History of Drug Use and Development

History of Drug Use and Development

• Drugs are substances influencing biological functions, not for nutrition
• Pharmacology studies drugs' uses, effects, and mechanisms

Poison Influence

• Curare, derived from plants, was used by Amazonian tribes for paralysis and anesthesia
• Ergot, a fungus on rye, caused epidemics, hallucinations, convulsions, limb death, and uterine contractions

Drug Discovery Categories

• Drugs can target the brain
• Drugs can fight infections

Drug Development and Trials

• Drug discovery involves identifying/studying a target, finding a binding compound, and efficacy/safety testing
• Preclinical studies occur before human testing, including pharmacology to determine action mechanisms and toxicology to assess risks
• Clinical trials include Phase 1 for tolerability in a small group of healthy volunteers (20-80)
• Clinical trials Phase 2 tests drug efficacy in a larger group of people (100-500)
• Clinical trials Phase 3 (Randomized Controlled Trials) determines safety/efficacy versus placebo on a large scale of participants (1000+)
• A Phase 3 clinical trial design includes enrollment of a study population meeting criteria, obtaining informed consent, double-blind treatment allocation, and measuring quality of life/compliance/statistics

Factors of Drug Action

• Drug targets involve drugs interacting with a selected target/receptor in the body
• An antagonist blocks a receptor's response
• An agonist activates a receptor, increasing its response.
• Threshold defined as the amount of receptors that need activation for a reaction
• Efficacy refers to a drug's maximal response
• Potency refers to the dose required to produce a response
• Therapeutic range: area between desired response and toxicity

Dose-Response Curve

• Dose-response curve displays the amount of drug needed for an effect
• ED50 is the dose resulting in 50% of the maximum effect

Pharmacokinetics

• Pharmacokinetics is the movement of a drug into, through, and out of the body
• The process includes topical, enteral, and parenteral drug administration
• After administration, absorption, distribution, metabolism, and excretion (ADME) occur

Routes of Administration

• Topical: application through/on the skin or inhaled
• Enteral: via mouth, GI tract, or rectum
• Parenteral: bypasses the GI tract, including intravenous (into veins), intramuscular (into muscle), and subcutaneous (into the deepest skin layer)

Bioavailability

• Bioavailability: fraction of administered dose reaching bloodstream

ADME

• Absorption: movement from administration site to bloodstream
• Distribution: movement from bloodstream to action site and other tissues
• Metabolism: drug conversion into a different compound for elimination
• Excretion: removal of the drug out of the body

Drug Half-Life

• Drug half-life refers to the time needed for the liver and kidney to remove half of the drug from the body

Drug Response Variation Factors

• Genetics, physiological and environmental factors, presence of other drugs, or presence of a disease can influence drug response

Adverse Effects of Drugs

• These are unintended effects produced by a drug
• Sometimes drugs with no initial adverse effects show significant toxicities later, because the reaction is rare, appears after prolonged use, or not detectable in animals

Addressing Drug Toxicity

• Toxicity is measured via the therapeutic index (TI)
• Higher therapeutic index correlates with a safer drug

Drug-Drug Interactions

• Occur when one drug alters the pharmacological effect of another

Drug-Food Interactions

• Occur when food interferes with drugs
• Grapefruit alters drug absorption and lead to overdose
• Tyramine in some cheeses can raise blood pressure

Central Nervous System (CNS)

• The cerebral cortex is the largest brain part that coordinates sensory/motor functions, mental processes, intelligence, memory, and vision, and can be stimulated or depressed by drugs
• The limbic system integrates memory, emotion, and rewards, controls behavior, and contains dopaminergic reward centers

Substance Use Disorder (SUD)

• Diagnosis requires meeting at least 2 criteria: social impairments, risky use, impaired control, withdrawal, and tolerance
• Addiction features emotional/mental preoccupation with drug effects, and craving regardless of consequences
• The dopamine hypothesis explains addiction as misused drugs increase dopamine in the limbic system
• Altered communication within brain reward pathways is caused by addiction

