Drugs of abuse 2 Flashcards
Where does cocaine come from
Erthryoxylum coca leaves….
Outline the types of cocaine and how they are taken
- ‘Paste’ …. extract around 80% of the cocaine from leaves using an organic solvent
- ‘Cocaine HCl’ - extract the cocain from the above paste, and then put it in acid. This form can then be dissolved in water and is useful for anaesthetic.
Both I.v. Oral, intranasal. They can’t be smoked or heated as they have a high boiling point, and will be destroyed before they reach this.
The solution to this is:
- ‘Crack’ - precipitate the cocain HCl with an alkaline solution (e.g. baking soda). You end up with cocaine rocks (i.e. the salt of the acid and base)
Then you can dissolve the crack in a non-polar solvent such as ammonia or ether= ‘Freebase’
For inhalation
What are the problems with cocaine on the nasal septum
Because it causes vasoconstriction and the tissue becomes necrotic
Outline issues with boiling point and solubility
Cocain HCl has a high boiling point, and would break down before being heated high enough to smoke… so bad if you want to abuse the drug….. so people would snort instead of inject or oral
But with crack cocaine or freebase, then the boiling point is lower so the drug can be inhaled before being destroyed by heat
Cocain HCl is more water soluble, crack cocaine is more lipid soluble (easily diffuses across lipid membrane)
Freebase allows you to make crack cocaine more pure (doesn’t have the baking soda… but more dangerous to handle)
Outline the effect of the rate of absorption on the length of action
Snort/ oral leads is slow absorption but longer action
Inhalation and IV fast absorption and reduced duration of action
Where is cocaine absorbed if taken orally
The pKa is 8.7, which is greater than the stomach.
High ionisation in the stomach…. so not absorbed until the intestine
Slower absorption than if it was unionised in the stomach, in which case it is absorbed in the stomach
Outline them metabolism of cocaine
75%-90% metabolised to inactive metabolite (ecgonine methyl ester and benzoylecgonine)
T1/2 is 20-90mins
Broken down by both plasma AND liver cholinesterases
YOU CAN REMEMBER THIS BECAUSE COCAINE IS A LA! AND IT’S THE ESTER FORM (ESTER SMOKES COCAINE) SO IT HAS TO BE AN ESTERASE BREAKING IT DOWN!
How do pharmacokinetics of cocain affect addictive ness
Speed of onset of euphoria (as the association between the drug and euphoria is great)
And quick loss as well due to being rapidly broken down in the blood stream and the liver
Explain the action of cocaine at high dose
The HCl form is a local anaesthetic
Na+ channel blocker but cannot block it from the blood side of the membrane… has to difffuse across the plasma membrane and then can access the open channels or diffuse into a closed channel from the inside
Why must cocaine be uncharged for Na+ Channel blockade
So that the cocaine can pass through the plasma membrane and block Na+ channels from the inside
What’s does cocain do at high and low dose
How does cocaine increase sympathetic activation
So cocaine acts as a sympathetic NS activator (see below).
However it is also a class 1 antiarrythmic agent (local anaeasthetic effect of blockng Na+ and K+)
These effects are opposing.
Enhanced sym. occurs as low cocaine dose, whereas local anaesthetic action occurs at higher dose
Increases synpathetic:
- Reduces reuptake of NA
- Centrally increases sympathetic outflow
- Sensitises adrenergic nerve endings to NA
NOTE: NOT JUST NA, ALSO AFFECTS REUPTAKE OF DA AND 5-HT!
Explain the euphoric effect of cocaine
At the nucleus accumbens, cocaine blocks the dopamine reuptake and this increases concentration of dopamine in the synapse
Increased D1R at the NAcc
Low dose cocaine does what
Inhibits reuptake of serotonin and NA as well as dopamine
Effect of normal cocaine effect and also effect in tolerance (chronic users)
Explain why tolerance occurs
Initial doses is positive/reinforcing (mood amplification, heightened energy, sleep disturbance, increased libido, anger verbal agression)
Further doses are negative/stereotypic (irritability, anxiety, exhaustion, disjointed flight of ideas, total anrexia)
BECAUSE cocaine increases concentration of dopamine in the synapse but by blocking reuptake, the neurone fails to replenish the dopamine. Further cocaine use results in much lower euphoria
Harmful effects of cocaine on the heart
- Increased MO demand:
Increased NA/ central sympathetic output increases:
- HR
- contractility,
- blood pressure,
- Reduces MO supply
Increased NA/ central sympathetic output leads to:
- coronary vasoconstriction,
- platelet activation (which can lead to atherosclerosis
- Endothelial injury (due to increased HR, contractility and BP), which can lead to atherosclerosis and reduced MO.
Points 1 and 2 all lead to myocardial ischaemia and infarction.
- Arrhythmias
This can be due to the myocardial ischaemia, but also
At the higher doses of cocaine use, the local anaesthetic action (i.e. Na+ blocking action) kicks in. This can lead to reduced left ventricular function.
Inflammation (also due to local anaesthetic effect) can lead to endothelial injury and reduced left ventricular function.
The arrythmia can lead to sudden death.
What’s is the effect of cocaine of hyperthermia
- Cocaine increases heat production:
SNS activation
increase muscle activity (voluntary and involuntary, and due to agitation)
- Cocain affects heat dissipation
Cocaine reduces vasodilation (bad for heat dissipation) but increases sweat production (good for heat dissipation)
But there is change in the set point for sweating and vasodilation (3 fold higher before sweating and dilation occurs)
Particularly naive users
WHAT time tissue half life of cocaine and what is the onset
90 minutes (compared to 7 DAYS for cannabis!)
