Pharm 14: Drugs of Abuse 2 (cocaine + nicotine) Flashcards
What are the different methods of dosing on cocaine?
- paste (mushed up w org solvent)
–> cocaine Hcl (dissolved in acidic solution)
–> crack
(precipitate cocaine out of cocaine HCl using alkaline solution (e.g. baking soda) –> then heat precipitate + inhale vapour)
–> freebase
(purify crack + dissolve in non-polar solvent (e.g. ammonia + ether)
how do the different methods of administrating cocaine differ ?
Inhalation + IV have similar speed of onset –> rapid effects
o Inhalation poorest for bioavailability in blood
snorting / orally –> slow onset
o Cocaine pKa = 8.7 (gets ionised in acidic environment) –> very slow absorption/onset
o Slower absorption –> means prolonged action
describe the metabolism of cocaine
a) what is it converted to
b) what is its half life
c) what enzyme is involved in its breakdown?
75-90% converted to inactive metabolites = ecgonine methyl ester, benzoylecgonine
o T1/2 = 20-90min (how long metabolism takes)
o Breakdown uses cholinesterases either in plasma or liver
how does cocaine pharmacokinetics contribute to the addictive potential of the drug?
Cocaine = addictive because–>
a) it has fast onset of effect –> reinforcing
b) short-lasting effect,
–> people use it over + over (drives addiction)
how does cocaine action differ at high dose vs low dose?
HIGH DOSE = Action as a Local anesthetic by blocking Na+ channels –> reduce propagation of APs
o LA actions more prominent at higher doses
LOW DOSE = Reuptake inhibition of:
a. NA/Ad
b. 5-HT
c. DA
–> Enhances SNS activity (due to uptake blockade)
in what 3 ways can cocaine stimulate SNS ?
- Cocaine stimulates SNS by:
1. Inhibiting catecholamine reuptake (low dose effect) at sympathetic nerve terminals
2. Stimulating central sympathetic outflow
3. Increasing sensitivity of adrenergic nerve endings to NA
how does cocaine act like a class I antiarryhthmic?
Cocaine also acts like a class I antiarrhythmic (Local Anesthetic at high dose):
- by blocking Na+ and K+ channels –> depresses cardiovascular function e.g. Left Ventricular function
how does cocaine stimulate vasoconstriction?
Cocaine also stimulates ET-1 from endothelial cells + inhibits NO production –> greater vasoconstriction (also due to greater a1 stimulation) + TPR –> decreased blood flow to heart
what effects does cocaine have on platelets?
activates platelets –> more aggregation + thrombosis
Cocaine Pharmacokinetics:
o Onset = Seconds
o Tissue t1/2 = <90min, short-lasting
o Elimination = ecgonine methyl ester, benzoylecgonine: Urine (75-90%)
Cocain Pharmacodynamics:
o Blockade of Na+ channels – LA at high dose
o Transport Inhibitor (low dose) –> euphoria (CNS), CVS problems
-
What is the tissue half life of cocaine?
t1/2 = <90min, short-lasting
What are the different methods of dosing on Nicotine?
Nicotine Dosing:
o Nicotine spray = 1mg
(20-50% bioavailability)
o Nicotine gum = 2-4 mg
(50-70% bioavailability)
o Cigarettes = 9-17 mg
(20% bioavailability)
o Nicotine patch = 15-22mg/day
(70% bioavailability - highest)
Cigarette smoke is acidic / basic
Absorption in alveoli independent / dependent of pH
Cigarette smoke is acidic
ie no buccal absorption.