Addictive Drug Characteristics

• Increase dopamine
• Produce novelty/new feelings
• Reduce anxiety

Drug Withdrawal

• It is an abnormal state when drug administration stops, with severity increasing with withdrawal speed
• Fear of withdrawal contributes to addiction
• Withdrawal symptoms are opposite of drug effects
• Stimulant withdrawal (e.g., cocaine, amphetamines) includes sleepiness, pain, anxiety, low mood, and tremors
• Opioid withdrawal (e.g., heroin, morphine, oxycodone) includes sweating, muscle aches, agitation, diarrhea, cramping, and vomiting

Drug Tolerance

• It is a state of progressively reduced pharmacological effect produced by a dose of a drug with repeated administration
• Tolerance is reversible upon drug discontinuation

Cross Tolerance

• Can occur between pharmacologically similar drugs
• Alcohol and benzodiazepines are similar, tolerance to alcohol translates to benzodiazepines

Factors Influencing SUD

• Genetics, pre-existing disorders, environment, and developmental factors can all influence SUD

Potential for Misuse

• Pleasurable drug effects increase the likelihood of repeated use
• Rapid drug administration increases the likelihood of it being misused
• Greater dose/frequency of use increases risk for developing tolerance, withdrawal, and addiction
• Greater drug availability increases likelihood of misuse

Amphetamines

• Are CNS stimulants, and synthetic organic compounds that can be synthesized quickly
• They increase excitation by increasing dopamine or norepinephrine in the synaptic cleft

Amphetamine - CNS Effects

• CNS excitation
• Feelings of euphoria and reward
• Appetite suppression
• Aggressive behavior/mood swings

Amphetamine - Short Term Use

• Chest pain/heart attack
• Cardiovascular collapse
• Increased respiratory rate

Amphetamine - Long Term Use

• Chronic sleeping problems
• Poor appetite
• Anxiety, repetitive behavior
• Elevated blood pressure and abnormal cardiac rhythm

Amphetamine - Potential For Misuse

• Produce a powerful euphoria
• Available in water-soluble salt forms, allowing large, injectable doses

Amphetamine - Potential For SUD

• Tolerance develops to euphoria and mood-elevating effects, and most effects of amphetamines
• Withdrawal: mood depression, sleep, large appetite, lack of energy
• Addiction: very addictive

Cocaine

• CNS stimulant and legally classified as a narcotic
• It has a mechanism of action that causes more CNS stimulation by reuptake inhibition that helps dopamine and serotonin into the pre-synaptic neuron
• Activation of post-synaptic neuron increases the concentration of neurotransmitters in the synaptic cleft

Cocaine - Long Term Use

• Toxic psychosis, including paranoia
• Hallucinations/sensations of crawling under the skin
• Impaired sexual function
• Permanent brain damage
• High blood pressure/irregular heart rhythm

Cocaine - Potential for Misuse

• Highly potent and produces a powerful euphoria

Cocaine - SUD

• Tolerance develops toward a mood-elevating effect
• Has withdrawal symptoms similar to amphetamines
• Addiction can occur, and behavioral effects are usually perceived as pleasurable

Cocaine vs. Amphetamines

• Cocaine lasts a shorter duration and is commonly sniffed or smoked
• Amphetamines last a shorter duration and are commonly administered intravenously

Nicotine

• Naturally occurs in tobacco

Nicotine - ADME

• Absorption: rapidly absorbed from GI tract, oral mucosa, and skin when inhaled
• Distribution: rapidly distributes to the brain throughout the body
• Metabolism: metabolized in the liver
• Excretion: metabolites exerted in the urine

Nicotine - Mechanism of Action

• It stimulates nicotinic receptors at the synapses
• Activation stimulates psychomotor activity, cognitive function, attention, and memory
• Large doses of nicotine cause agitation, tremors, and seizures, and the effect is often mediated through the CNS

