CNS Stimulants PDF

**CNS Stimulants** **Stimulant drugs in their excessive neuronal activity often act to increase excitability or block the inhibitory event of the synaptic neuron** **The two-type non-propagative responses that occur at the postsynaptic mb are**: i. EPSP: caused by the AP-inrush of Na+ intracellu...

**CNS Stimulants** **Stimulant drugs in their excessive neuronal activity often act to increase excitability or block the inhibitory event of the synaptic neuron** **The two-type non-propagative responses that occur at the postsynaptic mb are**: i. EPSP: caused by the AP-inrush of Na+ intracellularly (in conditions of lessened --ve environment & producing depolarization being excitatory event). ii. IPSP: caused by conditions of hyperpolarization of more --ve intracellular environment - Blocking the inhibitory processes causes excessive neural activities **(stimulant action)** - Increasing the excitation processes also enhances/increases the neural activities in excess **(stimulant action)** **An agent that causes any one of these two conditions, would cause an imbalance in the electogenic-pump-maintained excitatory / inhibitory balance of the mb.** **Mechanisms of blockade of the electrogenic pump maintained inhibitory events that causes excessive neuronal activity** - **Presynaptically:** - A presynaptic released inhibitory transmitter in same transmitting neuron causes its motor neuron-IPSP of hyperpolarization (**direct inhibition).** - A presynaptic released inhibitory transmitter could be targeted to encounter released excitatory transmitter of another neuron's nerve ending or axon as to reduce an excessive EPSP of it getting to the motor-neuron. This is a very common protective measure in the primary afferent pws to the brain, whereby the presynaptic inhibition functions to reduce unimportant sensory inputs of excessive excitation for unnecessary activation; (**indirect inhibition). \*\*\* The principal form of inhibition within the brain, however, is the postsynaptic type.** **The Potential action-mechanisms of Inhibitory-neuron blocking drugs:** i. Reduction in the amount of inhibitory transmitters ii. Blockade of release of inhibitory transmitters iii. Blockade of inhibitory transmitter to postsynaptic jxn iv. Change in the property of postsynaptic mb that reduces effectiveness of inhibitory transmitter v. Interference with Na^+^-Ca^2+^ ATpase activity vi. Depletion in GABA in its antagonism of excitatory actions (eg hydroxylamine) **Drug examples of Inhibitory-neurons blocker-stimulants** 1. **Picrotoxin: -** it blocks presynaptic inhibitory responses to produce its powerful CNS **-** it blocks presynaptic inhibitory responses in the caudate nucleus and which reflects Centrally. \- It specifically blocks GABA-presynaptic inhibition activity. **\*\* The blockade of presynaptic inhibition-reflex action of some drugs (eg., of mephenesin) do not cause stimulant (excitation) action.** 2. **Strychnine** (an alkaloid of nux-vomica seed): 1^st^ introduced as rat poison & has been used in suicide Attempts. \- it blocks various forms of direct and indirect inhibitory responses in the spinal cord \- it blocks recurrent inhibitory processes such as often seen in Renshaw cell & does not affect the firing level. The activity of glycine is also in-blw the terminal of Renshaw cell and the cell body of the postsynaptic-neuron, & thus serving as an inter-neuron collateral. 3. **Cardiac glycosides: The Na^+^/K^+^ ATPase-pump system controls the excitability of neurons:** **- (its activation produces inhibition & the blockade produce excitation).