Pharmacokinetics, Pharmacodynamics, ADMET

Caveats of ADMET

• ADMET considerations include; weight, gender which includes body composition, fat ratio, water content
• Hormones should be taken into account
• Pharmacogenetics/pharmacogenomics involves genetics which can have mutations
• Alcohol can cause mutations in enzymes for drug breakdown
• Genomics

Pharmacokinetics

• 200 mg of ibuprofen diluted in the blood stream is a microgram concentration
• Exhibit first-order kinetics
• Alcohol exhibits zero-order kinetics

Pharmacodynamics

• Includes biological and physiological effects and mechanism of action of how compounds works
• Involves what compounds target to elicit biological or physiological effects
• Mimic neurotransmitters

Dose-Response Relationship

• Represents the dose-effect relationship
• Measured as the dose in mg/kg, which is the mg of a compound per kg of body weight
• Efficacy (y-axis) indicates the peak level for a given effect; if one pill helps, maybe two or three causes side effects.
• Potency (x-axis) is the minimum amount of drug needed to yield efficacy; a smaller amount means a more potent drug.

Potency vs. Efficacy

• A compound that yields the same efficacy at a lower dose is more potent
• A taller efficacy curve indicates a more efficacious compound because it reaches the maximum population faster

Side Effects, LD50, and Therapeutic Window/Index

• Side effects occur when a 100% response is reached
• As concentration increases can cause alleviate inflammatory response hand in hand with drowsiness and desired and unintended effects
• ED 50 is the effective dose for 50% of the population
• LD 50 is the lethal dose for 50% of the population
• A wider ED 50 to LD 50 range indicates a safer therapeutic window
• Margin of Safety is the concentration or effective dose where 99% of the population has a response and a lethal dose of 0-1% showing a response, which is always smaller than the therapeutic window
• Most pharmacists are concerned with margin of safety

Concept of Timing

• Considers what happens when the effective dose starts to tail off
• Drugs act by introducing ligands and receptors
• The drug action is fairly selective, such that Neurotransmitter A interacts with receptor A but not receptor B

Drug Action at Receptors

• Agonists mimic neurotransmitters and artificially elevate neurotransmitter levels, shifting the DRC to the left and requiring less natural neurotransmitter for a biological effect
• Partial agonists mimic neurotransmitters to a point, causing a slighter left shift
• Competitive antagonists cause a right shift but do not block the effect
• Noncompetitive antagonists shift the curve right and down as the dose increases and reduces the effect
• Inverse agonists act underneath the curve
• Positive allosteric modulators (PAMs) act at a different site from the neurotransmitter and do not interact at the natural neurotransmitter site.
  • PAMs target previously inaccessible spots, which are unmasked by neurotransmitter binding
  • PAMs binds to a new opened spot, and shifts to the left and up causing an opposite biological effect

Psychological Characteristics of the User

• Addictive personality, sensation-seeking, and impulse control issues are psychological characteristics of the user.
• Certain genes related to compulsiveness and sensation-seeking are compounded by environmental influences

Risk and Protective Factors

• Risk factors are environmental conditions that lessen or increase the chance that something will occur
  • Example: parent's acceptance of drug use, poor academic performance, school absences, peer influence, starting at a younger age, and emotional conflict with their parents are risk factors
• Protective factors include the degree of attachment with parents (more attachment = less substance use) and parental supervision (not helicopter - that's bad)
  • More engaged parents who are interested in their kids' lives
  • Parents who create rules and stability
• Kids more engaged in school, commitment to performance and being the best they can be provide protective factors, as does activity involvement (athletics, music, religion)
  • More involvement = less boredom = less substance use
• Familiar environment creates a risk potential for children to be drinking.
• Right side talking about age- BIGGEST PREDICTORS OF SUBSTANCE USE DISORDER... developmental disorder

Learning Factors

• Include expectancies and beliefs; individuals may think they'll be okay because they saw their friend do it
• Dose will always win

