CNS Stimulants & Cognition enhancers

Dr. K. Rudhra Prabhakar M.B;B;S. M.D

Senior Resident

Introduction

Little clinical use, except methylxanthines

Can be classified in to:› Respiratory stimulants

( Analeptics).› Convulsants› Psychomotor stimulants› Psychomimetic drugs

Respiratory stimulantsDoxapram : MOA not clear, may excite central

neurons Short acting, high margin of safety. Low doses selective for respiratory centre ↑ Tidal volume & rate of respirationUses : Post-anaesthetic resp. depression COPD i.e. hypoxemic,hypercapnic res.fail Apnoea in premature infants

Dose- 2-5mg/min(max 4mg/kg) slow i.v infusion.

Contraindications: Hypoxaemic, normocapnic resp.failure-

asthma Resp.fail due to neurological &

muscular diseases. EpilepsySide effect: Restlessness Tachycardia High doses: convulsions & arrhythmias

Convulsants No clinical use Used as research toolsStrychnine: Alkaloid, convulsant poison. Spinal cord stimulant MOA: Blocking the receptors for Glycine In poisoning convulsion treated with-

Diazepam or clonazepam slow i.v

Opisthotonus

Picrotoxin: Blocks the Cl- ion channel of GABAA.

Bicuculline: Plant alkaloid, GABAA antagonist.

Pentylenetetrazole (PTZ): Direct depolarization of central neurons Provides useful animal model for

testing anticonvulsant drugs.

Psychomotor Stimulants

Amphetamine group: Amphetamine Dexamphetamine Methamphetamine Methylenedioxy Methampheta(MDMA) Methylphenedate Fenfluramine

Non-Amphetamine group Modafinil Atomoxetine Sibutramine PemolineCocaineMethylxanthines: Caffeine Theophylline Theobromine

Amphetamine & Non- Amphetamine

MOA: ↑DA conc. In synaptic cleft by Enter N endings by active transport Displace DA(also NE) from vesicles Also inhibits MOA-B, ↓DA metabolism.Pharmacological effects: (central) ↑ motor activity Euphoria & excitement Anorexia Stereotyped & psychotic behaviour

Peripheral effects

↑ BP, inhibition of GI motility Fatigue both physical & mental

reduced. Amphetamine psychosis on repeated

use- paranoid ideas, A & T hallucinations.

PK: Well absorbed orally Freely penetrates BBB Unmetabolised drug excreted in urine

usesADHD with minimal brain

dysfunction: Characterised by-

› Hyperactivity› Inability to concentrate› Impulsive behavior

Dexamphetamine, Methylphenedate, Atomoxetine quite effective.

Narcolepsy: Characterised by- Sleep attacks during day time Night mares in awakening state Cataplexy-reversible Methylphenedate is still used Modafinil- devoid of abuse liability

Appetite suppression

Fenfluramine, dexfenfluramine used earlier to treat obesity

Discouraged due to:- Tolerance Insomnia, pul.htn, abuse potential.Sibutramine new drug used now Blocks neuronal uptake of mainly NE &

5HT (also dopamine) at hypothalamic site that regulates food intake.

Use: Severe obesity with risk factors like

DM.Adverse effects: Dry mouth Headache Insomnia Constipation ↑in HR & BP CI in CVS diseases, withdrawn from

market

Adverse effects Tolerance Psychic dependence, rarely physical.Amphetamine overdose: Euphoria, dizziness, tremors, HTN Irritability, anorexia, insomnia Higher doses- convulsions, psychotic

manifestations, arrhythmias, coma Rx –diazepam(slow i.v), haloperidol Gastric lavage, acidification of urine HTN-nifedipine/labetolol, arry-esmolol

Sudden deaths occurred with MDMA. Induces heat stroke like condition-

rhabdomyolysis & renal failure Inappropriate secretion of ADHMethylenedioxy amphetamine (love

drug) 75mg- psychotomimetic effects 150 mg-LSD like effects 300mg- amphetamine like SE: tachycardia, HTN, arrhythmias

Methylxanthines Only caffeine if used as CNS stimulantPK: Oral- rapid but irregular absorption PPB:<50% Distributed all over the body Met: in liver by demethylation & oxid. Metabolites excreted in urine T1/2: 3-6hrs

AE: Gastric irritation, N, V Nervousness, insomnia, agitation Muscule twitch, rigidity ↑body temp,delirium, convulsions Tachy, extra systoles at high dosesUses: In Analgesic mixture for headache Migraine Apnoea in premature infants

Psychotomimetic drugs

Produce changes in sensory perceptions, thoughts, behaviour & mood.