Nicotine - Therapeutic Use

• Used to help people quit smoking

Nicotine - Short Term Effects

• Regular smokers experience mild euphoria, concentration, increased heart rate, and suppressed appetite
• Non-regular smokers experience dizziness, headache, nausea, vomiting, cramps, coughing, and gagging

Nicotine - Long Term Effects

• Cardiovascular disease: increased atherosclerosis and thrombi
• Lung disease: smokers syndrome
• Cancer

Nicotine - Passive Smoke

• Associated with the risks of cardiovascular disease and cancer

Nicotine - Potential for Misuse and SUD

• Smokers maintain nicotine blood level within a certain range
• Withdrawal: irritability, restlessness, anxiety, insomnia, and fatigue
• Addiction: an extreme urge to smoke

Caffeine

• An average cup of coffee has about 200mg of caffeine, energy drinks have about 300mg

Caffeine - ADME

• Absorption: rapid when taken orally with blood levels peaking 2 hours after ingestion
• Distribution: distributes across all body parts and into the brain/placenta
• Metabolism: genetics determine rate of metabolism and excretion
• Elimination: half-life varies from 2.5 to 10 hours among individuals

Caffeine - Mechanism of Action

• 100-250mg of caffeine increases mental performance while decreasing drowsiness and fatigue

Caffeine - Short Term Effects

• Mild mood elevation and reduced fatigue, insomnia and nervousness
• Cardiovascular effects include constriction of brain blood vessels/increase peripheral flow and muscle stimulation
• Stimulates breathing rate which is clinically used to stimulate breathing in pre-term newborns

Caffeine - Long Term Effects

• Restlessness, nervousness, insomnia, peeing, gastric upset, rambling

Caffeine and Smoking

• Smoking increases the metabolism of caffeine

Caffeine and Pregnancy

• Typical consumption isn't linked to fetal abnormalities
• Large doses can cause stillbirth, decreased fetal growth rate, and miscarriage
• Metabolism of caffeine is slower in pregnant women

Caffeine - Misuse and SUD

• Low misuse potential with the inherent harmfulness of caffeine being low
• Tolerance develops to caffeine and withdrawal, plus abrupt cessations can result in mild withdrawl

Drugs in Sports

• Classes of drugs used are amphetamines, anabolic steroids, benzodiazepines, blood doping/EPO, and diuretics

Amphetamines - Effects and Toxicity

• They increase endurance and speed by masking pain/fatigue
• Toxicity is fatal increases in blood pressure and withdrawal symptoms

Anabolic Steriods - Effects and Toxicities

• Increases muscle mass and strength
• Toxicities include aggression, acne, cardiovascular disease, altered liver functioning, reduced testosterone levels
• Leads to muscle growth by anabolic steroids stimulating muscle growth while stopping muscle breakdown (anti-catabolic effect), producing aggressive behavior or “roid rage"
• They are more effective in those with low testosterone, with small doses doing not much vs large doses increasing muscle gain/strength

Benzodiazepines - Effects and Toxicities

• Combats anxiety and insomnia
• Toxicities: impair psychomotor coordination/focus at higher doses and may cause disorder

Blood Doping and Erythropoietin (EPO) - Effects and Detection

• Stimulates red blood cell production, increasing oxygen delivery to muscles
• Detected via urine tests by measuring the age of red blood cells

Diuretics - Effects

• Reduces body weight by increasing salt/water excretion
• Sometimes used to mask other banned substances

Sedative Hyponotics

• CNS depressants
• Effects depend on dosage, from anti-anxiety to sedation (calmness, reduced activity) to hypnosis (sleep aid) to general anesthesia

Sedative Hypnoitics - Mechanism of Action

• Depresses brain activity by decreasing glutamate-induced nerve firing and increasing inhibitory signaling
• Most increase inhibitory signals from GABA neurons

Drugs Binding to Chloride Ion Channels

• Most sedative hypnotics bind to a chloride ion channel
• Leads to increased synaptic inhibition, thus decreasing neuronal responses
• Enhances inhibitory GABA effect

