CNS Stimulants & Drugs of Abuse

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CNS Stimulation??

“Range of behaviors that includes mild elevation in alertness, increased nervousness, anxiety & Convulsions”

• Analeptics.

• Psychomotor stimulants.

• Psychotomimetics.

• Analeptics – Respiratory stimulants & Convulsants.

• Psychomotor Stimulant– Excitement & Euphoria

– Decrease feeling of Fatigue

– Increase Motor activity

• Psychotomimetic Drugs ( Hallucinogens )– Changes in Thought Patterns & Mood

– Little Effect on Brain stem & Spinal Cord

NO CLINICAL USE

Group of Abused Drugs along with CNS depressants & Narcotic Drugs.

• Hyper excitability:associated with drug administration (Desired or Undesired)

– Results from

• Alteration in fine balance normally maintained in CNS(between excitatory & Inhibitory influences)

1. Potentiation/Enhancement of Excitatory Transmission

2. Depression/Antagonism of Inhibitory Transmission

3. Pre-synaptic control of Neurotransmitter Release

Balance

• Excitatory InfluencesExcitatory Neurotransmitters

• Inhibitory Influences

GABA …… Inhibitory Neurotransmitter

Glycine ….. Inhibitory Neurotransmitter

Classifications

On the Basis of Site Of ActionCerebral Stimulants

Xanthines (PDE Inhibitors ….. cAMP, cGMP

(ADENOSINE Receptor Blockade …. Stimulant action

– Caffeine, – Theophylline, (Also Bronchodilators)– Theobromine

(Tonic Uncoordinated Convulsions)

Medullary Stimulants– Picrotoxin (Close Cl- Channel … GABA)

( Tonic Clonic Coordinated Convulsions )

Spinal cord Stimulants – Strychnine ( Competitive Antagonist of Glycine)

(Tonic Clonic Uncoordinated Convulsions

Classification (on the basis of effects)

• Convulsants & Respiratory Stimulants– Amiphenazole

– Doxapram– CONVULSANTS

• Nikethemide

• Strychnine …. (spinal Cord Stimulant )

• Picrotoxin ….( Brain Stem Stimulant )

• Pentylinetetrazole (PTZ)

Cntd;

• Psychomotor Stimulants

– Amphetamine

– Cocaine

– Nicotine

– Methlexanthines

• Caffeine ( Cerebral stimulant )

• Theophyline

• Psychomimetic Drugs ( Hallucinogens )

– Lysergic acid ( LSD )

– Tetrahydro Cannabinol (THC )

– Phencyclidine (PCP)

– Mescaline

– Psilocybin

Convulsants & Resiratory stimulants

• Brainstem & Spinal cord

• Little effect on mental function

• Exaggerated Reflexes

• Increased activity of

– Vasomotor Centre

– Respiratory Centre

– Convulsions

(High Dose )

– Amiphenazole

– Doxapram

– CONVULSANTS

• Nikethemide

• Strychnine ….(spinal Cord Stimulant)

• Picrotoxin ….(Brain Stem Stimulant )

• Pentylinetetrazole (PTZ)

• Clinically used (Bigger safety margin, (OCCASIONAL )

– Amiphenazole

– Doxapram

– Nikethemide

• Experimental

– Strychnine

– Picrotoxin

– Pentylinetetrazole ( PTZ )

Strychnine (spinal cord Stimulant)• Plant Alkaloid ( Indian Plant )

• Poison …. Vermin, Stray dogs,

• Tonic …. Very low dose ( both weary brain & debillitated persons )

• Powerful convulsant

– Opisthotonous Position

• Violant Extensor spasm, Trigger With minor sensory stimuli

• MIMMIC Symptoms of TETANUS TOXIN

• Competitively Block receptors for GLYCINE

• TETANUS toxin Block Release of GLYCINE from inhibitory neurons

Opisthotonous Position

Pentylenetetrazole (PTZ)

• Mechanism of action Unknown

(GABA mediated Cl- conductance By BZPs is antagonised)

USES– In Epilepsy Research Work

– PTZ induced convulsions EEG wave pattern resembles Absence siezures ...