Psychopharmacological Factors

• Tolerance is a change in behavioral response to a given drug exposure
  • Most people become less sensitive to a given dose
• Sensitization occurs as someone becomes more sensitive to a given dose
• Drug abuse leads individual to take a substance more than intended and at higher doses, potentially leading to acute events and overdose
• Drug dependence causes a withdrawal state (physical and mental) when drug use is stopped
• Addiction is a substance use disorder, or seeking a substance at the expense of other factors in their life

Mithridates

• King of Pontus
• His father was poisoned by his wife who wanted power for her son
• He runs away and is fearful of being poisoned, so he took small amounts of different types of toxins to avoid his father's fate
• Unfortunately, it backfires, if he decides to poison himself to avoid punishment but it now doesn't work
  • This is the story of tolerance = mithridatism
  • Shift in dose response curve
  • Need a larger dose to achieve the same effect - rightward shift
  • For most people tolerance is to a specific behavioral end point

Types of Tolerance

• Dispositional; metabolic refers to pharmacokinetics.
  • Changes in enzymes within liver are responsible for breaking down those particular drugs
  • An increase in enzymes in the liver will make less substance available to have an effect when using a drug
  • Need more drug to achieve that same effect
• Functional (pharmacodynamics)
  • Changes in number of neurotransmitters being released or changes in receptor target for drug system
  • Less receptors = harder to have a biological effect
  • Temporarily desensitized; drug working at receptor but no action happening
  • Acute tolerance (Tachyphylaxis) is fast, likely to lose the tolerance just as fast
  • Protracted tolerance is more drawn out and chronic, takes a lot more time to lose
• Cross-tolerance
  • Someone might be taking one substance so there sensitivity to another substance changes
  • Alcohol use disorder; drinking very regularly, if you hide that from your anesthesiologist, the sedatives may not work on you; you may need more
• Reverse tolerance (sensitization)
  • The more you take something the more sensitized you become to the behavioral effects
  • Less common with biological effects
  • Marijuana causes changes how the drug impacts the neurotransmitter system and receptor; body views this as a foreign agent and makes adaptations to fight it
    • Trying to increase clearance or trying to create normative homeostasis around this

Cell Adaptation

• Functional and cellular-adaptive refers to pharmacodynamic processes; return to more normative state

Learning Factors

• Siegel's Experiment (1975), Shepherd Siegel was studying the effects of morphine
  • Active ingredient in opium
  • Particularly studying morphine and body temperature
  • Morphine is a sedative and that means it can cause changes in body temperature, drops by a little bit
  • Over chronic exposure to morphine you develop resistance to the body temperature drop
  • Had to move rats to a different experimental space because they were developing a tolerance
    • Once he moved them - the drop in body temperature returned
  • Pavlovian Conditioning
    • The rats had become associated with the cues in the room where they were getting drug exposure
    • The rats knew they would have an event from the exposure
    • The original room gave them a reaction when put back in, their body temp would go up in the original room to compensate for the temperature drop they experienced there
    • CONDITIONING
    • Environmental influences impact an individual's drug state and drug craving situation

Anticipation of Cocaine Triggers Dopamine Increase in Rats

• Dopamine in nucleus accumbens
• Few seconds before delivery, it is having an anticipatory rise in dopamine levels, it's excited before reward is even delivered... sometimes the anticipation of the reward could be better than the actual reward
• Pavlovian classical conditioning and compensatory reactions → conditioned compensatory reactions
  • Change in body temp
  • Change in dopamine release
  • Can in itself create situations we called conditioned withdrawal
    • An individual is anticipating a reward → no reward occurs so it creates an error state for the individual where a conditioned withdrawal occurs → withdrawal like responses
    • Can create a craving situation

