Week 5 - Amphetamines and Cocaine Flashcards
What are stimulants?
- Mimic sympathetic nervous system and work on neurotransmitters
What do the drugs stimulate the transmission of?
- Epinephrine (E)
- Norepinephrine (NE)
- Dopamine (DA)
- Serotonin (5-HT)
- “Sympathomimetic” - serotonin as indolamine
What type of amines are these neurotransmiters
Monoamines (MAs) or biogenic amines
What are E, NE and DA
Catecholamines - very similar chemical structures
What is the natural amphetamine?
Ephedrine - used by Chinese cultures
What are the synthetic amphetamines and what are they used for?
- D-amphetamine = ADHD
- L-amphetamine = mirror image as D but more potent
DI-amphetamine - ADHD and narcolepsy - Methamphetamine (speed) - ADHD and obesity
What are the amphetamine-like stimulants (synthetic)
- Methylphenidate (MPH/Ritaline)
- Pipradrol
What is cocaine?
- Extracted from leaf of coca plant native to Sth America = Cathionone (khat)
- Extracted from African shrub
Synthetic = methcathionone (bupropion)
Are amphetamines an acid or a base, and what is the pKa?
- Weak base - pKa = 9-10
What are the methods of administration?
- Oral
- Injection and inhalation
What are the advantages of oral administration of amphetamines?
- Ionized in digestive system (slower rate of absorption)
- Blood levels can be kept constant
- Medical uses
What is the pKa of cocaine and what are it’s main routes of administration?
pKa = 8.7
- Usually injected or inhaled
What is the oral administration of cocaine?
- Sucking coca leaves
- Mix leaves with lime (stone) (wood ashes) to decrease ionization (increase absorption) - makes more basic/lining of digestive tract more basic to increase absorption
What is tooting of cocaine?
inhaling vapor from heated powder
What is freebasing of cocaine?
Separates cocaine from HCl
What is crack cocaine?
Cocaine HCl + sodium bicarbonate
What is snorted
- powdered salt (cocaine HCl)
What is the absorption of amphetamines for oral administration?
- Determined by food in stomach and physical activity
- Peak blood levels within 30 min - 4 hrs
What is the absorption of amphetamines for inhalation
approx 2.5 hrs
What ist he absorption of amphetamines for IV
5 minutes
What is the absorption time for inhalation of cocaine?
10-20 mins
What is the distribution of amphetamines and cocaine?
Cross BBB and concentrate in brain, spleen and kidneys
What is the excretion of amphetamines?
- Depends on pH of urine: more basic = more reabsorption
- 50% excreted unchanged/ 50% metabolized by liver
- ½ life = 7-14 hours if acidic urine & 16-34 hours if basic
- Also excreted through sweat & saliva
- Metabolites can also be active with long half lives
What is the absorption of cocaine?
- ½ life = 45-75 minutes, also dependent on urine pH
- Metabolites may be present in urine 24-36 hours after admin.
- Metabolites also deposit in hair
What synapses do amphetamines effect?
5HT, E, NE and DA (esp)
What are the three effects of amphetamines at the synapse?
- Cause NT to leave into synaptic cleft
- Increase NT released due to AP
- Block reuptake (& inhibit MAO activity)
What is the effect of cocaine at the synapse
- Reuptake blocker
What is the effect on the PNS
stimulate epinephrine synapses - fight or flight
What is the effect on the CNS?
Multiple:
- Increased DA in nucleus accumbens (reinf & motivation)
- Increased DA in nigrostriatal system (motor activity)
- Cocaine blocks APs (via Na+ ion channel blocking) - local anesthetic (Procaine)
What are the effects of stimulants on the body?
- Increase HR and BP
- Vasodilation
- Bronchodilation
What are the side effects of stimulants on the body?
- Headaches
- Dry mouth
- Upset stomach
- -> Methamphetamines has fewer PNS effects
What are the effects on stimulants on sleep?
- Prevents sleep
- Insomnia
- Suppression of REM sleep
What are the effects of stimulants on mood?
- Improve mood (3-6hrs)
- ↓ fatigue/ ↑ energy
- Rush
- Followed by depression/crash
- Acute tolerance to pleasurable effects
- Cocaine has shorter-acting effects (<10-20mins ‘pleasurable’)
What are the effects of stimulants on behaviour?
- Stereotyped behavior – repetitive acts that are meaningless (e.g. pacing)
- Punding at high doses – repetitive meaningless acts that last for a long time (e.g. moving things back and forth)
What are the mental disturbances associated with stimulants?
- Amphetamine psychosis or ‘monoamine psychosis’
- Hallucinations, delusions, hostility/violence, paranoia
- Disappears in a few days with no lasting effects
- At high doses cocaine can also induce psychosis
- Formication – feeling of bugs crawling on skin (cocaine bugs, or “crank” bugs with amphetamine use)
What are the sensory effects of stimulants?
- ↑ visual acuity (CFF) & auditory acuity
* Time underestimated (seems longer than usual)
What are the effects of stimulants on performance?
- ↑ endurance
- Fatigue effects = ↓ (improve) RT & ↑ coordination (especially complex tasks)
- ↑ vigilance & attention
- Most effects seen on simple or learned performance vs. novel performance tasks; narrowing or “tunneling” of attentional focus
What are the effects of stimulants on athletic performance?