– To Check for Epileptic Tendency

Amiphenazole & Doxapram(Medullary Stimulant )

• Bigger safety margin (Resp. Stimulation to convulsion)

• Occasionally used in pt. with acute Resp. Failure.

• Doxapram cause

– Nausea

– Coughing

– Restlessness

Picrotoxin (Medullary Stimulant)

• Fish berry

• Block action of GABA …. Blocks Cl- Conductance

• Convulsions

Psychomotor Stimulants

Marked effect on mental functions & Behaviour

• Produce Excitement, Euphoria

Reduce Sensation of Fatigue

Increase motor Activity

– Amphetamine

– Cocaine

– Nicotine

– Methylexanthines• Caffeine ( Cerebral

stimulant )

• Theophyline

• Amphetamine

– Dextroamphetamine

– Methamphetamine

– Methylephenidate

• Methylene Dioxy MethAmphetamine

(EDMA …. ECSTASY )

STREET DRUG

Pharmacokinetics

• GIT,

• Nasal mucosa (Snoring)

• Cross BBB

• Unchanged in Urine. .. Excretion increase when Urine is Acidic

• Plasma half life 5 -20 – 30 hrs

( Urine Flow & pH )

Mechanism of action

• Release Monoamines– Noradrenaline, Dopamine, Serotonine (Fenfluramine)

Effect on Brian

• Locomotor stimulation

• Euphoria & Excitement

• Anorexia.

• Stereo typed behavior.

• Alertness. Grooming, Aggressive activity

• Peripheral Effect : increase B.P, Decrease GIT motility.

Clinical Uses• ADHD … ( Attention Deficit /Hyperactivity Disorder

– Methamphetamine

– Dexamphetamine

• Norcolepsy

– Disabling Condition … resemble Epilepsy

– Sudden, Unpredicted Fall asleep at frequent intervals during a day …. Amphetamine HELPFUL

• Appetite Suppressant

Toxicity• Amphetamine Psychosis, Schizopherinic attacks

• Repetitive attacks of Stereotyped behavior

• Tolerance/ Tachyphylaxis … to Peripheral Effects

• Sudden Death in “Ecstasy Users” ( single dose)– Symptoms like Heat Stroke ( High Temp. Dehydration)

– Muscle damage

– Renal Failure

Water intoxication

Inappropriate secretion of Anti-diuretic Hormone

Increased thirst Increase in Water intake Overhydration & Hyponatremia

COCAINE• Coca … ( S. American Shrub )

• Reduce Fatigue during work ( at high altitude)

• INHIBIT NOR-ADRENALINE REUPTAKE I

• Peripheral Effects– Sympathetic Effects

• Effects on Brain– Euphoria

– Garrulousness

– Increase motor activity

Pharmackinetics

• Nasal route ….. ( many others )

• Perforation of nasal septem

• CRACK (oral)…. A street drug (smoked)

• Topical L/A in ophthalmology in

• Experimental Tool for study of Catecholamine release/ uptake I

TOXICITY

• Cardiac dysrhythmia

• Coronary Thrombosis, Cerebral Thrombosis

• Slowly developing damage to Myocardium… Failure

If Used in Pregnancy

• Impair brain development

• Brain size decreases in utero.

• Neurological & Limb malformation.

• Sudden infant death.