Onset is seconds
WHy isn’t there a risk of death like with heroin Andy alcohol
Because it is a stimulant so cant shut down the cardiorespiraotry centre in the medulla
Outline the compoennets of cigarette smoke
Volatile (95%):
Nitrogen, CO, CO2, Benzene, HCN
and
particulate (5%):
Alkaloids (NICOTINE)
Tar
How comes smoking cigarette has lowest nitoctine absorption compared to the other administratin routes, despite having excellent perfusion
Only about half of the smoke actually gets to the lungs, and only half of that gets deep enough into the lungs for absorption
What is the lipid solubility of nicotine
Quite good
WHere is the nicotine found in cigarette smoke
Within the particulates (not volatile)… nictonine found in the tar droplets in the lungs, and absorbed through this
Outline how nicotine can be administered
Nicotine spray – 1mg
Nicotine Gum – 2-4mg Nicotine
Cigarettes – 9-17mg nicotine
Nicotine Patch – 15-22mg/day
Outline the bioavailability of nictonine via the different routes
PATCH is highest, CIGARETTE SMOKE is lowest (why!?)
Nicotine spray – 1mg 20-50%
Nicotine Gum – 2-4mg Nicotine 50-70%
Cigarettes – 9-17mg nicotine 20%
Nicotine Patch – 15-22mg/day 70%
Why can nicotine be chewed in gum and be absorbed in the buccal cavity but not absorbed in the buccal cavity in smoke
IN SMOKE NITOCTINE IS IONISED ionised so high pKa of 7.9 (cigarette smoke ACIDIC) and no buccal absorption but not ionised in gum so absorbed in mouth
EVEN THOUGH NICOTINE IONISED IN SMOKE, CAN STILL BE ABSORBED DOWN IN THE LUNGS BECAUSE THE AVEOLI DON’T PROVIDE MUCH BARRIER, ANYTHING GETS ACROSS REALLY EVEN IF IONISED
‘absorption in the alveoli is independent of pH’
Outline differences in administration with respect to weening
With cigarette smoking there is a huge difference between the peak effect just after smoking and plasma concentration 30 minutes later (which is why smokers continuously smoke to top back up to peak level)
With the other methods eg gum and skin etc, the dose is lower but it is smoother such that the peak dose does not fall dramatically
(note that the dose of cigarette smoke is higher, despite its poor bioavailability, due to being acidic, because the dose in cigarette smoke is higher than the dose being given in attempts to ween off nicotine)
How is nicotine metabolised
What is the half life of nicotine
Quickly converted to inactive metabolites (by CYP2A6) called called conitine
t1/2 = 1-4hrs
70-80%
Note that the half life is slightly longer than the cocain half life and that is because the cocaine is also broken down in the blood whereas the nicotine is only broken down in the liver
How does nicotine work
It binds to NAChR ion channel linked so influences both SNS and PNS… activating autonomic nervous sytem
How does nicotine induce euphoria
Nicotine activates NAChR on the dopaminerigic neuron in the VTA, so increases dopamine on the D1R
How does nicotine produce poor CVS effects, and compare with cocain
No local anaesthetic effect….
Less likely To produce acute cardiovascular effects than with cocaine (because no Na+ channel blocking/pro-inflammatory respinse)
Basically same as cocaine in terms of increasing sympathetic output which incrases platelet activation, coronary vasoconstriction, and Increasing HR, BP and contractility
BUT nicotine also worsens the lipd profile, so as well as the platelet activtion/endothelial injury causing atherosclerosis, there is also increased FFAs, increased VLDL and LDL
What is the effect of nicotine on metabolic rate
Increased metabolic rate (catabolic effect…. due to SNS)
Reduces appetite and weight gain occurs after giving up
Outline the effect of nicotine on neurodegenerative disorders
Protective
In Parkinson’s increases brain CYPs that can break downs neurotoxins which cause the disease
Alzheimer’s Disease: reduce beta-amyloid toxicity
and amyloid precursor protein (APP)
How does caffeine act as a stimulant
It is an adenosine receptor antagonist…. adenosine binds to adenosine receptor on the dopaminergic neurons and decreases dopamine release AND
also decreases D1 receptor activation on the NAcc neuron
Caffeine is an antagonist for adenosine so it blocks both these effects
Does vaping remove all the effects of smoking
Removes pulmonary effects associated with the volatile matter,
but the nicotine in the particulate matter is still causing all of those CVS effects
How are nicotine and cocaine similar in pharmacookinetics
Because they are raidly absorbed (inhalation) but then rapidly metabolised, both have short half life (cocain shorter than nicotine)
Why is the caffeine less euphoria causing
Caffeine is generally orally administered – so the euphoria effect is less obvious
How do you get the most cocaine into the bloodstream
IV…. even though inhalation is faster, less is lost. Lots is lost with inhalation so there is lower bioavailability
Outline the effects of cocaine on the heart at high and low dose
Cocaine stimulates the sympathetic nervous system by inhibiting catecholamine reuptake at sympathetic nerve terminals, stimulating central sympathetic outflow, and increasing the sensitivity of adrenergic nerve endings to norepinephrine
Cocaine also acts like a class I antiarrhythmic agent (local anesthetic) by blocking sodium and potassium channels, which depresses cardiovascular parameters. Of these 2 primary, opposing actions, enhanced sympathetic activity predominates at low cocaine doses, whereas the local anesthetic actions are more prominent at higher doses.
Why can coaine overuse results in seizure
due to a vasoconstricting effect in the brain (reduced blood flow to certain parts of the brain). Cocaine stimulates hyperpyrexia. The combination of vasoconstriction and hyperpyrexia are associated with seizure induction and epilepsy.