Narrowing of Therapeutic Window

• Tolerance is behavioral and biologically specific
• Specific to a behavioral effect
• For an organism to be able to develop tolerance they have to experience that behavioral phenomenon
• Opiate overdose; person might start feeling initially euphoric but soon they will feel tired and sedated
  • Push into the next dose response curve with motor effect... then next with sedative effects... keeping pushing will get it to lethal dose
    • Distance between sedative and lethal effects will get smaller

Additional Behavioral Pharmacology Concepts

• Reinforcement; Positive versus negative
  • Positive is the tone of the parents after a kid cleans their room “great job sweetie", positive is a reward for getting good grades, etc
    • In terms of substance use - euphoria is positive reinforcement
  • Negative is when a behavior is promoted to be increased to prevent something from occurring, promote a dog to stay in yard if the electric fence shocks them
    • In terms of substance use - an individual who goes through withdrawal state - promote alcohol intake to eliminate the bad effects of the withdrawal
    • DIFFERENT FROM PUNISHMENT - punishment reduces a response while reinforcement increases it

Punishment

• Example - put hand on hot stove - in pain and will not do it again

Animal Models of Testing

• Self-administration
  • Extinction and reinstatement
    • Drug craving triggers, reducing cravings, relapse, Look at positive reinforcement, negative reinforcement, etc. through lever pushing experiments
    • Reinstatement - could be short-term or long-term - whatever innocuous cue that might instill a craving may increase a response after a decent amount of time
    • Faster than extinction - lower addictive liability
    • Slower than extinction - higher addictive liability
  • Reinstatement - comes after extinction
    • Want to respond again
    • Dose can have a negative and positive reinforcement as well
    • Get too sick - never drink that much again
    • Conditioned place preference and aversion
  • Drug Discrimination
    • Interoception
    • Pleasurable or aversive
    • Comparing drugs
  • Experimental Conflict
    • If a low enough conflict you might wanna keep trying
    • If a strong conflict you won't want to try it again
• With greater addictive liability, people are willing to continue pressing for a reward despite the knowledge that there is something aversive to it
• Least aversion to consequences that have the most susceptibility

Placebos

• Why? As a control
  • Greater effects by believing something is doing something
    • Exorcisms
• Experimental “blinding” (single-blind)
  • Benjamin Franklin
  • Frank Mesmer
    • Thought horse could do math
      • Really was responding to a cue
    • Only patient does not know - doctors can see placebo effect
• Do not know what you are actually taking, does more than a simple control effect
  • May want to believe they are getting therapy
• Double-blind
  • Doctors and patients both do not know who gets the placebo
• Active placebos - Do no harm - You do not give someone who needs therapy a placebo You give them something else
  • Is what you are using better than standard
    • Someone gets the standard not the experimental

Stimulants

• Sources of stimulants are either naturally occurring or synthetic
  • Naturally occurring include; Cocaine (Erythroxylum coca), Ephedrine, and Cathinone
  • Synthetics include; Amphetamines(Adderall), Methamphetamine, Methylphenidate (Ritalin) Pipradrol (1950s obesity - banned 1970s)
    • Similar pharmacology and different routes of administration

Erythroxylum Coca

• Very commonly used in its natural form
• Buccal absorption - lower absorption rate - stimulant to go about daily activities
• Indigenous tribes use this regularly - Spanish conquistadores tried to control the population by controlling this plant

Cocaine

• Isolated 1850s
• From 1902 - 92% of all cocaine sold in tonics available from drug stores (without prescriptions)
• Sigmund Freud: Treatment of asthma, depression, indigestion, syphilis, etc.
  • Treatment of morphine and alcohol addiction; Opinion reversal

Notable Cocaine Abusers

• Jekyll and Hyde (Robert Louis Stevenson)
• Thomas Edison
• Jules Vern
• Ulysses S Grant
• Sherlock Holmes
• Coca-Cola contained 60mg cocaine per 8 ounces
• In 1914 Harrison limited cocaine from products
• 1920-30s decline in use (now amphetamines)
• Late 1960s = increase which peaked in 1980s
• Original athlete performance enhancer
• Commonly snorted
• Crack cocaine - smoking/injecting
• Yellow tiny - adulterated

