Marta Boffito, MD, PhD

Head of Clinical Trials, St. Stephen’s Centre (SSAT)Consultant Physician, Chelsea and Westminster Foundation Trust

Reader, Imperial College

16th edition of the International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy

Case presentation: recreational drug use

Paulo 28 years oldo MSM

o Seen on Monday am after exposure to HIV following 2 days of ChemSex parties: multiple partners and no condom use

Paulo 28 years oldo MSM

o Seen on Monday am after has been exposed to HIV following 2 days of ChemSex parties: multiple partners and no condom use

o After discussion, it is decided he is a candidate for PEP

Paul

o When asked, he reports:

– Use of recreational drugs for 2 years– No sober sex for 2 years– PEP twice already within the past 10 months

Paul

o He is prescribed TDF/FTC/LPV/r

o Importance of not taking recreational drugs over the next 4 weeks because of possible DDIs discussed in length/documented in notes

DDIs = drug-drug interactions

Paul

o Approximately 2 weeks after being prescribed PEP he comes back to the clinic

o Stopped PEPo Admission to A&E 5

days earlier after collapsing in a club on Saturday night…

At A&E admission

o Unconscious (unresponsive)o Endotracheally intubatedo Ventilated respirations of 14 per minuteo Bradycardico BP 170/120o T 35.1°Co Normal head CT scan and chest X-ray

I was high on crystal (from Friday night) and I took G during the night on Friday and on Saturday…

I collapsed before in clubs but I was never taken to A&E as the “medics” in the side

room sorted me out…

Paul

What do you think happened to Paul?

1. He took another drug and is not telling

2. He took G with ritonavir and was intoxicated by the increased G exposure

3. He took too much G

4. He took crystal with ritonavir and was intoxicated by the increased crystal exposure

5. He took G on top of too much alcohol

David Marc

GBL is liquidPeople take 0.5 to 1.5 mL, with 1 mL being the

most frequently taken doseHigh doses can be life-threatening (e.g. 3 mL)

but ANY dose can be dangerous

It is difficult to dose it right when high (on crystal, on G itself, etc), in the dark, with lube

on hands, etc

Is 100 mg RTV BD enough to boost GHB?

Would a RTV-free PEP have avoided admission to A&E?

33 cases of death for GHB overdose are reported every year but the reality is that

hundreds of young men are dying from it …

When combined with alcohol the increased sedation and vomiting causes even more

deaths …

GBL → GHBo gamma-Butyrolactone (GBL) is a hygroscopic colourless liquid /

soluble in watero GBL is:

- a solvent and reagent in chemistry- used as a flavouring- a cleaning solvent- a superglue remover- a solvent in some wet aluminium electrolytic capacitors- a prodrug for GHB, used as a recreational intoxicant with effects similar to alcohol

o 1,4-butanediol (1,4-BD) is also a precursor of GHB

G PKo GBL converted to GHB by endogenous lactonase enzymes

o 1,4-BD metabolized by alcohol and aldehyde dehydrogenases to form GHB

ETOH can inhibit this metabolic pathway and be a competitive substrate to alcohol dehydrogenase: enhancement of 1,4-BD effects

o Metabolism of GHB occurs either via:

i) GHB dehydrogenase, which transforms it into succinic semialdehyde (SSA), then into succinic acid, then ultimately excreted through breath as carbon dioxideii) by GABA transaminase with transformation into GABA

o Animal data show that GHB is degraded by first-pass metabolic pathways (i.e. CYP3A4)

Kohrs et al 1999; Brenneisen et al 2004; Lettieri et al 1976

Page last updated at 16:22 GMT, Wednesday, 23 December 2009GBL drug death identified by UK doctors By Dominic Casciani

GBL: Now a controlled drug

… Toxicologists in London found that a 25-year-old man died hours after taking GBL on its own while out clubbing … The report in the journal details how the man had been previously fit and healthy - but had returned home from a night out in 2008 "acting strangely“ … but he died from a prolonged cardiac arrest … post-mortem found that the quantity of GBL in the man's body was consistent with the amount seen in previous fatal overdoses involving GHB …

Student death

Dr Paul Dargan, of Guy's and St Thomas' NHS Foundation Trust in London, wrote: "There are numerous reported fatalities related to GHB ingestion … Student Hester Stewart died after taking GBL and alcohol … The doctors wrote that medical records showed that there had been recent increases in the number of patients suffering overdoses caused by GBL - almost certainly caused by the fact that GHB had been made a controlled drug in 2003 … The Brighton medical student died in April after taking GBL and drinking alcohol. Her parents lobbied the government to ban the drug saying they could not understand why it was banned for personal use in the US and Canada, but not in the UK …

Student Hester Stewart died after taking GBL and alcohol

GBL: Now a controlled drug

Crystal meth

o Methamphetamine: neurotoxin/potent psychostimulant

o Used as a recreational drug and rarely to treat ADHD and obesity

o Increases sexual desire/energy, lifts the mood, allows to engage in sexual activity non-stop for several days straight

