Pharmacology 101

1. Pharmacology 101 Drugs of Abuse

2. Basic Principles Pharmacokinetics What your body does to the drug Pharmacodynamics What the drug does to your body Psychotropic drugs Drugs that alter neurotransmission in the brain

3. Part 1 What the Body does to the drug & why that’s important

4. Pharmacokinetics ADME Absorption Drug has to be absorbed into bloodstream Distribution Drug has to be distributed to its target (where it will act) Metabolism Not all drugs will exert action, some be eliminated quickly-before eliminated, drug needs to be changed (metabolized) into a form that is easily eliminated or some drug are metabolized into active components Elimination Remaining drug or parts of drug will be eliminated via urine, feces, sweat, saliva.

5. Administration Multiple ways to administer drugs Orally, safest, most popular & slowest 20+ minutes to site of action Intravenously, quickest & most dangerous 15 seconds from arm to brain Inhalation-very quick, potentially dangerous both short term- (to the brain quickly) and long term (lung disease) but necessary if treating lung disorders-asthma Other routes Intramuscularly, rectally, sublingually, topically

6. ADME & Administration Route of administration absorption Large tissue surface area = greater absorption Distribution More absorbed = more distributed to brain Goal is to get Drug to brain Most direct route w/ greatest surface area for absorption = fastest

7. Absorption & Distribution IV Into circulation to heart to brain (15 sec) Inhalation Into lungs Huge surface area for absorption Immediate path to distribution Lungs>Heart>Brain Oral Large surface are for absorption (stomach-intestines) But has to go through liver first Job of liver is to prepare substances for elimination Most of oral drug lost to first pass metabolism is liver Most doesn’t get distributed to brain

8. Metabolism & Elimination Metabolism Liver First pass metabolism (why oral administration not as effective as other routes) Prepare substances to be eliminated- biotransformation Enzymes in liver regulate metabolism Lots of inter-individual variation in liver enzyme activity CYTP450-major metabolizer Small molecules to kidneys Large molecules to feces or back into distribution for another round of action Elimination Kidneys Intestines

9. Why ADME is Important Kinetic principles determine safety of drug Safety of drug related to dose response curve Amount of drug (dose) needed to generate a certain response From the dose-response curve we get the Therapeutic Index (TI) The greater the TI the safer the drug Drugs with TI under 10 are considered extremely dangerous-risk of overdose (OD) is high Alcohol has a TI = 10 LSD has a TI of >600 No reported deaths caused solely by LSD overdose

10. Drug Safety Therapeutic Index LD50/ED50 Lethal Dose Dose at which drug causes death in 50% (LD50) Effective Dose Dose at which drug cause response in 50% (ED50)

11. Elimination of Drug & OD Drugs are metabolized prior to elimination Rate of metabolism/elimination shortens/prolongs response to drug Two types of metabolism First order Exponential & based upon amount of initial dose Zero order Occurs at a set pace regardless of initial dose

12. Metabolism First-order Kinetics Each pass through the liver eliminates ½ of the drug from the system Each drug has a half-life t ½ -how long to get rid of half the drug t ½ range from seconds to days Drugs w/ longer t ½ usually store in fat, bone or other tissue & are released slowly over time Marijuana: t ½ 20 hrs- 10 days depending upon amount & potency of initial dose Elimination of a drug following first order kinetics usually requires 6 passes through the liver to be eliminated from circulation After 4 passes though the liver 94% of drug is eliminated

13. Metabolism Zero order kinetics Drugs that follow zero order kinetics metabolize at a constant rate regardless of size of initial dose Risk of OD w/ large first doses Alcohol follows zero order kinetics Regardless of how much or how little you drink alcohol will metabolize at a constant rate

14. Alcohol Big dumb stupid drug-need lots to get effect Small molecule, easily absorbed, distributes everywhere, gets to brain quickly Takes a lot of the drug (in comparison to other drugs) to exert a response Low TI = high OD rate Zero order kinetics

15. Alcohol 25-50mg of ethanol for every 100 mL of blood to get BAC of .025-.05%-to get minimal response BAC-blood alcohol content .08 = legal limit 1 drink (6 oz of ethanol) per 50lbs of person per hour

