Medical Pharmacology: Amphetamine and Related Drugs

"Amphetamines"

Attribution: Merritt P Lecture 19 Amphetamines https://www.youtube.com/watch?v=UPt1z_ysA-s (5/2019) Paul Merritt Youtube Channel https://www.youtube.com/channel/UCAMXreyILTDh2cxRre79Lhg

Amphetamine was first synthesized in 1887.
- Amphetamine, β-phenylisopropylamine, is related to ephedrine, which served as a precursor for the related agent, methamphetamine.
Amphetamine is classified as an indirect acting sympathomimetic agent, active at not only peripheral β- and α-adrenergic receptors but also at CNS sites where it acts as a potent stimulant.
- Amphetamine mechanism of action in the CNS is based on inducing biogenic amine release from storage sites in synaptic terminals.¹⁵²
- By contrast to epinephrine, amphetamine is both effective following oral administration and exhibits a several hour duration of action.
Comparative structures of amphetamine derivatives are illustrated below:
- Amphetamine Derivatives¹⁹⁸

With respect to the CNS stimulant action of amphetamines:¹⁹⁹

Agents that produce CNS stimulation within this grouping include:
- D-amphetamine
- D,l-amphetamine
- Pemoline
- Methamphetamine and
- Methylphenidate.
These agents can cause hypertension, behave as a respiratory stimulant and exhibit appetite depressant actions.
Amphetamines reverse fatigue and postpone the need for sleep as well as elevate mood.
Increased periods of wakefulness are also associated with subsequent periods of extreme fatigue with possibly associated depression.¹⁹⁹
- High dose amphetamine by the intravenous route of administration results in "an immediate feeling of ecstasy."
- Acute and chronic amphetamine intoxication frequently occur.
  - The most abused agent in this category, methamphetamine, is described as "crystal" by IV administration or as "ice" when smoked.
  - Amphetamine toxicity is characterized by notable enhancement of activating actions including restlessness, tremor, excessive motor and speech activity and insomnia.
  - Severe intoxication with these agents can cause hallucinations, delusions, and alterations in affect and thought processes.
    - These latter effects create a state that appears extremely similar to that noted in paranoid schizophrenia.
  - In chronic use, amphetamine is associated with tolerance and psychologic dependence.
- Drug withdrawal after prolonged oral or IV use is characterized by extended sleep (a substantial percentage of which is rapid eye movement (REM) sleep).¹⁹⁹
  - Upon awakening, the individual may experience extreme appetite, muscle pain, as well as profound fatigue and depression.
  - Management of amphetamine dependency involves both amphetamine discontinuation and administration of anti-psychosis agents.
    - Hypertension that occurs with amphetamine use may also have to be managed.¹⁹⁹

**Scale to assess the harm of drugs**^200,201

"A rational scale to assess the harm of drugs.²⁰⁰ Data source is the March 24, 2007 article: Nutt, David, Leslie A King, William Saulsbury, Colin Blakemore. 'Development of a rational scale to assess the harm of drugs of potential misuse' The Lancet 2007; 369:1047-1053. The data in the paper is obtained solely from questionnaire results obtained from two groups of people: the first comprised people from the UK national group of consultant psychiatrists who were on the Royal College of Psychiatrists’ register as specialists in addiction, while the second comprised of people with experience in one of the many areas of addiction, ranging from chemistry, pharmacology, and forensic science, through psychiatry and other medical specialties, including epidemiology, as well as the legal and police services; the experts are not named and were chosen by the authors. This is a tertiary source as it summarizes experts' opinions on the matter (which are secondary sources) without any direct references to primary sources. The data was first reported in appendix 14 of "Drug classification: making a hash of it?' "²⁰¹

Amphetamine: Cardiovascular System Effects:¹⁵²
- Following oral amphetamine administration, both systolic and diastolic blood pressures are increased.¹⁵²
  - This pressure increase may be sufficient to trigger, via baroreceptors, a parasympathetic-mediated decrease in heart rate (baroreceptor reflex).
  - Higher amphetamine doses are arrhythmogenic.
  - At least with therapeutic doses, amphetamine administration does not appear to alter either cardiac output or cerebral blood flow.
  - Amphetamine is typically administered as the racemate, with the l- and d-isomers comparably active with respect to cardiovascular system effects (l-isomer is slightly more active).
- Amphetamine is also active at smooth muscle.¹⁵²
  - For example, amphetamine-promoted urinary bladder sphincter contraction may be used in management of enuresis and incontinence.
  - Amphetamine gastrointestinal effects depend on the initial underlying tone (with high basal tone, amphetamine induces relaxation; if the G.I. tract is more relaxed initially, amphetamine administration results in contraction).¹⁵²

Amphetamine: Central Nervous System Effects:

With respect to CNS stimulating effects, amphetamine is classified as one of the most potent sympathomimetic amines. The amphetamine d- isomer is about 3-4 times more potent as a CNS stimulant compared to the l-isomer.¹⁵²
- Amphetamine both increases medullary respiratory center stimulation and decreases CNS depression caused by other agents.