How Substances Get to the US

• Plants grow in South America due to climate
• Politics make you think Mexican Border but its not
  • Land, sea, air
  • Overwhelming majority through air traffic Think about the substance and the population - Meth = LA
• • Most of the US population is EAST - Atlanta, Georgia!!!!! - I-95!!
• COCAINE = EAST COAST
• Cocaine binds closely to ink in money - 90% of ten dollar bills

Stereotype User

• Meth = bikers
• Most common demographics for cocaine/stimulant -White male

Cocaine - from Plant to Street

• Impacts administration
• After harvest, to processing plants for soaking (kerosene, sulfuric acid)
• Resulting paste allowed to dry, then placed at cigarette end for smoking
• Not in a form yet for injection or snorting so....
  • Converted into cocaine hydrochloride by adding chemicals, usually then adulterated
• In this form you cannot smoke it (powder) so...
• Freebase comes next
• CRACK COCAINE
  • Different agents to make it more suitable for smoking
  • Same ether used as an anesthetic is used
  • You need heat to do this - explosion
  • Dry it to let it harden into crystal forms
  • Makes a cracking sound when it crystalizes

Preparations

• Cocaine, Coke-HCl Nasal, injected (sometimes mucal or topical)
• Freebase
  • Ether - flammable
  • Crack - baking soda and water Orally would be broken down by stomach acid so not likely

Pharmacokinetics

• Dependent on route of administration Nasal/Mucus Mouth Membrane - 10-15 mins before drug action IV - thirty secs Smoking - fastest
• Difference between coke and amphetamines
• Duration of action
• HALF LIFE - cocaine = 30 mins / amphetamine = much longer (hours)
• Similar elimination for metabolites
• 2-3 days
• Benzoylecgonine (inactive) - this is what is tested for in a drug test
• Small amount converted to norcocaine (active) - not as active as the parent but does have some ability

Amphetamines

• Have a much longer half-life
• They have active metabolites as well - longer action Pharmacodynamics
• Potent local anesthetic
• lidoCAINE is an analog - blocks voltage sodium channels in periphery of neuron to prevent neural firing
• Powerful constrictor of vessels Irritation of cavities in nasal passages - nose bleeds is not the same This creates an acute hypertension
• Powerful psychostimulant with strong reinforcing qualities Potentiated the synaptic action of dopamine (less for norepinephrine, and serotonin) ...HOW?? Acute: blocks transporter reuptake of dopamine Cocaine is an antagonist at reuptake site A buildup of dopamine in synaptic cleft - does not clear out More dopamine in synapse = more time to interact with receptors
• Increase dopaminergic effect in the synapses
• Amphetamines do something similar and different Methamphetamine Cocaines big brother on steroids Synaptic point of view Amphetamine - block transporters Increase vascular release of dopamine Greater dopamine dump into synaptic space At transporters - reverse potential Excreted back out by transporter PROBLEM
• Lots of dopamine sitting in synaptic space could result in exposure to enzymes, and those neurotransmitters are going to be broken down... making body have to use more energy and resources to be able to restore normal dopaminergic levels

Positive Effects

• Sympathomimetic - mimics autonomic nervous system's sympathetic branch (fight or flight) Increased heart rate and blood pressure Increased arousal
• Increased alertness and task vigilance
• Brief duration of euphoria in higher doses Increasing dopaminergic tone REINFORCING QUALITY... craving The behavioral effect is going to get an increase wanting of next behavioral response
• Reinforcing and craving-inducing effects Increase dopamine in central brain Desensitize the system - overtime can have null effect
• Chasing the first hit - but can never get it