16. Alcohol Metabolism & Binges Distribution 1 hour to 90% of alcohol into bloodstream B/c absorbed quickly in GI tract-minutes to brain & initial effects Metabolized at rate of 1.5 oz of 80 proof p/hour or 1 beer p/hour 1 drink per/50lbs per hour to get BAC of .08 Metabolizes @ 1 drink p/hour How much can you have per/hour & stay w/in legal limit? How much can you drink per/hour before you kill yourself? BAC @ .4 – LD50-death in 50% of population Alcohol poisoning-DEATH @ approximately 5X the legal limit Takes less if you don’t drink, are taking other meds and/or have other medical conditions

17. BAC

18. BAC & Behavior

19. Alcohol & Tolerance Repeated use of alcohol creates tolerance to drug & cross tolerance to other drugs (sedatives) Combining alcohol & sedatives ?response & ?TI (takes less of either to kill yourself) With tolerance it takes increasing amounts of drug to get same response –TI doesn’t change But alcohol still metabolizes at constant rate still has narrow TI (LD50/ ED50) =10 So as tolerance sets in & use increases, risk of OD (alcohol poisoning) becomes greater b/c one approaches the upper limits of Lethal Dose in order to get desired response BAC can increase even after person has passed out Possible to ingest fatal amount of alcohol before passing out b/c it takes time for drug to get to brain

20. Signs of Alcohol Poisoning Mental confusion, stupor, coma No response to pinching Vomiting while asleep Seizures Irregular & reduced breathing less than 10 breaths p/min w/ more than 10 sec between breaths Bluish tint to skin color Cold, clammy feel to hands

22. Side effects

23. Alcohol & Genetics Alcohol metabolism requires stomach & liver enzymes from CYT P450 family-enzymes highly variable & genetically influenced Alcohol dehyrdogenase (stomach) Acetaldehyde dehyrdogenase (liver) Alcohol dehydrongenase converts alcohol into Acetaldehyde Another liver CYTP450 enzyme-acetaldehyde dehydrogenase into acetic acid which is eliminated via urine Acetaldehyde-very toxic, induces vomiting Many Asians lack sufficient acetaldehyde dehydrogenase activity to fully metabolize alcohol & begin vomiting more easily Many Indians have increased acetaldehyde dehydrogenase & don’t get sick as easily Acute high doses-binges of alcohol increase enzyme activity Chronic alcohol decreases enzyme activity-less enzyme more alcohol in system longer

24. Kinetics of Other Drugs Sedatives Benzodiazepines (diazepam, lorazapam, alprazolam “pam” & “lam”) High TI-difficult to OD Extremely long t ½ b/c metabolites (biotransformed substances are often active) Barbiturates Fast-asking, low TI-easy to OD Stimulants Amphetamine t ½ 10hrs depending upon dose (methamphetamine t ½ 5 hrs) Tolerance developed quickly TI low because of actions on heart Cocaine t ½ determined by route of administration Intranasal- 75 min. Oral- 48 min. Rapid tolerance TI low b/c actions on heart

25. Part 2 What the drug does to your body/brain

26. Pharmacodynamics All psychotropic drugs work by altering neurotransmission in brain All neurotransmitters have receptors in both the Central & Peripheral Nervous Systems So all drugs will exert action in both the central & peripheral nervous systems Actions in the peripheral nervous system are usually considered side-effects

27. Tolerance, Dependence & Withdrawal All Drugs of abuse involve tolerance, dependence & withdrawal to some degree or another Tolerance: need more to get the desired effect Dependence: need to maintain drug levels to maintain functioning-offset withdrawal effects Withdrawal: opposite of desired effect Sedatives Desired effect-relaxation & sleep As tolerance increases need more to maintain relaxation & initiate sleep Dependency involves preventing withdrawal effects Withdrawal- induces anxiety & insomnia

28. Peak Effects Some point after administration, a drug exerts its effect, the point at which the effect is strongest is the Peak Effect Repeated administration causes tolerance to a drug Tolerance delays & diminishes peak effect Tolerance requires more drug to elicit the same peak effect

29. Sedative-Hypnotics Sedatives-Hypnotics GABA agonists Decrease excitability of neurons Reduces heart-rate & respiration parasympathomimetic Cross tolerance w/ alcohol Used in high doses for anesthesia Moderate doses for sleep Low doses for anti-anxiety (anxiolytic) anti-depressive

