unit 9: drugs & substances of abuse

Drug of Abuse

• No medical indication

• Euphoria

• Altered perception

• “Compulsive”

Dependence

• Physical

• Tolerance

• Withdrawal Syndrome

• Non-psychoactive drugs

you **need** the drug to function

Addiction

• Psychological

• Compulsion

• Relapsing

• Craving

you **don’t need** the drug to function

Mesolimbic Dopamine System

• Reward (motivation)

• Pleasure, euphoria

• mPFC - Motor function (fine tuning)

• Compulsion

• Preservation

Drugs of abuse are associated with the **increase of dopamine**

Class 1: **GPCR**s

Opioids, THC, GHB

Class 2: **Channels**

• Benzodiazepines, Nicotine,, Ethanol

• ionic channels

Class 3: **Transporters**

• Cocaine, Amphetamine, Ecstasy

• protein transporters for reuptake, storage, recycling

**Schedule I**

* Heroin, Lysergic acid diethylamide

Regulation Schedules:

• High potential for abuse, no known medical use and lacks accepted safety for use

**Schedule II**

* morphine, cocaine, methadone, methamphetamine, phencyclidine

Regulation Schedules:

• Potential for abuse with proven and accepted medical use but with severe restrictions, because abuse may cause severe psycho/physio dependence

**Schedule III**

* Anabolic steroids, codeine and hydrocodone, with aspirin or Tylenol

Regulation Schedules:

• Less potential for abuse than schedule I or II

• moderate or low physical dependence or high psychological dependence

**Schedule IV**

* Valium and Xanax

Regulation Schedules:

• a low potential for abuse relative to the drugs or other substances in Schedule III

• limited physical dependence or psychological dependence

Schedule V

* Cough syrups and codeine

Regulation Schedules:

• low potential for abuse relative to the drugs or other substances in Schedule IV

Pharmacokinetic Tolerance

Tolerance:

• Reduction of concentration that reaches the binding sites/receptors

• Shorter duration of action

Pharmacodynamic Tolerance

Tolerance:

• drug receptor interaction

• binds somewhere instead of target receptor

β-arrestin

Tolerance: Pharmacodynamic

• binds to G-protein coupled receptors, decreasing its response to the presence of the drug

Desensitization

Tolerance: Pharmacodynamic

• receptor becomes immune or nonreactive to the drug present in it

Receptor internalization

Tolerance: Pharmacodynamic

• receptors are taken down from the cell membrane

• hide receptors to modulate

**imbalance** of neurotransmitters

Tolerance: Withdrawal Symptoms

if you immediately withdraw the endogenous sources, there will be ___

Post Acute Withdrawal Syndrome (PAWS)

Tolerance: Withdrawal Symptoms

Irritability and emotional outbursts, anxiety, low energy, trouble sleeping, memory problems, dizziness, increased accident proneness, and delayed reflexes

Addiction

• High motivation to obtain and use the drug

• Psychological compulsion to use and feel the effect of the drug besides the negative consequences

Non-Addictive

• non-psychotropic

• does not affect neurotransmission

• Alter perception; no reward/euphoria

hallucinogens

Non-Addictive:

take it just to feel their effects but it is not addictive and compulsion to use

**cortical**: cerebral cortex and thalamic system

Non-Addictive:

instead of targeting the hypothalamus, the dopaminergic which is the primary mechanism for addiction, it targets ___

• Opioids

• Cannabinoids

• GHB

• LSD, Mescaline, Psilocybin

Pharmacology of Drug Abuse:

Drugs that Activate G-protein coupled receptors

• Nicotine

• Benzodiazepines

• Alcohol

• Ketamine & PCP

• Inhalants

Pharmacology of Drug Abuse:

Drugs that Bind to Ionotropic receptors

• Cocaine

• Amphetamines

• Ecstasy (MDMA)

Pharmacology of Drug Abuse:

Drugs that Bind to Transporters of Biogenic Amines

Opioids

* Strong analgesics, **painkillers**

Opiates

Opioids:

morphine, codeine, thebaine, papaverine

Narcotic

Opioids:

sleep inducing

µ (mu)

Opioids: Receptor Subtypes

• Supraspinal and spinal analgesia

• sedation

• inhibition of respiration

• slowed gastrointestinal transit

• modulation of hormone and neurotransmitter release

δ (delta)

Opioids: Receptor Subtypes

• Supraspinal and spinal analgesia

• modulation of hormone and neurotransmitter release

κ (kappa)