Actions mimic psychoses- psychedelics Lysergic acid diethylamide (LSD) Mescaline Phencyclidine Cannabinoids

Lysergic acid diethylamide

Derived from cereal fungus ergot Hofmann synthesized & experimented

on himself. Act as agonist at 5HT2 receptors. Excitation threshold of retina ↓-visual

hallucinations Excitation threshold of RAS↓-hyper

arousal state Experiences may be bad or good trip.

Cannabinoids (Δ9THC)

Extract of hemp plant-C.sativa, C.indica Bhang- paste of powdered dried

leaves, used as drink Marijuana- dried leaves & flowering

tops, smoked in pipes or rolled as cigarettes.

Charas or hashish- resinous exudates leaves & flowering tops, potent smoked inpipe.

THC content more in hashish

Pharmacological actions

Initial CNS stimulation later sedation. Stimulatory phase- euphoria,

↑talkativeness, ↑appetite Felling of confidence, relaxation & well

being Other- analgesia, antiemetic Peripheral effects- tachy, VD,

reddening of conjunctiva

MOA, uses

Two types CB 1& 2 receptors CB1 in brain CB2 in periphery Anandamide-endogenous ligand CB1. Dronabinol, Nabilone- synt.analogues of

THC Use: CB1 Agonists- ↑appetite in AIDS pts. Dronabinol-antiemetic in cancer chemo. Rimonabant : CB1 antagonist, used for

obesity, dose-20mg OD before Breakfast Smoking cessation

Cognition enhancersIndications: AD, multi infarct dementia Mild cognitive impairment MR, learning defects, ADHD in children TIA, CVA, Stroke Organic psychosyndromes Sequale of head injury ECT, brain surgery

Mechanisms

↑ global/regional blood flow Direct support of neuronal metabolism Enhancement of neurotransmission Improvement of discrete cerebral

functions

Alzheimers disease

Main pathological features: Amyloid plaque Neurofibrillary tangles Marked ↓ in choline acetyltransferase

& loss of cholinergic neurons in brain.

Cholinergic activators

ACEs that cross BBB are preferred.Tacrine: Longer acting, reversible ACE Palliative for mild to moderate AD Orally active Improves memory, cognition, well

being Facilitates Ach release AE: hepatotoxicity

Donepezil, Rivastigmine & Galantamine

Newer reversible Anti cholinesterase Better penetration in to CNS Better tolerated & less toxic than tacrine Clinical results modest & temporary Donepezil: 5mg OD orally evening ↑ max

10mg after 4 wks Rivastigmine:1.5 mg orally BD ↑ to 3mg

BD after 2 wks Galantamine:4mg BD orally ↑to 8mg BD

after 2 wks

Transdermal Rivastigmine patch –applied every 24hrs

SE:diarrhoe, N, V, ↑urinationAcetyl-L-carnitine: Structural analogue of Ach ↓ signs & symptoms of dementia in AD ↑ cholinergic transmission Also have antioxidant properties, slows

progression of AD

Memantine

Excitotoxicity due to enhanced Glutamate transmission via NMDA recp.

Dose:5mg OD slowly ↑ to 10-20mg/day Non-comp. antagonist of NMDA recp. Better tolerated, less toxic.Miscellaneous : Nootropics-piracetam, aniracetam High doses of vit E(1000 IU B.D) Antioxidants-vit C, A, Zn, Se,

bioflavonoids or spirulina ↓ progression even in middle stage AD.

¡gracias"thank you" in Spanish