30. Sedative-Hypnotics

31. Dose-Response Curves-Sedatives

32. Sedative-Hypnotic Withdrawal Syndrome First 12-15 hours, patient appears to improve 16+ hours Restless, anxious, tremulous, weak, abdominal cramping Vomiting, orthostatic hypotension, tremors, increased deep tendon flexion, convulsions Days 2-3 Delirium, hallucinations (persecutory) disorientation to time & place Once delirium starts can’t be reduced by administration of other sedative hypnotics-has to run its course Includes hyperthermia (increased body temp), exhaustion, cardiovascular collapse & sometimes death Depending upon type of drug, withdrawal symptoms reach peak severity at days 2-3 & last upwards of a week ( & in some cases, some of the symptoms may last several weeks)

33. Sedative-Hypnotics Alcohol Large dose to get effect –compared to other sedatives Addictive Rapid tolerance Low therapeutic index GABA agonist Additive effect when taken w/ other sedative-hypnotics Makes cell membrane more fluid-inhibits the movement of NA+ & K+ across the membrane Prevents action potentials Decreases Glutamate (excitatory NT)-depresses NT even further Increase release of DA @ nucleus accumbens -reinforcement

34. Alcohol Peak Effect vs. Peak BAC Feel more of alcohol’s behavioral effects before BAC levels reach peak concentration This means that we begin to feel less drunk before the alcohol has been metabolized

35. Alcohol Withdrawal Symptoms begin 12-72 hours after last drink Tremors Nausea, vomiting, anxiety, sweating, abdominal cramps, hyperreflexia, increased BP w/ orthostatic hypotension, Hallucinations, seizures, muscle weakness, increased body temp-sweating Day 3 Exhaustion & cardiovascular collapse “The acute alcohol abstinence is self-limiting. If the patient does not die, recovery usually occurs within 5-7 days.”

36. Marijuana Leaves & Buds used as far back as 2737 BC-medicinally Last 100 years- recreationally Psychoactive component delta-9-tetrahydrocannabinol (THC) 30 metabolites Avg dose 20-30 mg

37. Marijuana’s Psychological Affects Impaired memory, speaking, problem-solving Lack of motivation Interestingly marijuana makes drivers more cautious (not better, but more cautious) Sedative Increased appetite Decrease pain

38. Marijuana Site of Action Cannabinoid Receptors located through-out the Cerebral cortex Hippocampus (memory) Hypothalamus (hunger & sleep) Amygdala (pleasure) Endogenous cannabis- neurotransmitter –anandamide (Sanskrit word meaning internal bliss) Variable activity on almost all other NTs

39. Marijuana Tolerance/Withdrawal Continued use-reverse tolerance-more sensitive to less With 10mg p/day tolerance doesn’t usually develop Psychological not physical dependence unless using well above the norm Acute intoxication-increased HR & conjunctival reddening of eyes

40. Stimulants Stimulant effect on the CNS Three main categories Convulsants and respiratory stimulants Act on brain stem and spinal cord Little to no effect on mental function Exaggerated reflex excitability High doses ? convulsions Psychomotor stimulants (Amphetamines & Cocaine) Affect mental function, behavior and motor activity Psychomimetics (Hallucinagens) Affect thought and perception, distort cognition Effects resemble psychosis

41. Psychomotor stimulants Amphetamines and Related Drugs Amphetamine, methamphetamine, dexamphetamine, methylphenidate, fenfluramine, Ecstasy (MDMA) Release catecholamine, inhibit catecholamine reuptake Cocaine Inhibition of catecholamine reuptake Local anesthetic Methylxanthines Caffeine, theophylline Inhibit phosphodiesterase Adenosine type 2 receptor antagonists

42. History-Amphetamines Amphetamines Sympathomimetic Synthesized in late 1800s Medical uses in 1920s -Benzedrine Asthma inhalers-bronchodilator Military used Benzedrine in WWII to help soldiers stay awake Discovered d-isomer more potent Developed Dexedrine Diet pill-suppresses appetite More modifications yielded methamphetamine (Desoxyn, Methedrine) Even more molecular modifications yielded methylphenidate (Ritalin), & tranylcypromine (Parnate) Amphetamine injected w/ heroin-speed ball- speed (began as cocaine & heroin together but as cocaine supplies diminished, amphetamines were substituted Methamphetamine-smoked ice or crystal meth

43. Amphetamines Central effects Locomotor stimulation Run around more Behavioral changes Less attention paid to surroundings Exploratory behavior reduced Conditioned response altered No evidence of positive learning effects Aggression increased Impulse control declines Become busier, not brighter Improved performance in simple tasks