Crystal meth

ADHD = attention deficit hyperactivity disorder

o Following oral administration well-absorbed into bloodstreamo Peak plasma [methamphetamine] in 3.13–6.3 ho Well absorbed inhaled and intranasallyo High lipophilicity, readily moves through the BBBo Excreted by the kidneyso Half-life variable: mean value of between 5–12 h

Crystal meth PK

BBB = blood brain barrier

Enzymes known to metabolize methamphetamine or its metabolites in humans

-CYP2D6-dopamine β-hydroxylase-flavin-containing monooxygenase-butyrate-CoA ligase-glycine N-acyltransferase

The “party drugs”

• GHB• Crystal meth• Mephedrone• MDMA• Ketamine• Nitrous oxide• Benzodiazepine• Erectile dysfunction agents (EDA)

Literature search / references

o Paul, Steve, Lukas, and Marc

o David StuartSubstance Use Lead, GUM/HIVSexual Health & HIV Care | 56 Dean Street, London

o BBC News, Evening Standard, Wikipedia, etc

o And a bit of reading …

Mephedroneo Mephedrone is a synthetic stimulant drug of the amphetamine and

cathinone classes

o Slang names include drone, M-CAT, and meow meow

o Chemically similar to the cathinone compounds found in the khat plant of eastern Africa

o Tablets or powder can be swallowed, snorted or injected, producing similar effects to MDMA, amphetamines and cocaine

o Metabolised by three phase I pathways (involving CYP2D6)

Mephedrone metabolismo Metabolised by three phase I pathways (involving CYP2D6): demethylated to the

primary amine (producing compounds 2, 3 and 5), the ketone group can be reduced(producing 3) or the tolyl group can be oxidised (producing 6). Both 5 and 6 are thought to be further metabolised by conjugation to the glucuronide and sulfate derivatives

Meyer et al 2010

MDMA

o 3,4-methylenedioxy-N-methylamphetamine is an empathogenic drug of the phenethylamine and amphetamine class

o Ecstasyo Eo Xo XTCo Mandy/Molly (w/out adulterants = cutting agents)

MDMA

o Metabolized by CYP2D6 and 3A4 (30%)

o Rumours:

o One published case of fatal interaction between ritonavir and MDMA [Henry et al. The Lancet 1998]

… give me some of your HIV drugs because I want to feel

higher …

Fatal MDMA intoxicationDr Matthias Schwab, Eva Seyringer, Robert B Brauer, Achim Hellinger, Ernst-Ulrich GrieseSirEntactogens represents a class of psychoactive synthetic compounds abused as recreational designer drugs, for example MDMA, methylene-dioxyethylamphetamine (MDE), or 3,4-methylenedioxyamphetamine (MDA). Originally these drugs were regarded as being “safe”, but an increasing number of severe adverse effects and even deaths have been reported, such as the report by J A Henry and I R Hill.1 Additionally, several cases of MDMA-induced hepatic damage requiring subsequent liver transplantation have been described.2, 3The responsible underlying mechanism is still unclear. One possible explanation is that deficiency in cytochrome P4502D6 (CYP2D6) expression could be a genetic factor that predisposes to an increased risk of MDMA-related toxic effects due to an accumulation of MDMA or MDMA-related drugs. In-vitro studies have shown that demethylenation of MDMA, MDA, and MDE is a major metabolic pathway catalysed by the CYP2D6 enzyme.4 This enzyme exhibits a genetic polymorphism with 7—10% of white people expressing no functional enzyme (poor metaboliser).5

The Lancet, Volume 353, February 1999

The Lancet, Volume 353, February 1999

EDASILDENAFILEffect of ritonavir (500 mg BD) on a single dose of sildenafil (100 mg) investigated in 28 healthy volunteers and caused an approximate 11-fold increase in sildenafil exposure (122).

TADALAFILNormally administered at 2.5 mg to 10 mg according to frequency of use, longer half-life (~ 17.5 h). Coadministration 20 mg single dose and ritonavir (200 mg BD) resulted in a 124% increase in tadalafil exposure.

VARDENAFILMost potent EDA normally at dose of 10 mg, rapidly absorbed, half-life of ~ 4 hours. Co-administration of 5 mg single dose and ritonavir (600 mg BD) increased vardenafil AUC by 49-fold and Cmin by 13-fold (125).

All metabolized by CYP3A4

Specific Drug SPCs

Diazepam and:

Ritonavir: contraindicated as co-administration likely to increase plasma concentrations of diazepam, increasing risk of extreme sedation and respiratory depression

Cobicistat: not studied; concentrations may be increased when co-administered with cobicistat; dose reduction may be necessary and concentration monitoring recommended

BZD

Novel Psychoactive Treatment UK Network; NEPTUNE

Guidance on the management of acute and chronic harms of club drugs and novel psychoactive substances

Acknowledgements

• David Stuart• Paul, Steve, Lukas, and Marc• Nneka Nwokolo• Tristan Barber• Saye Khoo• David Back• Owen Bowden Jones• Dima Abdulrahim• Margherita Bracchi