Sedative Hypnotics- Benzodiazepines

• Route of administration: capsules, tablets, sometimes intravenous or intranasal
• Mechanism of action: activation of the benzo receptor increases the frequency of chloride channel opening
• Therapeutic effects: relaxation, calmness, and relief from tension/anxiety

Benzodiazepines- Toxicities and Antidote

• Commonly overdosed on, but have a high therapeutic index
• Flumazenil is the antidote

Benzodiazepines - Adverse Effects

• Short-term use can cause drowsiness, fatigue, and impairment of thinking and memory

Benzodiazepines - Potential for Misuse

• Weaker reinforcing properties than other drugs

Benzodiazepines - SUD

• Internet harmfulness is low
• Tolerance can develop, and cross-tolerance can develop with alcohol
• Withdrawal: anxiety, headache, and insomnia
• Addiction may develop depending on genetics and the environment

Barbituates

• Sedative-hypnotics classified by duration of action: long-acting (1-2 days), short-acting (3-8 hours), and ultra-short-acting (20 minutes)
• They are now replaced by safer/more effective sedatives
• Oral use to treat epilepsy and used intravenously for Anastasia
• Mechanisms of action occur by activation of barbiturate receptors increasing duration of chloride channel opening
• Reduces use due to lethality and replaced by newer and safer drugs

Barbituates - Therapeutic Effects and Adverse Effects

• Causes calmness and relaxation in low doses and induces sleep if the dose is sufficient
• Adverse effects include suppressing REM sleep, memory impairment, hostility, and mood swings

The Misuse Potential of Barbituates

• Barbituates' misuse potential is equal to or greater than alcohol
• They can be used as an anti-epileptic

Alcohol - Absorption

• Rapid absorption
• 20% in the stomach
• 80% in the small intestine
• Absorption is affected by stomach emptying time, ethanol concentration, and food presence
• The peak blood alcohol concentration (BAC) can occur between 30-90 minutes

Alcohol - Distribution and Excretion

• It is distributed throughout total body water and crosses the placenta
• 95% metabolized in the liver
• 5% excreted in urine and sweat

Medical Uses of Ethanol

• As a skin disinfectant and hand sanitizer
• Counteract for methanol poisoning

Alcohol - Adverse Effects of Binge Drinking

• Memory loss
• Depression, irritability, and impulsivity
• OD risk

Alcohol - Effects of Chronic Use

• CNS: alcoholic dementia, neuron damage, and cognitive decline
• Cardiovascular: cardiomyopathy and hypertension
• Liver: progressive alcoholic liver disease

Alcohol - Effects in Pregnancy

• It causes fetal alcohol syndrome (FASD)
• No safe alcohol level in pregnancy

Alcohol and Drug Interactions

• There are acute interactions when alcohol and other drugs are mixed
• and chronic interactions, when long-term alcohol use affects drug metabolism

Alcohol - Potential for Misuse and SUD

• Moderate misuse potential and harm
• High doses can cause death
• Chronic use causes long-term health risks
• Less harmful than methanol
• Tolerance: chronic consumption
• Cross-tolerance with sedative-hypnotics and general anesthetics
• Withdrawal: convulsions, coma, possible death,
• Addiction: compulsive ethanol-seeking behavior, with severe withdrawal treated with diazepam

Cannabis Overview

• It includes psychoactive substances from the cannabis stevia/hemp plant where THC is most responsible for psychoactive effects

Cannabis

• Cannabis products are CNS depressants, euphoriants, and hallucinogens used for pharmacology when in high doses
• They became legal in Canada as of October 17th, 2018

Cannabis - Administration

• Smoked or inhaled (most common)
• Extracts (oils): vaped or orally consumed

Cannabis - Mechanism of Action

• THC binds to CB1 receptors in the brain/spinal cord,
• Activation inhibits excitatory neurotransmitters, leading to CNS depression