CNS stimulation may be based on cortical and reticular activating system stimulation.¹⁵²

The reticular activating system (RAS) involves brainstem to cortical connections. Important pathways originate in the upper brainstem reticular core and pass through synaptic junctions in the rostral intralaminar and thalamic nuclei to the cerebral cortex.²⁰³

Reticular Formation (see arrow)²⁰²

"Deep dissection of brain stem: Ventral view. (Reticular formation labeled near center.)"^202a

Consistent with this pathway is that bilateral thalamic intralaminar nuclei lesions are associated with patient lethargy.²⁰⁴

The RAS consists of several anatomical regions including: ^205,206
- midbrain reticular formation
- mesencephalic nucleus (mesencephalon)
- thalamic intralaminar nucleus
- dorsal hypothalamus, and
- tegmentum.

Amphetamine-Effects on Fatigue and Sleep:¹⁵²
- Amphetamine is effective in both prevention and reversal of fatigue.
  - One effect is to delay fatigue onset; also, fatigue effects already present may be somewhat reversed.
  - Amphetamine appears particularly effective in improving performance which already has been reduced due to lack of sleep and fatigue.
    - Performance improvement in this circumstances may be based both on improved attention span and more positive attitude with respect to the task.
  - If amphetamine use to combat fatigue and limit sleep has been prolonged, an extended period following drug discontinuation is required prior to return to normal sleep patterns (perhaps up to two months).
Amphetamine-Respiratory Effects:¹⁵²
- Amphetamine is a respiratory stimulant but this effect is noted in those individuals whose respiration has been depressed by CNS agents.
Amphetamine and weight loss:^152,207
- Amphetamine and related drugs have also been employed to depress appetite as part of weight-loss programs.
  - In this setting, weight-loss occurs because of decreased food intake as opposed to increased metabolism.
  - Based on injection-site studies, the appetite suppressant effect is probably in the lateral hypothalamic feeding region.
  - With continued use, amphetamine-induced appetite suppression declines as tolerance readily develops.
- The mechanism for amphetamine-induced appetite reduction is based on activation of catecholaminergic neurotransmission.^207,208,209
  - At certain doses, amphetamine acts to release CNS dopamine.²⁰⁸
    - Also, amphetamine can block the activity of the dopamine transporter, thus inhibiting dopamine reuptake and increasing synaptic dopamine.²¹⁰
  - Furthermore, hypothalamic neuropeptide Y (NPY) has been implicated in anorexic properties of amphetamine.²¹¹
Amphetamine-mechanism of CNS effects:¹⁵²
- CNS effects of amphetamine appear to result from catecholamine release from nerve terminal storage locations.
  - Amphetamine appears to act at both the neuronal dopamine transporter (DAT) and at the vesicular monoamine transporter 2 (VMAT2).
  - Amphetamine may induce exchange diffusion, reverse transport, and channel-like transport activity.

**Mechanism of Amphetamine Action (Low Dose)²¹²**

"Low-dose amphetamine can modify the action of dopamine and noradrenaline in the brain. Amphetamine increases the concentration of dopamine in the synaptic cleft in 3 ways: (1) It can bind to the pre-synaptic membrane of dopaminergic neurones and induce the release of dopamine from the nerve terminal; (2) amphetamine can interact with dopamine containing synaptic vesicles, releasing free dopamine into the nerve terminal; and (3) amphetamine can bind to the dopamine re-uptake transporter, causing it to act in reverse and transport free dopamine out of the nerve terminal. Amphetamine can also cause an increased release of noradrenaline into the synaptic cleft."²¹²

Lower doses of amphetamine are associated with increased vigilance, appetite supression and locomotor-stimulation.

These actions are likely mediated by increased the norepinephrine neurotransmitter release from central noradrenergic nerve endings.
- Blocking catecholamine synthesis by tyrosine hydroxylase inhibitors, such as metyrosine, prevents these consequences of amphetamine administration.
Certain locomotor effects and stereotyped behavior caused by amphetamine are likely due to increased dopamine release from neostriatal dopamine nerve endings.
- These latter behavioral effects probably require higher amphetamine doses; however, still higher doses result in perception abnormality and psychotic behavior.
  - Perception disturbances and psychotic behavior may be associated with an amphetamine effect on 5-HT (serotonin) release.