** **- Digoxin**, a cardiac glycoside blocks it; & the excitatory cardiac effect from digoxin blockade can convulse some lab animals (although, few withstand it). **Mechanisms of stimulant Drugs' enhanced-excitatory neuronal responses:** i. Increase in the released-transmitter amount of nerve impulses ii. Increase in the amount of excitatory neurotransmitter iii. Prolongation of the actions of excitatory transmitters, eg by blocking its dissipating enzyme iv. Increase in the sensitivity of postsynaptic mb to transmitters v. Leptazole produces its action by decreasing the synaptic recovery time from a stimulus, and which permits repetitive action of the stimulus. It acts directly on the medullary centre and thus, also a good analeptic. It specifically antagonizes trimethadione (used in petit-mal epilepsy). It does not affect neuronal resistance to impulse. Also some barbiturates like CHEB (5-cyclohexilydine ethyl barbituric acid) or DMBB which has its dextro-isomer to be convulsant (stimulant) and its laevo-rotatory form to be a depressant. **Classification of CNS stimulants (by similar mechanisms or sites of action)** **Central stimulants refer to the increase in behavioral activity of differing pharmacology of a varied group of drugs. Example, strychnine-induced convulsive activity, that differs from amphetamine-induced psychomotor agitation,etc.** +-----------------------------------+-----------------------------------+ | | **Class** | +===================================+===================================+ | 1. | **Reinforcers of NA (mimicking or | | | potentiating it)** | | | | | | i. **Behavioral stimulants (eg | | | cocaine, amphetamines)** | | | | | | ii. **Clinical antidepressants | | | tranylcypromine (MAOIs), | | | amitriptyline (TCA tricyclic | | | antidepressants)** | +-----------------------------------+-----------------------------------+ | 2. | **Miscellaneous behavioral | | | stimulants (of unknown mechanism, | | | may resemble (i.) above, but are | | | usually less potent than the | | | amphetamines, but more potent | | | than caffeine (eg., | | | methylphenidate, phenmetrazine, | | | benzphetamine)** | +-----------------------------------+-----------------------------------+ | 3. | **Convulsants (eg., strychnine, | | | picrotoxin, pentylenetetrazol, | | | bicuculline) 1˚ly block | | | inhibitory synapses within the | | | brain** | +-----------------------------------+-----------------------------------+ | 4. | **General cellular stimulants | | | (eg., caffeine)** | | | | | | **(ability to increase rate of | | | cellular metabolism within the | | | brain 2˚ to its behavioral | | | stimulation); thus, its | | | behavioral stimulation is | | | nonspecific and not as powerful | | | as the more specific agents** | +-----------------------------------+-----------------------------------+ | 5. | **Stimulants of certain | | | acetylcholine synapses (eg., | | | nicotine)** | +-----------------------------------+-----------------------------------+ | | | +-----------------------------------+-----------------------------------+ - **The behavioral effects of amphetamine, cocaine and the clinical antidepressants is thus, secondary to potentiation of NE action at the synapse and which can occur in 5 ways:** i. **Increase in rate of the transmitter (NE) synthesis** ii. **Decrease in the rate of NE-metabolic destruction by blocking or dissipation of the enzyme of its metabolism; (by which the MAOIs works; the MAO is found within the presynaptic nerve terminal for metabolizing the NE, and the blocking of its action results in high concn of NE)** iii. **Triggering release of NE from the presynaptic terminal; (amphetamine induces release of NE)** iv. **Prolongation of NE action at its postsynaptic receptor in blocking its active uptake back into the synaptic cleft & which is the primary mechanism of terminating its action, & also appears to be the prime action mechanism of both cocaine and TCAs)** v. **Drugs in mimicking the effect of NE may directly stimulate the postsynaptic NE receptor (another action mechanism of amphetamine)** - **Summary of the varied action mechanisms of drugs that increase NE activity at the synapse in inducing behavior or relieving depression** 1. **Amphetamine: - increase release of NE** **- direct stimulation of postsynaptic NE receptors** **- block of reabsorption of NE by presynaptic nerve terminal** 2. **Cocaine: - block of reabsorption of NE by presynaptic nerve terminal** 3. **Tricyclic antidepressants: - block of reabsorption of NE by presynaptic nerve terminal** 4. **MAO-inhibiting antidepressants: inhibition of the enzyme MAO** **The NE neurons Being a site of action of the behavioral stimulants, play a role in emotional behavior; and hence a NE theory of mania and Depression was postulated:** - **reserpine is an antipsychotic drug that depletes NE in the brain and if enough NE is depleted, severe behavioral depression occurs.