DOA 2 - Cocaine/Nicotine

Question 1

History of cocaine?

Answer 1

Cocaine/Erythroxylum coca

• leaves contain 0.6-1.8% cocaine

Question 2

Explain the forms of cocaine

Answer 2

Gets PURER/STRONGER as you go down:

• ‘Paste’ - 80% cocaine (ORGANIC SOLVENT)
• ‘Cocaine HCl’ - dissolved in ACIDIC SOLUTION
• ‘Crack’ - precipitated with ALKALINE SOLUTION (e.g. baking soda)
• ‘Freebase’ - dissolved in a NON-POLAR SOLVENT (e.g. ammonia + ether)

Question 3

How are the different forms of cocaine taken?

Answer 3

Oral, IV, Intranasal
• Paste
• Cocaine HCl

Inhalation
• Crack
• Freebase

Question 4

Explain the adminisatrion of cocaine in terms of pharmacokinetics

Answer 4

IV
• a FAST ONSET of action
• SHORT-LASTING high

Oral, nasal & smoking
• SLOWER ONSET/ absorption
• pKa = 8.7 SO oral cocaine is ionised in GIT
- less can be absorbed as cannot cross membrane
- i.e. if high pKa, unionised in alkaline, ionised in acidic
• PROLONGED action

Question 5

Explain the metabolism of cocaine

Answer 5

75-90% is metabolised very FAST into:
• Ecogonine methyl ester
• Benzoylecgonine
(NOT active)

T1/2 = 20-90mins

Can be metabolised in the blood via
• plasma & liver cholinesterases

Question 6

How do you think that cocaine pharmacokinetics contribute to the addictive potential of the drug?

Answer 6

FAST onset & SHORT half-life

Lots of methods to take the drug

Question 7

Main pharmacodynamics effects of cocaine?

Answer 7

Local anaesthetic

Re-uptake inhibition

Euphoria

Question 8

Explain the pharmacodynamics of cocaine as a LA

Answer 8

High-dose cocaine
• can BLOCK the Na+-channels to cause a LA effect
• inhibits conduction of AP

Needs to be taken into the neurone and work on the channel from the inside
• pKa of cocaine is 8.74, whilst the pH outisde = 7.4 & inside = 7.0
• outside the neurone, cocaine is unionised (as pH closer to pKa) so can move into the neruone
• once inside the neurone, it is ionised (+ve charge) so can work of the channel
• CHARGED COCAINE interacts with the target BETTER

Question 9

Explain the pharmacodynamics of cocaine as a re-uptake inhibitor

Answer 9

Low-dose cocaine
• MOA-A re-uptake inhibitor (uptake 1)

Can affect the re-uptake of NA, DA, 5-HT
• with NA, particularly the NA reuptake transporter

Question 10

Does cocaine influence dopamine affinity/efficacy for the dopamine receptor?

Answer 10

NO

As only increasing the no. of DA in the synaptic cleft
• will still bind to receptors (affinity) & cause a reaction (efficacy) so simply just increasing the receptor interactions

Question 11

Explain the pharmacodynamics of cocaine and its euphoric effect

Answer 11

REDUCES re-uptake of DA into the pre-synaptic neurone
• BLOCKS the dopamine transporter
• SO more DA in the NAcc (from the VTA)

Question 12

What are other pharmacodynamic effects of cocaine?

Answer 12

Harder to distinguish due to its generalised effect on MONOAMINES (DA, NA, serotonin etc)

Acute-use - mild/moderate effects
• Initially positively reinforcing effects such as mood amplification & heightened energy

BUT FLIPS TO

Chronic use - severe effects
• Tend to then start to exhibit severe effects such as total insomnia & decreased libido

Question 13

Two main -ve effects of cocaine use?

Answer 13

Cardiovascular (MI)

CNS - Hyperthermia

Question 14

Explain the pharmacodynamics behind the cardiovascular effects of cocaine?

Answer 14

Increased SNS output
Increased catecholamines (via effect on monoamine uptake)
• increases O2 demand on heart (as can lead to coronary vasoconstriction, endothelial injury, atherosclerosis)
• results in ischaemia of the heart muscle

Also leads to inflammation & reduced Na+ transport
• reduces L-ventricle function which can lead to arrhythmias & sudden death

Question 15

Explain the pharmacodynamics behind the CNS effects of cocaine

Answer 15

HYPERthermia
• increased agitiation, locomotor activity & involuntary muscle contraction INCREASES body temperature
• coupled w. HOT ENVIRON. can lead to hyperthermia

Mechanisms used to stop it can include
• sweat production
• cutaneous vasodilation
• central threshold for thermoregulation

Question 16

How would you expect cocaine to influence sweat production and cutaneous vasodilation?