Cannabis - Cannabinoid Receptors

• CB1 receptor in the brain causes cognitive effects, euphoria, and memory impairment
• CB2 receptor in the periphery has no psychoactive effects and is linked to the immune function

Cannabis - THC, ADME

• Inhaled: rapid onset, lasts 3-4 hours
• Oral: slower onset, incomplete absorption, delayed 30-60 minutes Weaker impact

Cannabis - Other properties

• Rapidly distributes to brain, lungs, heart and liver,
• crosses placenta, stored in fat
• Slow rate of metabolism
• THC metabolites are detectable for weeks/months in chronic users

Cannabis - Excretion

• Takes a half life of 30 hours and elimination from fat takes even longer than that

Cannabis - Short Term Effects

• Relaxation, euphoria, impaired coordination, increased appetite, and hallucinations
• Cardiovascular: increased heart rate, blood flow, possible postural hypotension
• GI tract: increased appetite
• Other: lower sex drive in males, disrupted ovarian cycle, driving/motor impairments

Cannabis - Long Term Effects

• A low dose causes minimal psychological harm
• High dose = memory loss, lack of focus, amotivation
• Possible permanent brain changes
• increased heart rate in heart disease patients
• Chronic bhroncitis, astma, lung irritation, and cannabis smoke is worse than tobacco with a Higher risk of lung cancer and COPD
• Lower sperm count in males
• Disrupts female ovulation
• Crosses placenta, linked to cognitive delay and hyperactivity in babies

Cannabis - Vaping Risks

• It is not safe and damages the lungs

Cannabis - Medical Use

• Used to treat nausea and vomiting, but isn't health Canada approved and authorized for specific cases

Cannabis - Misuse Potential

• There is a low to moderate harm associated with car accidents and accidental injestion by children,
• There can be a level of tolerance that develops to euphoria, cardiovascular and cognitive effects
• Irritability, appetite loss, sleep issues, agitation, and sweating

Opiods - Overview

• Opioids are derived from the opium poppy and historically used as crude extracts and now used as purified morphine and codeine

Opiods - Classifications

• 1. Endogenous: Affects pain perception, emotional response, mood, and reward pathways as a a result of naturally being produced
• 2. Natural Opiods that come directly from Opioum such as Morphine(severe pain/euphoria) and Codeine(converted in liver)
• 3. Semi Synthetic Opiods that are chemically modified versions of morephine such as Hydromorphone(5x ore potent) and Diacetylmorphine/heroin (2-5x potent)
• 4. Synthetic Opiods which are full synthetics such as Fetanyl(100x potent used for severe pain), Loperamide (OTC opioid to treat diareahha), and Methadone (prevents withdrawl)

Opiod Receptors

• Mu receptors are found in the brain and spinal cord, responsible for analegisea, respiratory depression, and muscle potential
• Kappa receptors are involved in analgesia, syphonia, and pupil concentration
• Delta receptors continue to spinal and brain analgesia, as well as effecting emotional resposnse to opiods

Opioids - Mechanism of Action

• Blocks pain pathways in the spinal cord and brain and reduces neurotransmitter release while helping response to pain via the limbic system

Opioids - Short Term Effects

• Analegesia reduces pain intensity and emotional reposnse
• Sedation and hypnosis, cough suppression, respiratory depression, endocrine effects, misosis, heart rate increase, and constipation

Opioids - Long Term Effects and Therapeutic Uses

• No major physiological effects but high risk of dependence and addiction

Opiod Use Disorder (OUD)

• Tolerance develops to most effects (cross tolerance occurs)
• Withdrawal symptoms such as anxiety, insomnia, sweating, chills, nausea, vomiting, and diarehea Addiciton causes strong cravings and compulsions due to euphoria

Opioids - Pragnancy

• Can cause cause premature brith, low weight birth, and Newbornss experience withdrawal symptoms

Opioids - OUD Treatments

• Bupernorphine, naxalone, are methadone all are options to treat