Opioids: Receptor Subtypes

• Supraspinal and spinal analgesia

• psychomimetic effects

• slowed gastrointestinal transit

Endorphins > enkephalins < dynorphins

Opioids: Receptor Subtypes

Endogenous Opioid Peptide Affinity

µ (mu)

Endorphins > enkephalins and dynorphins

Opioids: Receptor Subtypes

Endogenous Opioid Peptide Affinity

δ (delta)

Endorphins > > enkephalins and dynorphins

Opioids: Receptor Subtypes

Endogenous Opioid Peptide Affinity

κ (kappa)

Opium

Opioids:

• Papaver somniferum

• insomnia, hallucination, nightmares

• histamine release

• plant-derived

• powerful narcotic

morphine

Opioids: Opium

• painkiller principal active ingredient

Heroin (Smack, H, ska, junk)

Opioids:

• diamorphine

• white or brown powder

3-5 hrs

Opioids: Heroin

T1/2

5-10 hrs after

Opioids: Heroin

Withdrawal

thebaine

Opioids: Oxycodone

synthesized from ___

codeine

Opioids: Oxycodone

derived from ___

**Meperidine** (pethidine; Demerol)

Opioids:

• serious interaction with MAO’s

• attempts to illicitly produce meperidine has resulted in MPTP which can cause parkinsonism

methyl-phenyl-tetrahydropyridine

Opioids: Meperidine

MPTP

Periphery

Opioids:

opioids bind to the MOR preventing the transmission of pain signal which is perceived by our sensory receptors

receptors that block **Ca channels**

Opioids:

• reaching the presynaptic terminal in our dorsal horn

• prevent the release of neurotransmitter that transmit the pain signals to the postsynaptic

enhancing K+ conductance

Opioids:

Postsynaptically

inhibitory (GABAergic) interneuron

Opioids:

• pain-inhibitory neuron is indirectly activated by opioids (exogenous or endogenous), which inhibit ___

• results in enhanced inhibition of nociceptive processing in the dorsal horn of the spinal cord

Sedative-hypnotics

Opioids: Drug Interactions

• Increased central nervous system depression, particularly respiratory depression

Antipsychotic agents

Opioids: Drug Interactions

• Increases sedation

• Variable effects on respiratory depression

• Accentuation of cardiovascular effects (antimuscarinic and α-blocking actions)

Monoamine oxidase inhibitors

Opioids: Drug Interactions

• Relative contraindication to all opioid analgesics because of the high incidence of hyperpyrexic coma

• hypertension

Sedative-hypnotics

• alcohol, barbiturates, benzodiazepines, gamma-hydroxybutyric acid (GHB)

• can be short- to long- acting

• the longer the duration the less the withdrawal

Benzodiazepines

Sedative-hypnotics:

increase GABA activity, used for anxiety and insomnia

Barbiturates

Sedative-hypnotics:

enhance GABA activity, used for anesthesia and seizures

Z-drugs

Sedative-hypnotics:

bind to GABA receptors, used for insomnia

Alprazolam

Sedative-hypnotics: Pharmacokinetic Properties

Rapid oral absorption

Chlordiazepoxide & Diazepam

Sedative-hypnotics: Pharmacokinetic Properties

Active metabolites; erratic bioavailability from IM injection

Chlorazepate

Sedative-hypnotics: Pharmacokinetic Properties

Prodrug; hydrolyzed to active form in stomach

Eszopiclone

Sedative-hypnotics: Pharmacokinetic Properties

Minor active metabolites

Flurazepam

Sedative-hypnotics: Pharmacokinetic Properties

Active metabolites with long T1/2

Lorazepam, Oxazepam, Zolpidem

Sedative-hypnotics: Pharmacokinetic Properties

No active metabolites

Temazepam

Sedative-hypnotics: Pharmacokinetic Properties

Slow oral absorption

Triazolam

Sedative-hypnotics: Pharmacokinetic Properties

Rapid onset; slow duration of action

Zaleplon

Sedative-hypnotics: Pharmacokinetic Properties

Metabolized via aldehyde dehydrogenase

Benzodiazepines

Sedative-hypnotics:

• rare occurrence of physiologic dependence

• Enhance the activity of GABA neurotransmitter

Therapeutic Dose Dependence

Sedative-hypnotics:

Benzodiazepines

weight loss, change in perception, paresthesia, headache

**Flunitrazepam**: anterograde amnesia

Sedative-hypnotics:

Benzodiazepines

date rape

Rohypnol

Sedative-hypnotics:

Benzodiazepines

roofies

Barbiturates

Sedative-hypnotics:

• GABA-A receptors

• Short - acting drugs due to the risk of dependence and overdose

• Unpredictable

Alcohol

Sedative-hypnotics:

• GABA-A and NMDA

• euphoria

Gamma Hydroxybutyric Acid

Sedative-hypnotics:

• GABA-B

• found in the body & in fermented drinks

• Georgia homeboy

• euphoric, sedative, anabolic

chlordiazepoxide or phenobarbital

Sedative-hypnotics: Gamma Hydroxybutyric Acid Treatment

• Short acting and Long acting drugs

disulfiram, naltrexone

Sedative-hypnotics: Gamma Hydroxybutyric Acid Treatment

• alcohol

Marijuana

Sedative-hypnotics: Cannabinoids

• Cannabis sativa

• cannabinoid receptors (CB1)

• antiemetic - prevents vomitting

• 2-3 inhalations

• Amotivational syndrome

tetrahydrocannabinol

Sedative-hypnotics: Marijuana

addictive component

Hallucinogens

Sedative-hypnotics:

substances that cause hallucinations

**Lysergic Acid Diethylamide** (LSD)

Sedative-hypnotics: Hallucinogens

• Claviceps purpurea

• synthetic agent related to ergot alkaloids

• one of the most potent drugs

• 5-HT1a & 5-HT1c agonists

Mescaline

Sedative-hypnotics: Hallucinogens

• Lophophora williamsii

Psilocybin

Sedative-hypnotics: Hallucinogens

• Psilocybe mushroom (shrooms)

Ketamine

Sedative-hypnotics:

• anesthetic primarily in race horses

• “special K” “vitamin K”

• dream-like states, fatal respiratory problems

Phencyclidine

Sedative-hypnotics:

• phenylcyclohexylamine derivative

• veterinary anesthetic

• antagonize NMDA

• Olney’s lesions

• long t1/2

Scopolamine

Sedative-hypnotics:

• Hyoscyamus niger

• block central muscarinic receptors

Cocaine

Sedative-hypnotics:

• Erythroxylon coca

• inhibit reuptake of dopamine and NE

• feeling of bugs under skin, paranoia and schizophrenia like state

1hr, repeated 30 min

Sedative-hypnotics: Cocaine

• t1/2

Amphetamines

Sedative-hypnotics:

• alpha-methyl-phenethylamine

• increase catecholaminergic neurotransmitters

• dopamine not be metabolized thus released

• antiobesity drugs

• treats narcolepsy and ADHD

Ecstasy

Sedative-hypnotics: Amphetamines

• Methylene-dioxymethamphetamine (MDMA)

• intimacy and empathy

• “raves” designer drug

Stimulants

reverse the effects of fatigue on both mental and physical tasks

**Nicotine** (*Nicotiana tobacum*)

Stimulants:

• tobacco products

• nicotinic cholinergic receptor agonist

• strong psychological and physiological dependence

Caffeine (1,3,7-trimethylxanthine)

Stimulants:

• coffee, tea, some soft drinks, and many non-prescription medicines

• xanthine alkaloid from Coffea arabica

• adenosine receptors

Inhalants

• psychoactive effects

• alcohol-like intoxications, hallucinations

anesthetic gases

Inhalants:

• difficulty in concentrating, dreaminess, euphoria, numbness, tingling

• N2O= 35% used; 100% death

• ether & chloroform

industrial solvents

Inhalants:

• gasoline, toluene, benzene, trichloro-ethylene

• 5-15 min

• euphoria, “drunk” feeling, disorientation slow passage of time

organic nitrites

Inhalants:

• amyl nitrite, isobutyl nitrite

• dizziness, rapid heart rate, lowered BP, “speeding,” flushing of skin

• enhance, prolong erection

Anabolic Steroids

• Synthetic substances that mimic the effects of testosterone in the body.

• cyclopentanoperhydrophenanthrene ring

• bone growth, appetite, puberty, muscle growth

• change in libido, irritability, violence, mood swings, forgetfulness, confusion

• fatigue, depressed mood, craving for steroids

• hypertrophied muscles, acne, oily skin, hirsutism in females, gynecomastia in males, needle punctures

• high LDL; low HDL

• elevated liver function