Acute Side Effects

• Appetite suppressant - no blood flowing to gut
• Sleep prevention
• Irritability - ability to detect rewards and pleasure
• Involuntary motor activity re subtle (oral lingual) → licking around gums and teeth uncontrollably
• Stereotyped behavior - REPETITIVE BEHAVIOR
• Formication - peripheral sensory overload
  • Spiders crawling on you
• Snow lights (visual disturbances)
• Paranoid delusions/overdose/death - untimely mortality
• Seizures
• Depression - with chronic usage and even in recovery state
• Dose dependent
• Most of drug related ER visits

Tolerance and Withdrawal

• Experienced users get tolerance to euphoria
• Tachyphylaxis (rapid tolerance)
• Chronic use contributes to withdrawal
• Major treatment problem: helping patients resist urge to start compulsive cocaine use...not detox
• Block reinstatement

Sensitization

• Consistent finding in studies of cocaine and other stimulants More evident with intermittent use Often measured by behavioral hyperactivity Also involves conditioning Coke users report strong response in seeking cocaine before administration

Long Term, High Dose Effects

• Paranoia, psychotic behavior, hallucinations, interpersonal conflicts, bizarre violent behavior may ensure for long periods after stopping usage and Increase in other drugs of abuse

Cocaine and Alcohol

• Taking the edge off
• Liver enzymes that metabolize both produce cocaethylene; Just as capable at blocking dopamine transporters Much longer half life than cocaine Active metabolites for up to two weeks

ADHD

• hyperactive state with ritalin/adderall that Paradoxical effects: More stimulant actually calms people down

Other points

• Problems, other types of behavioral manifestations and state dependent learning. Where you Use agents to focus attention to get a leg up and when taking the exam without the drug you get cloudy and actually have trouble with memory recall

Nicotine

• Comes from nicotiana tabacum plant with 0.6-3% average about 1%
• Nicotine first isolated from leaves of tobacco in 1828
• Cancer link speculated as early as 1600s
• In the body - has toxic effects dose dependent similar to cyanide

Cigarettes

• Mass popularization with used to be for the elite and ability to afford it = can smoke it
• A new way to cure tobacco with a method of how you can get the tobacco enriched - sweeter
• Color curing - use smokehouses
• Mechanization of production with ATC - American Tobacco Company which Easily package and distribute cigarettes Washington
• Confederate in the Civil War tried to increase profit so he could get married
• Became known to some as Duke of Durham
• Mass modernization of cigarettes in the US - DUKE UNIVERSITY founded on tobacco companies
• The safety match : Quick strike - do not have to start a whole fire to light a cigarette advertising and mass marketing: Got lesson from patent medicines with Targeted kids - baseball cards
• Honis Wagner card - went against tobacco company - did not want to be associated with using tobacco - got his card pulled

Tobacco Use

• Huge decrease in tobacco use since 1960 peak and when in the 1960s and 1970s the surgeon general emphasized smoking causes bad health thus resulted to
• Studying smoking Importance due to social and clinical significance.
• Ubiquitous - widespread resulting to Prototypic addictive disorder Addictive Liability or when having High risk of addiction, If you take the number of individuals who have ever used a substance compared to those who have the substance use disorder → risk of addictive liability 1/3 people will develop a use disorder after using nicotine, where it results in PARADOX: why greater addictive liability → nicotine does not cause euphoria compared to other drugs * The clue is toxicity being the An alkaloid - nitrogen containing compound also morphine cocaine and caffeine with Hygroscopic chemistry

Forms of Tobacco

• Cigarettes: optimize the addictive effects of nicotine because smoke allows rapid absorption to the brain and Short lived psychoactive effects lead smokers to repeatedly dose themselves

Body and Nicotine Level

• 10-15 seconds to brain when inhaled
• Smokeless tobacco: chewing tobacco with Fifteen minutes to brain when buccal and Nicotine gum - through stomach - longer (30 mins) (oral)
• Transdermal patch (longer duration but longer to brain as well).
• Toxicity comes HOURS later - hard to reverse
• Nicotine 0.5-2 mgs in a cigarette with Amount absorbed depends on the smoker - number of puffs - length of drug. Nicotine in blood

