The drugs of abuse etc which killed Jacko

1. CASE STUDY 1- THE
DEATH OF MICHAEL
JACKSONUmara Malik, Katy James, Tom Lewis, Nia Parry & Alex Ratcliffe.

2. Introduction:
Michael Jackson’s death was ruled a homicide by the Los Angeles
county coroner’s office.
The singer suffered a cardiac arrest at his Los Angeles home.
An official at the coroners office said a fatal combination of the drugs
were given to Jackson hours before he died.
Propofol & Lorazepam were the “ Primary drugs responsible for Mr.
Jacksons death” But a cocktail of other drugs including: Diazepam,
Midazolam, Lidocaine and Meperidine - were also detected in his
system.

3. Timeline of Drugs Leading up to Michael Jackson’s Death
6 weeks prior...
Jackson's personal physician, Dr. Conrad Murray, told LAPD detectives that he had
been treating the singer for insomnia for about six weeks, and had been giving
Jackson propofol every night (50 mg, i.v.). Dr Murray told police that he
subsequently reduced the singer's dose of propofol to 25 mg per night, with the
addition of lorazepam and midazolam.
2 days before death...

4. Lorazepam
Routinely prescribed anxiolytic for individuals
with psychosocial stress.
Trigger the egress of inflammatory myeloid
progenitor cells such as CD11b+.
Lorazepam lipid solubility suggests a lower
risk of amnesic side effects. (Modell et al,
1985)
Potential side effects at high doses: coronary
vasodilation and neuromuscular
blockade. (Mohler, 2012)
At 2am and 5am 2mg doses of Lorazepam were administered intravenously...
In the central nervous system Lorazepam
Binds to Gamma-Aminobutyric acid A.
On GABA-A Lorazepam binds to central
benzodidzepam binding site (CBBS).
(Ramirez et al, 2017)
Lorazepam binds to form a
conformational change in the receptor
structure as well as the chloride channel.
Hyperpolarisation causes an inhibitory
effect of the GABA throughout the
central nervous system. (Griffin et al,
2013)
Figure 1_ (Griffin
et al., 2013)

5. Valium and Midazolam were administered intravenously...
•
Formed of:
•2 Alpha subunits
•2 Beta subunits
•1 Gamma subunit
Figure 2.
(Griffin, Kaye & Bueno, 2013)
Two days before
death Valium was
administered
orally.
Valium was again
administered
orally at 1:30am
on the day of
death.
Midazolam was
administered
intravenously at
3am and 7:30am.

6. Cocaine (benzoyl-methyl-ecgonine) is an alkaloid.
Cocaine binds differentially to the dopamine, serotonin
and norepinephrine transporter proteins forming a
complex to prevent re-uptake (Rotham et al 2000).
Dopamine, serotonin and norepinephrine accumulates
in the synaptic cleft, which activates the postsynaptic
dopamine receptor (Jonkman et al 2013).
Cocaine produces anaesthesia by inhibiting excitation
of nerve endings, by reversibly binding to and
inactivating sodium channels.
Cocaine interactions with Lorazepam...
Figure 3.Chemical structure
of cocaine.
Image retrieved from:
https://pubchem.ncbi.nlm.nih.gov/compoun
d/Cocaine#section=Structures

7. Lorazepam
A drug of the benzodiazepine
group, used especially to treat
anxiety.
Lorazepam hyperpolarizes GABA-A
causing an inhibitory effect of the
GABA throughout the central
nervous system. (Griffin et al,
2013).
Physiological effects: Lower heart
rate, sedative effects, muscle
relaxant, anti-anxiety, and amnesic
effects.
Cocaine interactions with Lorazepam...
Cocaine
An illegal stimulant and sometimes medicinally as a local anaesthetic.
Cocaine has an excitatory effect on the Mesocorticolimbic dopamine
pathway in the CNS.
Physiological effects: constricted blood vessels; dilated pupils; and
increased body temperature, heart rate, blood pressure, erratic, and
violent behavior, restlessness, irritability, anxiety, panic, and paranoia
(Schwartz et al 2010).

8. Cocaine interactions with Lorazepam...
Figure 4- Acute effects of cocaine.
Cocaine affects the cardiovascular system
through 2 major pathways: increased
sympathetic output and a local
anesthetic effect (Schwartz et al 2010)

9. Propofol binds to GABA-A receptor, opening
the chloride channels and allowing chloride
ions to enter the cell.
The duration of GABA activated chloride
channels is increased.
There is hyperpolarization of the cell
membranes and a reduction of the activity of
neuron, by inhibiting the post synaptic
membrane. (Jenkins, 2010).
Routinely prescribed anxiolytic for individuals with
psychosocial stress (Xu et al, 2011)
GABA agonist, anesthetic and leads to unconsciousness
(Lee et al, 2018)
Side effects: cardiopulmonary physiology, for example
hypoventilation, hypotension, apnoea and the loss of
reflexes within the airways. (Jevtovic-Todorovic et al, 2003)
Figure 5.
Chemical structure of Propofol
(Kotani et al, 2008)
At 10:40am 25mg Propofol with lidocaine was given intravenolusly …,,..

10. Dr Murray reduced the dose of Propofol to 25mg and added Lorazepam
Propofol inhibits NMDA subtype of glutamate receptor.
Propofol and Lorazepam combined effect is synergistic. (Orser et al,
1995)
Dosage reduced because there's a risk of: hypertriglyceridaemia
(Carraso et al, 1993), pancreatitis (Possidente et al, 1998), delayed
seizures, haemodynamic impairment (Islander & Vinge, 2000) and
severe protracted metabolic acidosis. (Perrier, Baerga-Varela & Murray,
2000).
Lorazepam- moderate half-life, aid prevention of seizures, fewer side
effects of withdrawal of Propofol.(Ritson & Chick, 1986). Combined is
safe and controls symptoms from withdrawal.
At 10:40am 25mg Propofol with lidocaine was given intravenolusly …,,..

