Central Nervous System Stimulants

Question 1

What do CNS stimulants do

Answer 1

• increase the activity of CNS neurons
• can be the produced either through enhancement of excitation or suppression of inhibition
• in sufficient doses, all CNS stimulants can cause convulsions
• CNS stimulant have clinical usefulness in treatment of ADHD and Narcoplesy
• and they are used ( and abused) for non-therapuetic purposes

Question 2

Caffeine

Answer 2

• a methylxanthine, similar structurally to purines

- theophylline and theobromine are very similar in structure and mechanism

Question 3

MOA caffeine

Answer 3

• primary effect at normal caffeine doses: competitive antagonist of adenosine receptors
• postsynaptic adenosine receptors produce IPSPs (hyperpolarize)
• presynaptic adensosine receptors inhibit glutmate release

-caffeine inhibits these inhibitory effect (dis-inhibition) resulting in CNS stimulation

Question 4

What does caffeine do at higher doses

Answer 4

• inhibits cAMP phosphodiesterase
• results in increased cAMP; responsible for its beneficial effects in the treatment of asthma (not as efficacious as other methylxanthines)
• induces the release of calcium from intracellular (ER) stores

Question 5

pharmacological action of caffeine

Answer 5

• CNS stimulant

- peripheral effects

Question 6

Caffeine as a CNS stimulant

Answer 6

• increased alertness; increased attention during sustained tasks
• decreased fatigue and drowsiness
• can cause nervousness, restlessness and tremors
• high doses stimulate medullary respiratory and cardiovascular centers

Question 7

Caffeine peripheral effects

Answer 7

• positive inotropic and chronotropic effects (direct effects on the myocardium)
• dilates coronary and systemic blood vessels; constricts cerebral blood vessels (this may underlie the beneficial effects of caffeine in headache)
• produces diuresis
• increases gastric secretions
• modest bronchodilation

Question 8

Therapeutic usefulness of caffeine

Answer 8

• primarily used to stay awake (various over the counter prescriptions)
• added to some aspirin preparations to treat headache (excedrin)

Question 9

caffeine overdose

Answer 9

-excessive CNS stimulation: nervousness, insomnia, excitement

Question 10

consequences of chronic use of caffeine

Answer 10

• tolerance: develops to the stimulant effects of caffeine
• physical dependence: develops to caffeine at the dose of two cups of coffee per day

-withdrawal symptoms include feelings of fatigue and sedation; headaches and nausea; vomiting (rare)

Question 11

Sympathomimetic stimulants

Answer 11

• act through the enhancement of catecholaminergic neurotransmission
• cocaine
• amphetamine
• methylphenidate

Question 12

Cocaine

Answer 12

• extracted from coca plant
• local anesthetic
• illicit use
• cacoaine is a weak base; therefore, unionized it is in the unprotonated form (B) which predominates at alkaline pH (native people chew leaves with soda lime
• 3 major forms: hydrochloride salt, purified free base, and impure base “crack”

Question 13

How are free base cocaine and crack cocaine made

Answer 13

• extracting the hydrochloride salt from an alkaline solution into an organic solvent
• crack is made by adding bicarbonate to the hydrochloride salt
• both crack and free base are absorbed more quickly across membrane; but more importantly they are more volatile than the salt form and can be smoked

Question 14

pharmacokinetics of coaine

Answer 14

• well absorbed through any mucous membrane
• time to peak effect and duration of action are depndent upon the route of administration (shortest are iv and smoke)
• metabolized in plasma and liver
• short plasma half life (50 min) even shorter CNS half life (10-30 min)
• urine screens detect metabolites

Question 15

MOA cocaine

Answer 15

• potent inhibitor of the reuptake of NE, DA, 5-HT
• cocaine binds to the transporter itself and inhibits the binding of the neurotransmitter
• reinforcing effects are due to increased dopamine in the synapse
• increases the activity of tyrosine and tryptophan hydroxylase (due to loss of end product inhibition) -increase NT synthesis
• is a local anesthetic and vascosontrictor

Question 16

Pharmacological effects of cocaine

Answer 16

• peripheral sympathomimetic effects (due to inhibition of NE reuptake in periphery)
• vasoconstriction, tachycardia
• increased alertness and vigilance (due to inhibition of NE reuptake in CNS synapses)
• euphoria elation, feeling of well being (due to inhibition of DA reuptake in the mesolimbic circuit
• as a result, cocaine has a high abuse liability

Question 17

toxic effect of cocaine

Answer 17

• tolerance and physical dependence occur with heavy use, but they are mild
• mild withdrawal symptoms
• neurotoxicologic consequences to long term use: due to damage of dopaminergic neurons
• overdose can cause seizure;CV effect (myocardial infarction and arrhythmias)
• effects on developing fetus-more significant than alcohol
• premature labor, low birth weights, many learning and emotional problmes, attaachment disorder

Question 18

Cocaine and its psychological dependence

Answer 18

• profound psychological dependence
• drug craving and seeking
• users crave the drug even 10 minutes after last dose
• abuse liability is greater with dosage forms that deliver drug rapidly to the CNS (smoking or iv)
• withdrawal symptoms: dysphoria, depression, sleepiness, fatigue
• cocaine cravings can be reduced by drugs that increase GABA including ganapentin, vigabatrin, baclofen

Question 19

Amphetamine and methamphetamine

Answer 19

• structurally similar to Norepinephrine
• weak bases
• well absorbed orally; the free bas methamphetamine can be smoke (crystal meth)
• amphetamine is metabolized to a variety of metabolites and about 50% is excreted unchanged; methamphetamine is metabolized to amphetamine
• relatively long half lives (much longer than cocaine)

