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