11. Dr Murray diluted propofol with lidocaine as it is used to reduce pain
associated with propofol injection.
Propofol is a phenol and causes skin and mucous membrane irritation
on administration (Tan & Onsiong 2002)
Klement and Arndt (1991) suggested pain is related to the
concentration of propofol.
The addition of lidocaine to propofol causes destabilisation of the
emulsion and reduces anaesthetic efficacy (Gersonde et al 2017).
At 10:40am 25mg Propofol with lidocaine was given intravenolusly …,,..

12. y
Lidocaine is a local anaesthetic and the molecular targets are
voltage-gated sodium channels (Cummins 2007).
Acts as a nerve blockade by stabilising neuronal membranes by
inhibiting ionic fluxes required for the initiation and conduction of
impulses (Fozzard et al 2011).
Lidocaine agents bind to sodium ion channels and become ionised
(cations).
Lidocaine cations then then bind to the inside pore of sodium channels
(Sheets & Hanck 2003) and preventing nerve depolarisation.
No pain signals generated.
At 10:40am 25mg Propofol with lidocaine was given intravenolusly …,,..

13. Voltage-gated sodium channels are composed of an alpha subunit of
260 kDa associated with beta subunits of 33-36 kDa (Fozzard et al 2011).
Alpha subunits have four homologous domains (I to IV) containing six
transmembrane alpha helices (S1-S6) (Fozzard et al 2011).
The S4 segments serve as voltage sensors and move outward to initiate
activation (Catterall et al 2019).
The S5 and S6 segments and the short membrane-associated loops
between them form the pore (Catterall et al 2019).
At 10:40am 25mg Propofol with lidocaine was given intravenolusly …,,..
Figure 6: Voltage-gated sodium
channels
(Catterall et al 2019)
Available from:
https://doi.org/10.2218/gtopdb/F82/
2019.4.

14. Flumazenil reverses the toxic pharmacological effects of
benzodiazepine overdose.
Acting by competitive inhibition, flumazenil binds to extracellular
surface of GABA-A receptors displacing and preventing further binding
of benzodiazepine molecules (An & Godwin 2016) (Sivilotti 2016).
This inhibits their ability to produce sedation, impaired cognitive
function, reduced muscle coordination and anaesthesia.
Sudden antagonism of benzodiazepine effects may unmask convulsant
activity of other drugs taken at the time (Braitberg 2017).
Nor does it reverse the effects of propofol and opioids (Sivilotti 2016).
Following the last dose of propofol, the Dr administered 0.2mg of flumazenil intravenously...
Figure 7. Flumazenil competitively
binding to the GABA receptor at
the same location as
benzodiazepines.
(Katzung & Trevor 2015)

15. Demerol and the opioid receptors
Fast-acting synthetic opioid analgesic.
Agonist action at opiate receptors (predominantly µ type receptors)
(Livertox, 2012).
Binds to and depresses opiate receptors in the spinal cord and CNS,
altering perception of and response to pain.
Opioid receptors mediate neuronal inhibition
Belong to the G protein-coupled receptor family
Extracellular N-terminus
7 transmembrane helical twists
3 extracellular & intracellular loops
Intracellular C-terminus
Figure 8 (McDonald & Lambert, 2015)
The seven transmembrane structure of opioid
G-protein-coupled-receptors and the intracellular changes
occurring following the binding of an opioid agonist.
Demerol was reported to have been found in Jackson’s body at the time
of his death…

16. Intracellular signalling mechanism of Demerol
Opioid receptors signal via a second messenger (cyclic AMP) or an ion
channel (K+) (Inturrisi, 2002).
Binding causes a conformational change that triggers signalling via
guanine nucleotide-binding proteins and modulates the activity of
down-stream effectors such as adenylate cyclase (Pathan & Williams, 2012).
Signalling leads to the inhibition of adenylate cyclase activity thus
reduced cAMP levels (McDonald & Lambert, 2016).
Hyperpolarisation of the cell.
The release of nociceptive neurotransmitters such as substance P, GABA,
dopamine, acetylcholine and noradrenaline is inhibited (Johnson & Lambert,
2002).
Figure 9 (McDonald & Lambert, 2015)
The seven transmembrane structure of opioid
G-protein-coupled-receptors and the intracellular changes
occurring following the binding of an opioid agonist.
Demerol was reported to have been found in Jackson’s body at the time
of his death…

17. Conclusion...
We have come to the conclusion that Michael suffered cardiac arrest due to the combination of drugs in his
body, with the most significant drugs being the anaesthetic propofol and the anxiolytic lorazepam.
Although it was not reported, we can suggest that Michael Jackson was also taking cocaine. This drug
increases the potency of lorazepam and can mask the side effects of the benzodiazepines administered. In
response to this, Dr. Murray continued to administer these drugs to Michael when the first administration
would still be present in his body.
In addition, adverse side effects of benzodiazepines can become present when administered with other
drugs. The suggested use of opioids (Demerol) can increase the significance of cardiovascular effects.
Similarly, lidocaine inhibits the ionic fluxes required for the initiation and conduction of electrical action
potential impulses necessary to facilitate muscle contraction i.e. the heart. Subsequently, in cardiac myocytes,
lidocaine can block or slow the rise of cardiac action potentials and their associated cardiac myocyte
contractions, resulting in possible effects leading to cardiac arrest.