ADMET

• Quickly distributes throughout body Reaches brain in 7-20 seconds Detected in blood, saliva, and urine - metabolized/eliminated in 2 hours
• Liver converted to cotinine and Detectable for weeks
• Tobacco also contains inhibitors of enzymes that metabolize catecholamines
• Dopamine, norepinephrine, serotonin with Subtle increase in those catecholamines

PD Actions

• Complex and unpredictable changes that occur after administration that are due to Stimulation

• Sympathetic response with Sympathomimetic - increase in heart rate, tightening of vessels, increase BP while it Subsides and has desensitization

• Major CNS Effects for Stimulant and relaxant by Epinephrine release in PNS as Users report feelings of relaxed and calm but also sharp and alert Dose effect showing (biphasic), At Low endWeakanalgesia and At High end→ tremors and convulsions Nicotinic Acetylcholine receptors

• At low At lower doses - in the brain - more sensitive ones feel the effect First vape hit in the morning is the most impactful of the day because you are sensitized The more you smoke in a day you get desensitized Nicotine is acute tolerance

Nicotine

Higher affinity for brain versus systemic nACh receptors; Due to subunit composition Increases level of several neurotransmitters and Acts as a CNS volume control and. DA in reward circuitry → mild reward and relaxation Normal amounts of dopamine released → increased Ach stimulus → enhance perception of reward - More acetylcholine → increase volume (reward) with Less acetylcholine → less volume (reward) but as Nicotine enhances quality of other neurotransmitter systems besides dopaminergic ones then Continuous enhancement - greater addictive liability Alkaline properties - when increased = bad effects : Nicotine poisoning harvest in the field results Die fairly quickly - Fatal dose on LD50 = 60 mg (30 mg reported) with Smoking tobacco usually contains 0.5-2 mg

Nicotine Poisoning

• 8-20 mg per cigarette and Symptom of onset is rapid. - and has alkaline properties as if when increased = bad effects Sympton has
• Nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweats, headache and dizziness, disturbed hearing and vision, mental confusion, marked weakness SLUDGE EFFECT of which causes Salivation and Lactation

Smoking

• Develop chronic tolerance; Where these individuals start to have changes in receptor makeup within the brain/Relates to individual having greater awareness for pleasurable effects but also amplify withdrawal response; Why one of the hardest addictions to break?; Change in receptor makeup-Change in reward circuitry/Synaptic plasticity,Combined alcohol/nicotine effect. Environmental stimuli; Be around people smoking makes people anxious; Transitions to Smoking Use Disorders; Will a beginner continue or increase?? Adolescence

Smoking and Health

• Cancer:Been around since 1600s (Not due to the nicotine, Studies of males/Studies of physicians, Other ingredients in the tobacco plant contribute to cancer) Smoker nominal / 1 pack substantial risk increase -Correlational evidence from England Most cases happen in the young years: increase risk factor x5. Has CVD = Rates of heart attacks,strokes, blood clots, and aneurysms are very higher than for non smokers
• Correlational Data- The higher CVD and Cancer=Decades earlier on how a healthy persons dies due heart disease? How does smoking cause cancer
• Smoke contains BP a potent mutagen
• Mutagen-Causes mutations in DNA genes(cancer suppressor genes) (Diagnosings Hot-spots in the lungs when activated during the metabolism from BP
• SPEEDS UP mutation effects -CVD from the POISIN=The Carbon Monoxide emission from the carbon replaces the red blood cells and then Emphysema (the walls stretch out and doesn’t function in CO2 transfers)

Why Smoker heart Disease are high risk?

• Heart Work that causes Atherosclerosis( Narrowing of vessels) Then Thrombosis - (clotting occurs ) , Heart attack + atherosclerosis ( Heart attack and high blood pressure) :Kills more than Lung Cancer + High Cholesterol can effect liver, diabetes and heart, and brain