CNS Stimulants Flashcards
Amphetamines: MOA
DL-amphetamine, Dextroamphetamine, Methamphetamine
MOA:
1) substrate (competitive inhibitors) of neuronal monoamine uptake transporters NET and DAT
2) enter synaptic nerve ending and displace stored NE and DA (displacer effect)
3) interact with VMAT-2
4) NE and DA transported out via DAT and NET working in reverse
5) at high conc., inhibit MAO (normally breaks down DA and NE
Amphetamines: Effects
DL-amphetamine, Dextroamphetamine, Methamphetamine
Effects:
1) release DA and NE from nerve terminals in brain
2) increase extracellular [NE] and [DA] near synapse
3) stimulant lasts a few hours, followed by depression and anxiety -locomotor/rewarding effects driven by DA
Prolonged use:
1) amphetamine psychosis -treat with antipsychotics (DA receptor antagonists)
2) drug stopped after few days: deep sleep followed by lethargy, depressed/anxious feelings (possibly suicidal), hunger
Amphetamines: Pharmacokinetics
DL-amphetamine, Dextroamphetamine, Methamphetamine
Pharmacokinetics:
1) readily absorbed from GI tract
2) snorted/injected or smoked in crystal form
3) freely penetrate BBB
4) excreted mainly unchanged in urine
3) plasma half-life varies (5-30 hours, depending on urine flow)
Methylphenidate (Ritalin): effect, MOA, pharmacokinetics, clinical use
effect: profound and sustained elevation of extracellular NE and DA
MOA: inhibit NET and DAT transporters (NOT substrate -doesn’t enter nerve terminal or facilitate NE/DA release)
pharmacokinetics: orally active, slowly absorbed via intestine and colon (peak level after 2 hrs)
- pre-systemic metabolism, so only 20% enters systemic circulation ADHD
Modafinil: effects (and proposed MOA), pharmacokinetics
effects:
1) increase extracellular DA levels in striatum and nucleus accumbens (likely inhibits DA reuptake by binding to DAT)
2) enhanced release of 5HT, glutamate, and histamine
3) inhibition of GABA release
note: no euphoria when administered by mouth
4) wakefulness promoting agent (rather than classic amphetamine-like stimulant)
5) brightens mood
6) enhances cognitive performance (gaining pop. as “lifestyle drug”)
pharmacokinetics: well absorbed from gut, metabolized in liver, half-life = 10-14 hrs
Modafinil: clinical uses
1) narcolepsy treatment (also shift work sleep disorder, excessive daytime sleepiness assoc. with obstructive sleep apnea)
2) adult ADHD (not kids b/c develop severe skin rash)
MDMA (ecstasy): pharmacological effects
pharmacological effects:
1) inhibits monoamine transporters, esp. 5HT transporter
2) releases 5HT (also similar changes with DA and NE)
3) followed by monoamine depletion
- effects on 5HT function determine psychotomimetic effects (different than amphetamines)
- DA and NE changes account for initial euphoria and later rebound dysphoria
- not addictive
MDMA (ecstasy): serious acute and long-term pharmacological effects
acute: sudden illness and death, even after small doses
1) acute hyperthermia -damage skeletal muscle, renal failure (exacerbated by energetic dancing, high ambient temp)
2) excess water intake and retention (due to inc. physical activity and feeling hot; MDMA causes inappropriate secretion of ADH) –> overhydration and hypoatraemia (water intoxication)
3) heart failure in indiv. with undiagnosed cardiac condition
after-effects
1) depression, anxiety, irritability, aggression
2) long-term deleterious effects on memory and cognitive function in heavy MDMA users
Cocaine: pharmacological effects
effects:
1) binds and inhibits NET, DAT, and SERT
2) euphoria due to inhibition of both DA and 5HT reuptake
3) peripheral sympathomimetic actions
4) increased body temp due to inc. motor activity + reduced heat loss (b/c vasoconstriction from #3)
overdose:
1) tremors and convulsions
respiratory and vasomotor depression
Note: transgenic mice lacking D2 receptor have reduced locomotor enhancement, but still self-administer cocaine
Cocaine: pharmacokinetics
1) readily absorbed by many routes
2) hydrochloride salt: nasal inhalation or IV
3) crack cocaine: smoked, vaporizes at 90 degrees C
4) duration of stimulant effect ~30 minutes, much shorter than amphetamine
5) rapidly metabolized by liver
6) occasionally used as topical anesthetic (ophthalmology and nose and throat surgery)
Cocaine: adverse effects
1) serious cardiovascular events
- cardiac dysrhythmias
- aortic dissection
- myocardial or cerebral infarction/hemorrhage
- heart failure
2) dependence -can have severe impact on quality of life
3) exposure during pregnancy
- reduced brain size
- limb malformations
- inc. incidence of brain lesions, SIDS
- may also be influenced by other lifestyle issues other than cocaine use
methylxanthines (caffeine, theophylline): pharmacological effects, clinical uses
1) CNS stimulation b/c antagonize effects of adenosine, act on A1 and A2 receptors
2) diuresis b/c vasodilation of afferent glomerular arteriole –> inc. GFR
3) stimulation of cardiac muscle
4) relaxation of smooth muscle, esp. bronchial muscle
5) effects on cardiac and sm. m. resemble beta-adrenoceptor stimulation (inhibit phosphodiesterase –> inc cAMP –> effects mimic mediators that stimulate adenylyl cyclase
clinical uses:
1) respiratory stimulant in treatment of apnea of prematurity
2) theophylline = bronchodilator in treating severe asthmatic attacks