44. Amphetamines Release biogenic amines Amphetamines NE and D most important for desired street effect Fenfluramine 5-HT release more pronounced Prevent reuptake Central effects Locomotor stimulation Euphoria, excitement Behavioral changes Anorexia (especially fenfluramine) Peripheral effects Sympathomimetic Increased BP, decreased GI motility

45. Amphetamines Stereotypical Effects at high doses Repeated actions, inappropriate to environment Dose dependent Repetitions increase with dose Euphoria With IV administration – orgasmic Confident, hyperactive, talkative, overtly sexual, reduced fatigue (physical, mental) Duration of Effect Related to PK, averages 3-6 hrs PK half-life 5 hrs to 30 hrs Routes of administration – oral, inhalation, mucosal Metabolism P450 mediated

46. Amphetamines Tolerance and dependence Tolerance Rapid for peripheral and anorexic effects Slower for central effects Dependence No true physical dependence Coming down – unpleasant (catecholamine depletion) Sleep (deep, long), depression, anxiety, hunger Insistent memory of euphoria ? psychological dependence Binge use drugs

47. Behavioral Effects of Amphetamines Performance enhancer @ low doses, impairs performance @ high doses Increased alertness Decreased fatigue Decreased appetite At high doses precipitates psychosis, stereotypic behaviors, aggression & violence Rebound depression, suicidality upon withdrawal Rapid tolerance BUT increased sensitivity to psychotic effects If use elicits psychotic behavior, each additional use is going to be more likely rather than less like to elicit negative reaction

48. Amphetamine Mechanisms of Action Increases release of catecholamines DA & NE by increasing leakage of the neurotransmitters both at rest & during action potential Inhibits reuptake (which means more has to be produced) Inhibits one of the enzymes that metabolize the neurotransmitters

49. Cocaine Sympathomimetic Derived from coca leaf Freud used it to treat depression & self-medicated In wine & coca cola Local anesthesia-eyes Derivatives-lidocaine-topical anesthetic Rapid tolerance Highly addictive

50. Cocaine Forms of administration Cocaine - HCl salt (H2O soluble) Intravenous With heroin (speedballs) Nasal inhalation Causes atrophy and necrosis of nasal septum Crack cocaine – free base Smoked

51. Cocaine Binges last ~12 hours-several days w/ some users re-dosing every 15 min. Usually crash between binges Mood elevation, perceived increase in self-esteem, mental & physical capacity Appetite & sleep are decreased Increased sexual interest, impaired judgment, hyperactive Psychological Toxicity Hyper vigilance Paranoia Suspiciousness Aggressive & homicidal against those perceived persecutory Physiological toxicity Myocardial infarction Arrhythmias Seizure

52. Amphetamine/Cocaine Withdrawal The Crash Increased anxiety Increased irritability Depression Need for sleep Withdrawal shouldn’t kill you.

53. Opioids (narcotics) Heroin From the seeds of the poppy plant Metabolized into morphine 2x as strong as morphine 25X as strong as codeine Produce action by interacting w/ opioid receptors to activate endogenous opioids Enkephalins Endorphins Dynorphins CNS effects Analgesia (pain relief) Drowsiness Changes in mood-euphoria but also numbing Decreases diarrhea In pain free individuals Not always pleasant Induces vomiting Long term use Sexual impotence Constipation Insomnia Excessive sweating

54. Opioid Withdrawal Begging/pleading for drug 8-12 after last dose Tearing Yawning Sneezing Sweating 12-14 hours Tossing restless sleep-several hours to days Upon waking still restless As the syndrome progresses (7-10 days to complete) Dilated pupils Anorexia Gooseflesh-cold turkey Violent yawning & sneezing Pronounced weakness & depression Nausea, vomiting diarrhea Increase BP & HR, cold-sweats Abdominal cramps & pain Muscle spasms-kicking the habit

55. Caffeine Caffeine Behavioral Effects t ½ 5 hours Psychological & mild physiological dependence & withdrawal effects Increased alertness, attentiveness, decrease fatigue Too much-restlessness, jitters, anxiety Increase gross motor functioning, decreases fine motor skills Mechanism of Action Blocks adenosine receptors (chronic use causes up-regulation of receptors Vasoconstrictor Increases DA in nucleus accumbens-to some degree