** - **Lithium, also useful in treatment of mania act by blocking the presynaptic release of NE and thus decreasing the synaptic NE amount that gets to the receptor site. However, lithium also treats depression of depleted NE and which seems to contradict the NE hypothesis of mania & depression, but what appears to happen is that as lithium slowly relieves the period of mania (blockade of NE-release), the overshoot of its activity brings up periods of depression that spontaneously disappear in a cyclical process.** **Its also been noted that Manic depressive patients experience wide swings in mood, ranging from deep depressions to extreme mania. As the mania is relieved, the brain levels of NE become more stable and the periods of depression decrease.** **CNS stimulants or agents that cause arousal are of 4 groups:** i. **Psychoactivators or mood elevators:** they stimulate mental activity or alertness eg amphetamine or methylphenidate ii. **Analeptics:** like leptazol (pentylenetetrazol), ethamiran, picrotoxin etc. in normal doses stimulate the nerve cells of the midbrain and medulla & are generally used to upkeep failing respiration from depressant drugs like general anaesthesics. iii. **Spinal cord stimulants:** eg., strychnine which precipitates exaggerated spiral reflexes iv. **Antidepressants:** eg., imipramine, MAO-inhibitors etc relieve depression without inducing excitement or delirium. **CNS stimulants of clinical importance:** 1. **Antidepressants:** drugs which relieve depressive symptoms without inducing mental excitement, delirium or fits. They increase synaptic monoamines (dopamine, 5-HT, NA) in the brain, & restore REM (rapid eye movement) latency often shortened during depression, possibly by decrease in 5-HT. The transition from NREM to REM-sleep is normally activated by 5-HT. i. **Imipramine:** a tricyclic cpd, closely related to chlorpromazine, **tends to block uptake-1 of NA**, an act more pronounced by its metabolite, desimipramine. This its antidepressant effect usually takes about 1-2 hours to occur, within which there is also prominent antimuscarinic block with loss of accommodation etc. ii. **Monoamine oxidase inhibitors:** which are of 2 groups: iii. **lithium:** used prophylactically in manic depressive illness to calm manic patients as mood stabilizer. Available in its carbonate form and of unknown MOA. 2. **Spinal cord stimulants: (strychnine and tetanus toxin**): they interrupt glycine-mediated inhibitory pws to produce the classical trend of events of spinal cord convulsants & are mostly used as lab tools in investigations to assess for anticonvulsant drugs; (are usually only of toxicological interest). Their initial event is pdtn of exaggerated afferent stimuli and as there is no reciprocal inhibition, tonic fits (convulsion) occurs. This is followed by progressive stimulation of larger cord areas and then activation of the spinal motor. The posture that presents from the fits of the drugs depends on the relative strength of the flexor and extensor muscles. Humans show predominant extension of the back muscle (opistho-tonus) and arrest of the respiratory muscles. Then, there is development of Hypoxia at which the musculature is unable to maintain its tetanic state and so regains its normalcy as also respiration. Further afferent stimuli then initiate a repetitive cycle. Usually, the victim succumbs during one of the hypoxic episodes probably due to paralysis of vital brainstem centres. In most cases, death is rapid. 3. **Analeptics: (picrotoxin, leptazol, nikethamide):** 4. **Psychoactivators: (amphetamine, methylphenidate, methylamphetamine):** they elevate mood and stimulate mental activity. Amphetamine is an indirectly acting sympathomimetic, but it crosses the bbb & its dextro-isomer form (D-amphetamine) has marked Central stimulant actions. Another grp of psychoactivators is the **xanthines (caffeine, theobromine etc).** **- coffee, tea and cocoa** contain varying amounts of xanthine derivatives: i\. coffee contains caffeine ii\. tea contains caffeine and theophylline iii\. cocoa contains caffeine and theobromine