Absorption in alveoli independent of pH
–> ionised nicotine will still cross alveoli
what is the aim of nicotine replacement method ?
aim of replacement method = maintain consistent nicotine level in blood to remove cravings;
–> as opposed to cigarette where you get rapid, large peak then quick fall
Describe the metabolism of nicotine
a) how is it broken down
b) what is its half life
Metabolism:
o Hepatic CYP2A6 breaks it down –> to cotinine (inactive metabolite)
o Half-life = 1-4 hours
= short-effect, yet fast onset –> addictive
How do you get feeling of euphoria with nicotine?
nicotine directly stimulates VTA at nAChR –> stimulates greater DA release onto NAcc
What are the effects of nicotine on the cardiovascular system?
part a)
- increased SNS output
- increased catecholamines
- increased HR
- increased contractility
- increased BP
- -> increases oxygen demand of heart
part b)
- increased platelet activation
- -> decreases oxygen supply
part c)
- increased coronary vasoconstriction
- -> decreases oxygen supply
part d) - increased free fatty acids (VLDLD/LDL) --> increases risk of atherosclerosis --> decreases oxygen supply
–> can cause myocardial ischemia / MI
How does nicotine affect the lipid profile?
- increases lipolysis
Free fatty acids, VLDL
–> But lowers HDLs
Nicotine:
Increases/decreases metabolic rate
+ increases/ decreases appetite
Increases metabolic rate + decreased appetite
What are the effects of nicotine on neurodegerative disorders:
a) Parkinsons’
b) Alzheimers’
Does smoking have therapeutic value in treating Parkinson’s or
Alzheimer’s?
chronic nicotine = protective for neurodegerative disorders:
a) Parkinsons’
- -> increase in brain’s capacity to metabolise neurotoxins (via increase in brain CYPs)
b) Alzheimers’
- -> decreases beta-amyloid toxicity
- -> decreases amyloid precursor protein (APP)
What is the tissue half life of nicotine?
2-3 hours
effects of caffeine
caffeine = adenosine receptor antagonist
normally:
- adenosine binds to its receptors on NAcc –> decrease DA release + decreases D1 receptor function –> -ve for euphoria
- caffeine = antagonist
- -> causes euphoria
at high dose of Cocaine Hcl, it can act as a local anesthetic
explain how
cocaine hcl = local anesthetics
- cocaine –> sodium channel blocker
- cocaine diffuses accrocs plasma membres –> into cytoplasm then:
a) accesses open channel (hydrophilic pathway)
b) diffuses into closed channel (hydrophobic pathway)
*cocaine has to be uncharged –> then only it can diffuse easily across the membrane
How does cocaine induce euphoria?
- cocain blocks dopamine transporter in NAcc
- so lots of dopamine accumulates in the synapse
- so there is increase in stimulation of dopamine receptors (D1R)
–> so more powerful euphoric effect
note: at low dose –> effects tend to be positive / reinforcing
(euphoria)
at high dose –> effects tend to be negative/ stereotypic (chronic/tolerant cocaine use)
(irritability)
-
how can cocaine cause myocardial infarction
in general
part a)
- increased SNS output
- increased catecholamines
- increased HR
- increased contractility
- increased BP
- -> increases oxygen demand of heart
part b)
- increased platelet activation
- -> decreases oxygen supply
part c)
- increased coronary vasoconstriction
- -> decreases oxygen supply
–> can cause myocardial ischemia / MI
how can high dose cocaine cause arrhythmia ?
- high dose cocaine = acts as local anesthetic
a) decrease na+ transport in heart
b) can also cause inflammation –> affecting endothelial cells + decreases function of left ventricles
–> which can cause arrhythmias / sudden death
how does cocaine cause hyperthermic effects?
- cocaine overdose causes:
- -> increased agitation
- -> increased locomotor activity
- -> increased involuntary muscle contraction
= increase heat production
cocaine –> interferes with vasodilation + sweating
–> increases threshold for vasodilation + sweating
(change in set point)
–> can damage brain
note: peak effect of cigarettes is much quicker than other methods of administration
-
how does onset of euphoria effects differ between nicotine + cocaine?
- nicotine increases activity of nerve itself
- cocaine increase DA survival in synapse
