Pharm 14 - Drugs of Abuse - Cocaine/Nicotine Flashcards
What are the 4 forms of cocaine
- Paste
- Cocaine HCL - dissolve in acidic solution
- Crack - precipitate with alkaline solution (e.g. baking soda)
- Freebase - dissolve in non-polar solvent (e.g. ammonia and ether) - very dangerous to make but purer
Paste and HCL = IV/Oral/Intranasal
Crack and Freebase = inhalation
How does a high pKa influence rate of onset of drug
Means that the drug is largely ionised in the stomach, so has a prolonged action as it doesn’t cross the membrane easily
Smoking has a faster onset than IV, but IV has more bioavailability. Why
Because a lot of drug is lost when smoking
Cocaine is metabolised by the liver (and plasma) into inactive metabolites, which are?
Ecgonine methyl ester benzoylecgonine
What breaks down cocaine?
Plasma and liver cholinesterases
What 2 factors make cocaine VERY addictive
- Speed of onset, euphoria usually comes within seconds
2. Rapid metabolism of drug means that effects are lost very quickly - Half life of cocaine is 20-90 minutes
At higher doses, cocaine can be used as a local anaesthetic. How?
It can block sodium channels. However, it must be uncharged to diffuse into the lipid bilayer, before entering a closed Na channel (hydrophobic pathway). Or it diffuses into cytoplasm then blocks an open Na channel (hydrophilic pathway).
Cocaine’s main effect (At lower doses) is as a monoamine reuptake transporter blocker. How does this work?
e.g. Dopamine is released into the synapse, where it has its effects. Cocaine is a monoamine transporter blocker, so dopamine can’t be removed from the synaptic cleft. Therefore, dopamine in synaptic cleft for longer so has more prolonged effects = euphoria.
Blocking the dopamine receptor occurs at the Nucleus Accumbens
Does cocaine influence affinity/efficacy for the dopamine receptor?
NO
What are the differences between low dose cocaine and high dose cocaine
Low dose = more positive effects
High dose = negative stereotypical effects
Low dose and high dose varies from person to person
How can cocaine cause MI
- Increases SNS output due to prolonged NA action in synapse
- This means greater demand on the heart
- Coronary vasoconstriction also occurs = heart less O2 supply
- Platelet also activated
- Leads to tissue ischaemia and MI
- Local anaesthetic effect (i.e. blocking Na) also increases chance of arrhythmias and MI
Cocaine also causes hyperthermia, how?
Causes heat production due to (increased locomotor activity, increased involuntary muscle contraction).
Increases the threshold for sweating and cutaneous vasodilation also.
Cutaneous vasodilation and sweat production. Which one does cocaine enhance and which one does it inhibit
Enhances sweat production
Inhibits cutaneous vasodilation
What are 4 different ways of intaking nicotine
- Nicotine spray - 1mg
- Nicotine gum - 2-4mg
- Cigarette - 9-17mg
- Nicotine patch - 15-22mg daily
Cigarette smoke is acidic and so ionises nicotine (which is alkaline). What does this mean
No buccal absorption of nicotine
Why do people chain smoke?
To try and maintain a high blood nicotine level.
Upon inhalation, quick onset but the effects are lost quickly
The liver breaks down nicotine into its inactive metabolite, Cotinine. Why is nicotine so addictive
It is broken down very quickly
T1/2 = 30 mins to 1-4 hrs
What does nicotine do?
It binds to NAChR and activates it - causing Na influx
How does nicotine increase dopamine secretion
Binds to cell bodies of dopaminergic neurones in the Ventral Tegmental area (VTA). Activates and Causes increased firing rate - hence more dopamine secretion in the Nucleus Accumbens
Nicotine has many CVS effects, which are
- Worsens lipid profile (increases VLDL and LDL)
- Increases SNS activity - more demand on heart
- Coronary vasoconstriction = less myocardial O2 supply
- Increases thromboxane A2 - increases platelet activity
- Promotes atherosclerosis
Nicotine increases metabolism, so what happens to chronic smokers when they stop?
They put on weight
Nicotine decreases appetite
How does nicotine have neuroprotective effects?
Nicotine increases CYP 450 system of the brain - brain better able to metabolise neurotoxins - therapeutic for Parkinsons
Also diminishes proteins that contribute to Alzheimers
How does caffeine work?
- Adenosine binds to Adenosine (A1) receptor and negatively impacts dopamine function; decreases dopamine release and decreases D1 receptor function
- Caffeine = Adenosine receptor antagonist
(3. Only a relatively small fraction of the pathway)