Answer 16

Both are related to ACh as moderates its effects so cocaines effects may not be as useful (as effects NA)
• tends to INHIBIT cutaneous vasodilation
• tends to ENHANCE sweat production

Cocaine also elevates threshold for sweating/cutaneous vasodilation X3

Question 17

What do cigarettes produce?

Answer 17

95% volatile substances
 • Nitrogen
 • CO/CO2
 • Benzene
 • HCN

5% PARTICULATES
• Alkaloids e.g. NICTOINE
• Tar
- Nicotine diffuses OUT of the tar droplets in the lungs when deposited

Question 18

Explain the dosing of nicotine in terms of the different forms it can be administered in

Answer 18

• Nicotine spray - 1mg
- 20-50% effective

• Nicotine gum - 2-4mg
- 50-70% effective

• Cigarettes - 9-17mg

• 20% effective
• pKa = 7.9 SO cigarette smoke is ACIDIC so NO buccal/mouth absorption
• absorption in the ALVEOLI is INDEPENDENT of pH however

• Nicotine patch - 15-22mg
- 70% effective

Question 19

How does nicotine lead to addiction?

Answer 19

Again similar to cocaine
• SHORT-LASTING action
&
• FAST REDUCTION in [plasma]

Question 20

Explain the metabolism of nicotine in terms of pharmacokinetics

Answer 20

T1/2 = 1-4hours

Hepatic CYP-2A6 metabolises 70-80%
• into COTININE
• NOT active & RAPIDLY cleared

Question 21

Difference in metabolism between cocaine & nicotine?

Answer 21

Cocaine CAN BE metabolised in the BLOOD
• Nicotine can NOT

HENCE why cocaine is metabolised FASTER

Question 22

Explain the pharmacodynamics behind nicotine

Answer 22

Nicotine binds to NICOTINIC receptors
• found on ACh receptors (onenote!!)
• stimulates Na+ transport

Question 23

Using pharmacodynamics, explain how nicotine can cause euphoria

Answer 23

nAChRs are found on the soma of the DA nuclei in VTA
• stimulation of these receptors stimulates DA release in the NAcc

This is DIFFERENT to cocaine which works on DA reuptake whilst nicotine is DIRECTLY affecting the nerve

Question 24

Using pharmacodynamics, explain the cardiovascular effects of nicotine

Answer 24

Stimulation of the nAChRs leads to SNS activation & increased catecholamines (as stimulating ACh receptor)
• affects CNS & adrenals
• increases HR & SV
• vasoCONSTRICTION of skin arterioles
• vasoDILATION of coronary arterioles, skeletal muscle arterioles

(similar effects to cocaine then = MI)

Also INCREASES lipolysis, FFAs, VLDLs
DECREASES HDL
INCREASES TXA2
DECREASES NO
 • long-term use = CVD

Question 25

Using pharmacodynamics, explain the metabolic effects of nicotine

Answer 25

Nicotine leads to
• INCREASE in metabolic rate
&
• DECREASED appetite

SO after STOPPING smoking, can lead to WEIGHT GAIN (no longer have faster metabolism)

Question 26

Using pharmacodynamics, explain the neurodegenerative disorders associated with nicotine and if it is a good/bad thing

Answer 26

Parkinson’s disease
• INCREASE in brain CYPs (neurotoxin enxymes)
• INCREASES BREAKDOWN of these neurotoxins (which normally cause Parkinson’s)

Alzheimer’s disease
• DECREASE beta-amyloid toxicity
&
• DECREASES APP (amyloid precursor protein)

SO nicotine seems to be PROTECTIVE against both diseases

Question 27

How does caffeine cause euphoria?

Answer 27

By BLOCKING A1 receptors

ADENOSINE acts of its A1 receptors
• found ON the NAcc & the D1R
• INHIBITING the reward pathways

Caffeine hence BLOCKS these A1 receptors
• STIMULATING the rewards pathway

ONENOTE!!