Question 20

MOA for Amphetamine and Methamphetamine

Answer 20

• Potentiate NE, DA and 5HT signaling
• via actions at the trace amine associated receptor (TAAR1)
• TAAR1 is a GPCR, via cAMP/PKA phosphorylates reuptake carriers (DAT, NET, SERT( and VMAT2
• results in inhibition of uptake and reversal (release of the amines) from terminal or vesicles (VMAT2)
• partial agonist of alpha receptors
• MAO inhibitor at high doses
• more NE-like effects than cocaine

Question 21

Pharmacological properties of amphetamine and methamphetamine

Answer 21

• arousal; increased wakefulness; decreased fatigue
• enhance athletic and intellectual performance (quantity is improved, not quality)
• elevated mood, increased self-confidence
• respiratory stimulant
• decreases appetite
• peripheral sympathomimetic

Question 22

pharmacological properties amphetamine

-what is the active form

Answer 22

mixture of steroeisomers; active form is dextroamphetamine

Question 23

pharmacological properties methylphenidate

Answer 23

-not technically an amphetamine, but structurally and mechanistically very similar

Question 24

pharmacological properties methamphetamine

Answer 24

-gets into brain better, higher abuse liability

Question 25

pharmacological properties lisdextrofetamine

Answer 25

-prodrug of dextroamphetamine

Question 26

clinical uses amphetamine and methylphenidate

Answer 26

1. Narcolepsy- use is complicated by risk of abuse and tolerance development 2. Attention Deficit Hyperactivity Disorder: excessive motor activity, racing thoughts, difficulty in sustained attention; academic underachievement. is effective in many children 3. exogenous obesity: obesity that is considered to be outside the control of the individual

Question 27

side effects of amphetamine and metylphenidate taken at therapeutic doses

Answer 27

- insomnia - abdominal pain - anorexia, weight loss - suppression of growth - high body temperature - facial tics

Question 28

toxicity of amphetamines and methylphenidate (occurs at much higher doses than used for ADHD)

Answer 28

- acute toxicity: sympathomimetic effects; restlessness, dizziness, tremor - psychosis due to excessive DA - neurotoxicity: permanent intellectual problems; neuronal degeneration - meth mouth: sever tooth decay, cause by a combination of dry mouth, lack of oral hygiene, increased consumption of sugared drinks, and teeth clenching and grinding - abuse liability: esp iv or smoked methamphetamine; worse long term than cocaine - sudden cardia death due to sympathetic activation

Question 29

Nicotine-what is it and what is the mechanism of action

Answer 29

- naturally occurring alkaloid in tobacco products - MOA: agonist of nicotinic cholinergic receptors *NMJ: initially activates muscle contraction, but then desensitizes * autonomic ganglia: - sympathetic: release of epinephrine form adrenal - parasympathetic: GI effects * receptors in CNS: - found in many brain regions; including nucleus accumbens (target of dopamine in the mesolimbic reward circuit) - are monovalent cation channels; activation produces a membrane depolarization, thus produces excitation

Question 30

Pharmacological actions of nicotine

Answer 30

1. CNS stimulant-increases alertness 2. Increases dopamine release in limbic, reward centers-is reinforcing 3. muscle relaxant 4. activates the chemoreceptor trigger zone and causes nausea (common with first exposure)

Question 31

Explain why smoking is highly reinforcing

Answer 31

1. reaches the brain very rapidly (lungs to brain in 7 sec) 2. Increases dopamine signaling in the nucleus accumbens reward pathway 3. each puff of smoke is a separate opportunity for the brain to associate smoking with reward; therefore it is highly addicting even though a single administration of nicotine is not as rewarding as a single administration of cocaine

Question 32

what is the relationship between environmental factors or cues and smoking

Answer 32

Environmental factor or cues become associated with the reward as well - setting ("I only smoke in bars") - time of day ("I only smoke after dinner") - preparation ("seeing an ashtray makes me want to smoke")

Question 33

can people really only be a social smoker

Answer 33

-not really because the number of administration perday (STRONG association between smoking and euphoria) and the environmental cues give it a high dependence liability

Question 34

Describe nicotine tolerance`

Answer 34

- occurs over a very short period of time (hours: tachyphylaxis) - therefore the first cigarette of the day is the best

Question 35

nicotine withdrawal symptoms

Answer 35

- irritability, hostility, impatience - anxiety - depression - difficulty concentrating - increased appetite, weight gain

Question 36

treatment of nicotine dependence

Answer 36

1. Nicotine replacement: most widely used and there are many preparations - active: nasal spray, gum, lozenge, sublingual tablet, inhaler - passive: patches -a large percent of patients using nicotine replacement are not smoking at 6 weeks but only 20% are abstinent for one year

Question 37

Pharmacotherapies for smoking cessation

Answer 37

- bupropion | - Varenicline

Question 38

bupropion

Answer 38

- antidepressant - used as a sustained release preparation - reduces craving and lessens some of the nicotine withdrawal symptoms (esp depression) - side effects: insomnia, dry mouth

Question 39

Varenicline

Answer 39

- partial agonist of nicotinic receptors - rationale: reduce craving by activating the nicotinic achetylcholine receptor; will not desensitize like nicotine itself, also blocks the effects of nicotine if the person smoke (partial antagonist effect)

Question 40

Side effects for varenicline

Answer 40

- nausea, headaches, constipation | - FDA concern for increase suicidal thoughts and depression

Question 41

other drugs used to treat ADHD that are not classified as stimulants

Answer 41

- atomoxetine | - clonidine

Question 42

atomoxetine

Answer 42

-selective norepinephrine reuptake inhibitor (SNRI); antidepressant

Question 43

Clonidine

Answer 43

alpha 2 adrenergic receptor agonist

Question 44

Guanfacine

Answer 44

alpha 2 adrenergic receptor agonist