) is more potent than B (20mg), so less needs to be taken. - **Therapeutic range:** the range that keeps blood conc. above the minimum conc. to produce the desired response, but below the conc. that produces an unacceptable toxicity. - The wider the range, the safer the drug. ### Pharmacokinetics - The movement of a drug into, through, and out of the body. ### ADME: Absorption, Distribution, Metabolism, Excretion - These are the four key processes that occur after administration. - These factors determine the conc. of drug in the blood and so in turn the conc. of drug at the site of action. ### Routes of Administration - **Topical** - Drug is applied directly to a particular place on or in the body. - ie. On the skin, through skin, inhalation. (Quantities small - less toxic, but requires proper use). - Examples: *nicotine patch* - **Enternal** - Administration via the GI tract (either the mouth or an artificial opening). - ie. mouth, rectum. - **Parenteral** - Administration bypassing the GI tract. - ie. intravenous, intramuscular, subcutaneous. ### Bioavailability - The fraction of an administered dose that reaches the blood in an active form. - Differs between drugs always. - The only time it is 100% is when drugs are administered intravenously. ### Absorption - The movement of a drug from the site of administration into the blood. - For this to occur the drug must be able to cross biological membranes. - They can do this in multiple ways: - Diffusion across aqueous pores. - Drugs w/ small molecular weights and water soluble. - Diffusion through lipids (most important) - Pass through the membrane by dissolving in the lipid portion - High-low conc. - Depends on the drug's lipid solubility - Active transport/carrier transport. ### Distribution - The movement of a drug from the blood to the site of action and other tissues. - The conc. of drug at any sites of distribution is at equilibrium with the conc. in the blood. - The rate at which a drug is distributed in or out of an organ depends on the blood flow to that organ. - The greater the bloodflow, the quicker it reaches and vice versa. - Can play a role in terminating the effect of a drug. ### Drug Metabolism - The conversion of a drug to a different chemical compound in order to eliminate it. - Usually devoid of pharmacological action. - For this to occur, the drug must be water soluble. - It is removed by the kidneys. - Most drugs are converted to more water soluble compounds. - Most of this occurs in the liver. - *P450s* are the enzymes capable of biotransforming drugs. - Found in most tissues but present in high conc. in the liver. - **Phase 1** - Adds or unmasks a functional group to prepare the drug for the addition of a larger water-soluble molecule. - **Phase 2** - Adds a large water-soluble moiety. - Usually glucuronic acid or sulfate. - After this the drug can now be excreted. ### Excretion - Moving the drug and its metabolites out of the body. - *Kidney*: most drugs are eliminated this way (those of sufficient water solubility) - *GI Tract*: some will be eliminated through feces after biotransformation in the liver. - *Lungs*: volatile or gaseous drugs are eliminated this way. - *Breast milk*. - Sweat + saliva ### Drug Half Life - The time needed for the liver + kidney to remove half the drug from the body. ### Variation in Drug Response - Generally, the recommended dose of a drug is the amount that will the desired effect in most people, not all people. - This is because of the wide difference in drug response within a population. - Factors for drug response variation: - *Genetics* - influences the enzymes present for biotransformation (makes them slow or fast) - *Environment* - certain exposures increase the enzymes in the liver. - *Disease states* - may alter the manner drugs are handled. - *Altered physiological states* - ie older people are more susceptible to drug action. - *Presence of other drugs* - one drug can change the biological effect of a second. ### Drug Toxicity and Drug Interactions - **Adverse effects of drugs:** - any effect produced in a patient that is not the intended effect. - Extension of therapeutic effects. - When there is too much of the drug in the blood. - Commonly happens in drug overdose. - Unrelated to the main drug action - ie. nausea. - May or may not be expected. - Allergic reactions - Withdrawl and Addiction - Unwanted physiological + psychological effects. - Teratogenesis - When drugs produce birth defects. - Adverse biotransformation reactions - When the metabolite produced can bind to tissues causing tissue or organ damage. ### Predicting Adverse Drug Reactions - A drug may seem to have little to no adverse effects when first introduced, but then later on turn out to have significant toxicities. - This makes it hard to predict adverse drug reactions. - Drug toxicity may be rare. - It may only appear after prolonged use. - May be unique to a particular time period (ie pregnancy). - May not be detectable in animals and only appear once tested on humans. ### Therapeutic Index - Measures drug