Pharmacology 11a - Drugs of Abuse
Anil Chopra
1. Describe the ‘reward’ pathways in the brain activated by drugs of abuse. Which are the main abused substances and how do they specifically activate reward pathways?
2. Describe the pharmacokinetics for the major drugs of abuse (e.g. routes of administration, metabolism).
3. Describe the basic pharmacology for the main abused substances.
Drugs of abuse target specific areas in the brain mainly the Nucleus Accumbens (Ventral Striatum), Ventral Tegmental Area.
Rewarding stimulus in the ventral tegmental area causes an action potential to be generated and travel along the axon to the nucleus accumbens. This causes the release of dopamine.
Routes of Administration:
- Nasal (snort) - slow
- Oral (eat) – very slow
- Inhale (smoke) - rapid
- Intra venous (inject) – rapid
Classification of Drugs
There are 4 main types of drugs:
Narcotics/Painkillers – opiate drugs like heroin
Depressants – ‘downers’ e.g. alcohol, benzodiazepines (valium), barbiturates
Stimulants – ‘uppers’ e.g cocaine, amphetamine (‘speed’), caffeine
metamphetamine (‘crystal meth’)
Miscellaneous – e.g. Cannabis, Ecstasy (MDMA)
Name – cannabis, anandamide
Usage – euphoria
Mode of Action – Binds to GABAergic CB1 (Cannabinoid) receptors in the hippocampus/cerebellum/ cerebral cortex/basal ganglia. They are G-protein coupled receptors which cause the inhibition of the enzyme adenylate cyclase. This causes cAMP to be produced and act as a second messenger. They also bind to CB2 receptors on immune cells.
Contain a number of different cannabinoids
Tetrahydrocannabinol is the active ingredient.
- the concentration of tetrahydrocannabinol (THC) in the drugs are increasing
- in the 60’s there was 10mg, now there are 300mg
Side effects and Pharmacokinetics
- Sometimes taken orally but mainly inhaled.
- Distributes itself in a number of tissues
- Metabolised by liver and kidney
- ½ life of 7 days.
Side effects:
- Psychosis, Schizophrenia!!
- Food intake – Hypothalamus
- Memory loss – Limbic regions
- Psychomotor performance – Cerebral cortex
- Immunosuppression
- Tachycardia / vasodilation
- The up-regulation of CB receptors can cause multiple sclerosis and pain as well as ultimately resulting in obesity and stroke.
Name – cocaine
Usage – induce euphoria, a local anaesthetic, stimulant and appetite suppression.
Mode of Action – cocaine binds to the “dopamine transporter” that causes dopamine to be transported back into the pre-synaptic cleft in the nucleus accumbens. There is therefore more dopamine in the synapse which brings about the feeling of euphoria. Cocaine also blocks sodium channels, thereby interfering with the propagation of action potentials; thus, like lignocaine and novocaine, it acts as a local anesthetic. Cocaine also causes vasoconstriction, thus reducing bleeding during minor surgical procedures.
Side Effects & Pharmacokinetics
- It comes in a number of different forms:
- “paste” – 80% cocaine – taken orally and intranasally
- “ cocaine HCl” – dissolved in acidic solution – taken orally and intranasally
- “crack” – precipidate with alkaline solution – inhaled
- “freebase” – dissolved in non-polar solvent – inhaled
- It is metabolised hepaticlly (cocaine is converted to ecgonine methyl ester benzoylecgonine by the liver) and excreted in urine.
- ½ life of 20-90 minutes.
Side Effects
- Increases sympathetic stimulation to the heart which increase heart rate, induces vasoconstriction and increases platelet activation.
Name - nicotine
Usage – one of the main drugs in cigarettes.
Mode of Action – nicotine can bind to nicotinic Acetylcholine receptors on the surface of neurones in the ventral tegmental area (VTA), this increasing the release of dopamine and hence causing euphoria. These are sympathetic neurones in the CNS and the adrenal glands which causes a number of side effects:
Side Effects and Pharmacokinetics
- Comes in many forms
- Nicotine spray – 1mg
- Nicotine Gum – 2-4mg Nicotine
- Cigarettes – 9-17mg nicotine
- Nicotine Patch – 15-22mg/day
- Metabolised by the liver (Cytochrome P450 2A6) converts the nicotine to cotinine.
Side effects
- Increase in heart rate and stroke volume
- Vasoconstriction of arteries to skin and heart.
- Vasodilation of arteries to skeletal muscles
- Increases lipolysis, which increases LDL levels in blood and decreases HDL levels.
- Increases thromboxanes and decreases nitric oxide levels – thus increasing the risk of cardiovascular disease.
- Increases metabolism and suppresses appetite.
- Decreased sensitivity to dopamine can increase the risk of Parkinson’s disease.
Name – caffeine, chocolate
Usage – contained in many drinks as stimulant
Mode of Action – nicotine blocks the adenosine A1 receptor on post and pre synaptic neurones in the VTA. This normally has an inhibitory effect but in the presence of caffeine this inhibition is lost which results in a rewarding stimulus. Chocolate can directly stimulate VTA receptors.