**Mechanism of Amphetamine Action (High Dose)**²¹³

"High-dose amphetamine can modify the action of dopamine and noradrenaline in the brain. At high doses, amphetamine increases the concentration of dopamine in the synaptic cleft in 4 ways: (1) I can bind to the pre-synaptic membrane of dopaminergic neurones and induce the release of dopamine from the nerve terminal; (2) Amphetamine can interact with dopamine containing synaptic vesicles, releasing free dopamine into the nerve terminal; (3) Amphetamine can bind to monoamine oxidase in dopaminergic neurones and prevent the degradation of dopamine, leaving free dopamine in the nerve terminal; and (4) Amphetamine can bind to the dopamine re-uptake transporter, causing it to act in reverse and transport free dopamine out of the nerve terminal. High-dose amphetamine has a similar effect on noradrenergic neurones; It can induce the release of noradrenaline into the synaptic cleft and inhibit the noradrenaline re-uptake transporter."²¹³

Amphetamine Toxicity: ²¹⁴
- The mechanisms of amphetamine (and similar agents) toxicity are related to specific nervous system effects.²¹⁴
  - Amphetamine increases sympathetic nervous system activity by several actions including:
    - CNS stimulation
    - Peripheral catecholamine release
    - Monoamine oxidase inhibition and
    - Inhibition of catecholamine reuptake.
  - Amphetamines and related agents such as fenfluramine (removed from U.S. and many other markets), dexfenfluramine (also removed from U.S. and many other markets), MDMA (3, 4-methylenedioxymethamphetamine, "ecstasy") and PMA (paramethoxyamphetamine) may cause both serotonin release and serotonin uptake inhibition.²¹⁴
    - These agents are characterized by low therapeutic index, meaning that toxicity may occur at doses only somewhat above ordinary doses and are associated with substantial tolerance development with repeated usage.²¹⁴
- Clinical presentation of amphetamine toxicity:²¹⁴
  - Acute CNS effects associated with amphetamine toxicity include euphoria, anxiety, talkativeness, restlessness, agitation, seizures and coma.²¹⁴
    - Amphetamine-induced hypertension or cerebral vasculitis may cause intracranial bleeding.
  - Acute peripheral presentations due to amphetamine toxicity include sweating, tremor, muscle fasciculations and rigidity, tachycardia, hypertension, acute myocardial ischemia and infarction, even in the absence of coronary vascular disease.²¹⁴
    - Accidental intra-arterial injection of these agents can result in localized vasospastic response severe enough to cause in gangrene.
  - Death due to amphetamine toxicity can occur as a result of ventricular arrhythmias, status epilepticus, intracranial bleeding, or hyperthermia.²¹⁴
    - Hyperthermia in this setting can occur following seizures and muscle hyperactivity and may be sufficient to induce brain damage, rhabdomyolysis, and myoglobinuric renal failure.
  - Chronic amphetamine toxicities may manifest as weight loss, cardiomyopathy, pulmonary hypertension, effects on dentition, stereotypical behavior, paranoia, and paranoid psychosis.²¹⁴
    - Psychiatric sequelae may last for days or weeks.
    - Abrupt cessation following amphetamine habitual use results in patient fatigue, excessive sleeping, extreme appetite and depression.
  - Use of fenfluramine or dexfenfluramine in combination with phentermine (fenfluramine and dexfenfluramine have been removed from the US market and many other markets) for typically three months or longer is associated with increased risk for pulmonary hypertension and fibrotic valve disease (mainly aortic, mitral, and tricuspid regurgitation).
    - Valvular pathology appear identical to that associated with carcinoid syndrome.²¹⁴

Therapeutic Uses of Amphetamine:¹⁵²

Amphetamine was used to promote weight loss; however, due to abuse concerns, amphetamine is no longer approved for this purpose.

Amphetamine is, by contrast, approved for treatment of narcolepsy and ADHD.

**Narcolepsy as an autoimmune disorder: Stanford University**

Attribution: Mignot E Narcolepsy as an autoimmune disease (2009) https://www.youtube.com/watch?v=siYsh2gp_0E Stanford medicine Youtube Channel https://www.youtube.com/channel/UCDrQaGaHpOav5y7m1SCSJRg

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