Cocaine

Quick summary

 

Localised vasoconstriction

Abuse potential

Irritant property --> Cannot be used on cornea or as injection

 

 

 

 

Usage

What is the drug used for?

Structure

• Cocaine is extracted from leaves of Erythroxylon coca, which is a plant growing in the Andes mountains

Structure

What is the proper name of the drug's structure?

What does the drug's structure look like?

Structure-activity relationship

How does the drug's structure change its activity or characteristics?

Pharmacodynamics

Main actions

Mechanisms of action

What receptors does the drug act on?

Where are these receptors?

What are the effects of these actions?

Effects by systems

 

CNS

[BGK9:p135]

• Main action of cocaine in CNS is inhibition of dopamine reuptake in the "pleasure centre" of the brain.
• Amphetamine-like activity, but strong and shorter in duration

 

(CNS, CVS, Resp, GIT, others)

Side Effects/Toxicity

Cocaine toxicity

[???]

• Blocks presynaptic uptake of NE and dopamine
  --> Increases postsynaptic concentration of NE and dopamine
  --> Sympathetic nervous system stimulation
  --> Vasoconstriction

Pharmacokinetics

Time to peak plasma concentration of cocaine

• Intranasal: 30-40 minutes
• IV: 5 minutes

Time to maximal physiological effect

• Intranasal: 15-40 minutes

Duration: >60 minutes after peak effect

Adverse physiologic effects

• Coronary vasospasm
• Myocardial ischaemia
• Myocardial infarction
• Ventricular cardiac dysrhythmias (ventricular fibrillation)
• Hypertension and tachycardia
  --> Increased myocardial oxygen requirements
• Dose dependent decreases in uterine blood flow
  --> Foetal hypoxaemia

Treatment of cocaine toxicity

• Nitroglycerin
• Esmolol (but beta-blockade may accentuate coronary artery vasospasm)
• Nitroprusside
• Alpha-adrenergic blocking drugs
• Benzodiazepine (control seizures)

 

 

What are the side-effects of the drug?

What happens in overdose? What are the toxic side-effects?

 

 

Pharmacokinetics (PK)

Absorption

How is the drug absorbed? Route of administration?

What is the bioavailability with non-IV routes?

Distribution

Where does the drug first get distributed to (e.g. VRG, muscle, fat)?

Where do the drug accumulate mostly?

How fast does it redistribute?

Does it cross BBB or placenta?

(Includes the Vd and Protein-binding)

Metabolism

Significant hepatic metabolism [SH4:p186]

But primary metabolism is still by plasma esterase (cholinesterase)[SH4:p203]

Cocaine metabolism takes place mainly in the liver [http://www.inchem.org/]

Metabolised (hydrolysed) by plasma and liver cholinesterase [SH4:p187]

Plasma cholinesterase activity may be decreased in pregnancy, neonate, elderly, and severe hepatic disease
--> Decreased metabolism [SH4:p187]

I think it is implied that the enzyme involved is plasma cholinesterase, NOT non-specific plasma estereases
* Non-specific plasma estereases are NOT affected by pregnancy, etc

 

 

 

 

How is the drug metabolised? Where does the metabolism take place(Liver, kidney, other organs)

What are the metabolites? Are they active or toxic?

Elimination

[SH4:p187] Cocaine 10%-12% are excreted unchanged in urine

But

[SH4:p203] <1% of total dose is excreted unchanged in urine

I believe the second statement is false. Other sources also suggest significant renal excretion of unchanged cocaine

[http://www.inchem.org/] 1-9% of cocaine excreted unchanged in urine

 

 

How is the drug eliminated? How are the metabolites eliminated?

How much of the drug is eliminated unchanged?

Clearance

Action profile

T1/2 (in different phases, alpha, beta, etc)

Onset of action, duration of action, time to peak effect

Physicochemical properties

pKa 8.5 [MCQ:Q73] Need better source [???]

 

 

Acid or base? pKa?

Pharmaceutics

Presentation

Composition

Price

Clinical

Administration

route of administration, and the dosage for each different route.

 

Indications/contraindication/precautions

When should the drug be used?

When should the drug NOT be used?

When should the drug be used, but only with caution?

 

Interactions

What other things can the drug interact with?

 

Special consideration

What issues should be considered when the drug is used in special circumstances, e.g.:

• Pregnancy/lactation
• Elderly
• Paediatrics
• Renal disease
• Hepatic disease

 

 

Trivia

History

 

Others