toxicity. - Tells you how safe a drug is. - The higher it is, the safer the drug and vice versa. - *TI=TD50/ED50* - *TD50* (Toxic Dose 50) = the dose of the drug that is toxic to 50% of the pop. - *ED50* (Effective Dose 50) = the dose that is effective in 50% of the pop. ### Drug-Drug Interactions - Occur when one drug changes the pharmacological effect of a 2nd drug. - They can occur at many points: - **Absorption** - A drug may increase intestinal movement, speeding up the movement of the 2nd drug through the intestine, therefore decreasing the amount of the 2nd drug that makes contact with the intestinal wall, thereby decreasing absorption. - **Metabolism** - A drug can block the biotransformation of a 2nd drug in the liver, therefore increasing the conc. of the 2nd drug in the blood and its pharmacological effects. - **Excretion** - A drug may facilitate the removal of a 2nd drug, decreasing its conc. and effects. ### Drug-Food Interactions - Involve the interference of food taken with drugs concurrently. - Example: *Tyramine* + *Antidepressants* - Tyramine is found in well-matured cheeses, and is capable of raising blood pressure. - It is broken down by the enzyme MAO in the liver. - Some antidepressants are inhibitors of MAO. - So if the two are consumed together, the tyramine will not be broken down and so its blood pressure raising effects will be greatly intensified. - Example: Grapefruit + other citrus fruits. - A component of grapefruit inhibits the enzymes that biotransform drugs in the GI tract. - This results in an increase in the absorption of the active drug. - Could potentially lead to overdose ## Physiological and Pharmacological Aspects of the Central Nervous System **Cerebral Cortex (Cerebrum)** - The largest part of the brain that is very rich in neurons. - Overall functions include: sensory + motor coordination, mental processes, intelligence, memory, vision, judgement, thought, speech, emotions, and consciousness - Which can be excited or inhibited by drugs. **Limbic System** - The region of the brain that integrates memory, emotion, and reward. - With the hypothalamus, it controls emotion + behaviour. - Contains the dopaminergic reward centers. - Targets for commonly misused drugs + associated w/ addiction. **The Neuron** - Is the functional unit of the brain. - Nerve cells capable of generating + transmitting electrical signals. - *Neurogenesis* - the process of new neurons being continuously generated. - *Neuroplasticity* - connections between neurons is constantly being reshaped. - Made up of 3 important structures: - **Dendrites** - Short + highly branched. - Function as the receiving antennae for incoming info/signals. - **Soma/cell body** - Largest part containing nucleus + cytoplasm. - **Axon** - Single fibre that extends from soma to synapses. - Cytoplasm contains an abundance of pre-packaged neurotransmitters. **The Synapse** - The junction between two neurons. - Where one neuron's axon ends and another's dendrite begin. **Synaptic Transmission** - The passing of signal from one neuron to another. - Very rapid + usually chemical in nature. - Action potential - influx of Na+ -> release NTS - NTS diffuse across - bind influx Na+ -> threshold **Termination of Response** - NTS can be taken back up by the presynaptic neuron via *transporters*. - NTS can be broken down by enzymes in the cleft (ie. AchE). - NTS taken up by adjacent glial cells. **Drugs and Synaptic Transmission** - Synapses are the target sites for many drugs. - Some interrupt synaptic transmission while others enhance or facilitate it. - Modifies brain activity. **Examples of NTs and their Receptors:** - **Glutamine** - The primary excitatory NT in the CNS. - Found in almost all neurons. - Acts on glutamatergic receptors. - Neurons that release these are important for learning. - **Serotonin** - Hyperactivity of the serotonergic system is involved in anxiety and hypoactivity in depression. - Some CNS stimulants act by increasing serotonin in the synapse. - **Catecholamines** - **Dopamine** - Involved in the control of some hormone systems, motor coordination, and motivation and reward. - Alterations to the motivation + reward systems is thought to be involved in addiction. - **Norepinephrine** - Can bind to a large number of receptor types (alpha + beta) - Activation of these receptors usually leads to excitation of the cell. - Targeted by some CNS stimulants. - **Acetycholine** - Produces an excitatory response in the CNS. - Binds to two types of receptors. - *Nicotinic* - Also stimulated by nicotine. - *Muscarinic* - Involved in learning, memory, and cognitive function. - Drugs that block these cause amnesia. - Loss of these is thought to be associated with Alzheimer's disease. - **GABA** - The primary inhibitory NT in the CNS. - Receptors found in high conc. in the cerebral cortex. - CNS depressants enhance GABA receptor function. - **Opioid Peptides** - Three classes exist: enkephalins, endorphins, and dynorphins. - All three vary in selectivity to three receptors: *mu*, *delta*, and *kappa*.