Xanthines• PDE inhibitors ….. Bronchodilation

• Adenosine Receptor Blockade ….. Stimulant effect

• 100-200mg ( 1 cup Coffe) ….. Alert, Decrease Fatigue

• 1.5 Gm (13 cups) ….. Tremor, Anxiety

• 2-to-5 Gm ……………… Spinal Cord Stimulation

• Tolerance develop quickly to Stimulant Action

• Withdrawal causes fatigue & Sedation

• Increase HR & Contractility ….. Angina?? Dysrhythmia

• Diuretic Action

• Increase HCl in & Gastric secretions

• Insomnia, Anxiety, Agitation, CONVULSIONS (Lethal 10Gm)

Nicotine• Tobacco, 2nd most used CNS stimulant after CAFFEINE

• Used to smoking cessation therapy– Euphoria, arousal, Relaxation, Improve attention

• Toxicity– Respiratory paralysis, Hypotension (High Dose)..Medulla

• Peripheral effects are mixed ….. GANGLION BLOCK

• Decrease Coronary flow …. Angina?? …Raynaud …

• Absorbs through skin …. Poison

• Cross BBB

• Irritability, Tremors, Intestinal Cramps, Diarrhea Lung Cancer

• Ganglion Stimulation …. Depolarizing Block

Nicotine WITHDRAWAL

• Due to Physical Dependence

• Irritability, Anxiety, Restlessness, Difficulty in Concentration, Intestinal Cramps, Appetite is affected, Headache, Insomnia,

• Smoking cessation Programme– Electric/Battery Operated Ciggrates

– Transdermal Patch

– Chewing Gum

– Behavioural Therapy

– BUPROPION (antidepressant) decrease craving

Psycotomimetics (Hallucinogens)

• Induce Perceptual sense

• Colorful changes in

enviornament, changes in shapes & color

• Incapable of decision making as thought process is affected

– Lysergic acid ( LSD )

– TetrahydroCannabinol (THC )

– Phencyclidine (PCP)

– Mescaline

– Psilocybin

Lysergic Acid Diethylamide (LSD)

• 5-HT agonist at pre synaptic receptors in CNS

• Activation of Sympathetic NS

• Hallucination with Brilliant Colors

• Mood alteration

• Tolerance &Physical dependence occurs

• No True dependence

• S/E … Hyper reflexia.

• Nausea, Muscle weakness, Psychotic changes

Tetrahydrocannabinol (THC)

• Alkalod in Marijuana Endcannabinoid are identified

• Euphoria, Drowsiness, Relaxation

• Decrease Muscle strength & high skilled motor acvtivity

• APPETITE stimulant

• Visual Hallucinations Delusions

• Enhancement of Sensory activity

• THC receptors (CB1)… G-Protein coupled

• Immediate effect when smoked …. 2-3 hrsLasts “6” hrs

• P450 metabolize …. Elimination through Bile

• Indicated in AID pts ….Loosing weight

• Adverse effects

– Increase HR &B.P

– Reddening of Conjuctiva

– Tolerance & Mild dependence with frequent use

• RIMONABANT (CB1 receptor antagonist) in clinical trials for treatment of OBESITY

Drugs of Abuse

Drug Abuse

• Use of an illicit drug

• Excessive/nonmedical use of licit drug

• Deliberate use of chemicals (Not considered as drugs by lay public)

Why used:

Anticipated felling of pleasure due to CNS effects

(Strong feeling of EUPHORIA or ALTERD Perception)

Repetitive use …. WIDESPREAD Adaptive changes in Brain …… Compulsive Use ……. ADDICTION

• Dependence (physical/physiological dependence)

( NOT ALWAYS CORRELATED WITH DRUG ABUSE e.g. Bronchodilators, Organic Nitrates, Nonpsychactive drugs)

• Addiction (Psychological dependence)

Compulsive, Relapsing drug use despite Negative consequences

– Chronic exposure– Habbit formed

– Lose self control

– Triggered by craving

• OPIOIDS (analgesic) …… few desire due to withdrawal

• COCAINE …. One person out of Six become addicted within 10 yrs of 1st Exposure to the drug

Each Drug has its on Acute Effects

BUT

Strong feeling of Euphoria & Reward is Common to ALL drugs of Abuse

Dopamine Theory of ADDICTION

• Mesolimbic dopamine system is the primary target of addictive drugs. – VAT …. Ventral Tegmental Area

(A tiny structure at the tip of brain stem which projects Nucleus Accumbens)

• The Amygdala,

• Hippocampus,

• Prefrontal Cortex)

All addictive drugs activate mesolimbic dopamine system

Withdrawal

• The state in which adaptive changes become fully apparent once drug exposure is terminated.