1 % improvement on swimming and track performance
–> Banned substance
What are the effects of stimulants on appetite?
• Anorectic effects; mechanisms unclear
↑ ‘other’ (motoric) behavior
Stimulation of areas of the hypothalamus (e.g., Yu et al., 2017)
↓ DA midbrain activation to (sweet) rewards (Melrose et al., 2016)
• ↑ metabolism & ↓ food intake = weight loss
• Evidence about thalamus being dulled, also maybe that the dopamine pathway of food is suppressed
What is the unconditioned behaviour in animals?
• ↑ SMA (Low and intermediate doses) • Stereotyped behaviours • Auto-mutilation (Higher doses) • ↓ food & water Conditioned Behavior
What is the conditioned behaviour in animals?
- Rate dependency effect (↑low-rate behaviours, ↓high-rate behaviours); doesn’t apply to punished behavior
- Operant effects of cocaine not as significant as amphetamines
Can amphetamines and cocaine be discriminated?
- Amphetamines create dissociation (e.g. drug state discrimination)
- Amphetamines & cocaine discriminate from saline but not as well as barbiturates or benzodiazepines
Do amphetamines generalise?
- Amphetamine generalizes to cocaine, MPH, & some MAO inhibitors
- Amphetamines do not really generalize to caffeine, nicotine, barbiturates, hallucinogens
What is the self administration of amphetamines in humans?
- Sporadic (run-abstinence cycle)
- Depends on reason for taking the drug
- ‘speed freaks’
What is the self-administration of cocaine in humans?
• Sporadic (run-abstinence cycle)
• Usually mixed with other drugs
o Speedball (+heroin) or mixed with depressants
What is the self-administration in animals?
- Cocaine administration by rats
- More reinforcing than any other drug (monkeys)
- Erratic pattern of administration
- Monkeys will self-administer lethal dose
What is the self-administration in animals increased by?
o Stress
o Prior experience
o Caffeine, heroine and alcohol
What is the acute tolerance of stimulants?
- Cocaine – disappears rapidly (<24 hrs)
* To subjective effects but not BP and HR
What the the chronic tolerance?
- Appetite suppression – 2 weeks
- HR and BP
- Lethal effects
- No tolerance to effects on sleep
What are the withdrawal effects?
- Depression – within ½ hr for cocaine and hrs for amphetamines
- Dose dependent severity
- REM rebound, frequent awakenings
- LT cocaine use can cause on-going depression; may be treated with anti-depressants
- LT, amphetamine use can lead to suicidal thinking/attempts; may present as if clinically depressed, with changed (often increased) sleep and appetite
What are the clinical uses of amphetamines?
• ADHD (Ritalin, Dexedrine, Adderall, Cylert)
o Paradoxical effect
o Suggests ADHD due to deficiency in NE & DA
• Obesity (Dexatrim, Tenuate, Sanorex)
o Tolerance to effects in 2 weeks – continue to increase dose
• Narcolepsy (Provigil – nedaphonil)
o Few side effects
o No tolerance to sleep effects
• Some cold and flu preparations
What are the clinical uses of cocaine?
• Local anesthetic
o In nose, mouth etc. to ease discomfort of tubes
o Dental work
What are the harmful effects of amphetamine?
• Restlessness, confusion, dizziness
• Punding, stereotyped behaviour
• Paranoid psychosis
• Internal bleeding & strokes from ↑ BP
• Cessation may → suicidal depression, & sleep disturbance (REM rebound)
• Brain damage from ruptured blood vessels in the brain; DA neuron damage (see Thompson et al., 2004)
• Lifestyle effects
HIV/AIDS, hepatitis (IV users)
Immune functioning (nutritional deficiencies, sleep disturbance)
What are the harmful effects of cocaine?
- Jaundice / liver disease
- Inflammation & ulcers in the nose (& damage to septum)
- Cocaine runs (financial problems)
- Paranoia, hallucinations, cravings, antisocial behaviour, attention & concentration probs, blurred vision, weight loss
What are the harmful effects of cocaine and amphetamine on reproduction?
• ↑ sexual activity low doses: prolong erection, delay ejaculation; enhance female libido • Continuous high doses of cocaine: disinterest • Birth abnormalities • ‘crack babies’ Retardation of growth Premature Abruptio placentae Behavioral problems
What happens in cocaine overdose?
- Muscle weakness
- Respiratory depression
- Cardiovascular effects – sudden-death
What are the phases of cocaine overdose?
2 phases (‘caine reaction’):
- Excitement followed by headache, nausea, vomiting, convulsions
- Lose consciousness, respiratory depression, cardiac failure, death (hypoxic brain damage risk)
What is the treatment of overdose?
• OD treatment: diazepam (control seizures), artificial respiration (control breathing), chlorpromazine (antipsychotic) antagonist to toxic effects of cocaine
What is the treatment for stimulant addiction?
• Detoxification
• Strong probability of relapse due to intense craving
• Pharmacotherapies: (used with mixed success)
Antidepressants (e.g., bupropion/Zyban)
Modafinil
Oral d-amphetamine
Naltrexone
• Behavioral Therapies
Contingency management, community reinforcement