In Human withdrawal symptoms with OPIOIDS is very strong

Each drug has specific Molecular target with distinct cellular mechanism

• THREE classes are Distinguished

– G protein linked (Gio

– Ionotropic receptors OR Ion channels (GABA)

– Dopamine Transporter

Calssification

• Drugs That activate G protein-coupled Receptors– Opioids, – Cannabinoids, – Hydroxy butyric acid (GHD) (Gio)– LSD, (Non addictive, 5HT2A– Mescaline, – Psilocybin

• Dtrugs that bind to Ionotropic receptors.– Nicotine, – Alcohol, – BZPs, – Phencyclidine, ( Non addictive, NMDA receptors)– Ketamine (Non addictive, NMDA receptors)

• Drugs that bind to Transporter of Biogenic Amines– Cocaine,– Amphetamine, – Ectasay

Ketamine, Phencyclidine(PCP)

• G/A ….. Dissociative ( Only Ketamine clinically)

– “Club Grug”s

– “AngleDust, Hog, Special K”

• Use Dependent

• Competitive antagonism on NMDA receptors

• Crystalline Powder in pure form

• IN STREET….. Liquid, Cap. Pills to be Snored. Ingestion, Inj. Or Smoked

Contd…….

• Psychedelic effects last for 1 hr

• Increased B.P. Impaired memoery, Visual Alterations

• At high doses Unpleasant Out-of-body & near Death experiences are on record.

• DO NOT CAUSE DEPENDENCE & ADDICTION

• PCP may lead to long lasting Psychosis resembling Schizopherenia

Inhalants

• Nitrates

• Ketones

• Aromatic Hydrocarbons

• House holds, Industrial Products

• Sniffing, …Inhalation from open container

• Huffing, … Soaking of Cloth in volatile substance before inhalation.

• Bagging … Breathing in & out of paper or plastic bag filled with fumes

Contd …

• Inhalant use is particular in children & young adults

• Alter function of ionotropic channels.

• Nitrous oxide bind with NMDA Receptors

• Fuel additives bind enhance GABA receptors function

• MOST INHALANTS products cause Euphoria: increase excitability of VAT …. TOLUENE … Addictive

• Amyl Nitrate (“Popper”) Produce SM relaxation & enhance Erectile function … But not Addictive

• MANAGEMENT of TOXIC EFFECTS ….. Supportive

DEPENDANCE & ADDICTIONTREATMENT

• Addiction is not Irreversible• Reversal of action of drug is Life Saving• FDA approved antagonists are only for Opioids &

BZPsTreatment of opioid WITHDRAWAL• STRATEGIES

– Alpha2 Antagonis CLONIDIDINE– Slowing Tappering of long acting Opioids.– Agonists acting on the same receptor acting on the

same receptors of abused drug (only for Opioids & Nicotine

• Contd ….For example

– Heroin addicts …… Methadone

– Smoking …. Nicotine Transdermal Patch

• To Reduce Craving:

• FDA approved ….. Naltexone for Opioid & Alcohol addicts

• For Nicotine Addiction….. Partial agonists …..

– Cytsine (plant extract) Vareniciline (synthetic)

– BUPRIPIONE …. An antidepressant …. FOR NICOTINE CESSATION THERAPY

ALCOHOL (Ethanol)

• Dependance become apparent 6-12 hrs after cessation of Heavy drinking as WITDRAWAL

• TREATMENT:

• Supportive

• Bzps ….. Oxazepam, Lorazepam .. As no Heapticmetabolism

• Chlordiazopoxide: … Preffered as long acting…. If LFTs Normal ….