Cocaine cardiotoxicity

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Cocaine cardiotoxicity
Robertas Badaras Vilnius Toxicology Clinic 2004
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Coca leaf (Erythroxylon coca)
Coca leaves have been chewed by South American
Indians for many thousands of years to induce a
mild and long-lasting euphoria. Cocaine is
prepared from the leaves of the plant
Erythroxylon coca, and is available as cocaine
hydrochloride (a water-soluble powder) and as
"freebase" or "crack" cocaine (heat stable,
melting at high temperatures, thus allowing it to
be smoked)
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1519 to Europe!
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History of use I

• 1596 - cocaine use in medicine was introduced by
  Spanish physicians
• 1859 - A. Nieman crystallized cocaine
• 1861 Merck started commercial production of
  cocaine

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History of use II

• Vin Mariani - 1863

History of use I
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History of use III

• In 1884, William Stewart Halsted performed the
  first nerve block using cocaine as the
  anesthetic. Subsequently, Halsted became the
  first cocaine-addicted physician on record.

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History of use IV

• That same year, Sigmund Freud published the essay
  "Uber Coca," in which he advocated the use of
  cocaine in the treatment of asthma, wasting
  diseases, and syphilis. As with Halsted, Freud
  also fell prey to cocaine dependency

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History of use V

• In the 19th century there was an official
  exhibition of the products containing cocaine IN
  USA ( about 15 products )

In 1885 was stated the production of
Pembertons French Wine Cola, which later was
renamed Coca Cola. But in 1906 the addition of
cocaine to the drink was stopped
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History of use VI

• In 1893 for the first time 6 cases of cocaine
  related deaths were reported in Lancet
• In 1914 in USA Harison introduced a law
  prohibiting the sale of cocaine

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Cocaine in USA

• Cocaine use in the United States has been
  reported to be as high as 5 million regular
  users, with as many as 30 million with a history
  of past use.
• In 2001
• 5 of population in the age group of 18 -45 years
  used cocaine regularly
• Substance Abuse and Mental Health Services
  Administration, 2001

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Kokainas JAV - mirtys

Regular cocaine use was associated with an
increased likelihood of MI in younger patients.
Approximately 1 of every 4 nonfatal MIs in
persons aged 18 to 45 years was attributable to
frequent cocaine use in this survey. Behavior
modification by public awareness and education
may reduce the cardiovascular morbidity
associated with cocaine use. Qureshi AI, Suri
FK, Guterman LR, et al. Circulation. 2001
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Cocaine and athletics I
Former Tour de France winner Marco Pantani (the
Pirate) was found dead in the Italian seaside
resort of Rimini
"The death of Marco Pantani was caused by acute
cocaine intoxication Dr.Giuseppe Fortuni
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Cocaine and athletics II

• When you hear about an athlete dying suddenly
  and the autopsy reports that he had a heart
  attack with multiple necrotic areas in the heart
  and dilated cardiomyopathy, think of cocaine.
• (Keller DJ, Todd GL. International Journal of
  Cardiology, 1994)

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Cocaine and Bulgaria
?
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Pupils favorite drugs in Lithuania - 1999
Cocaine Lithuania
ESPAD 99 tinvestigation
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Pupils favorite drugs in Lithuania -2003
ESPAD 03 tyrimo duomenys
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Drugs price in Lithuania (Lt)
Kriminalines policijos biuro ONTT Narkotiku
kontroles valdybos duomenys
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Toxicodynamic

• In the Preganglian nerve endings the reuptake
  of neuromediators is reduced
• Of noradrenalin, adrenalin (excess of
  catecholamines enlarge adrenergic stimuliation
  of ? recetors leading to vazokonstriktion ir
  hipertention, there is also a partial stimulation
  of ? adrenergic receptors)
• Serotonin (SSRI efekt)
• dopamin

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Inhibition of reuptake
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Interaction with another substance of abuse

• Use of cocaine together with alcohol leads to the
  production of cocaethylene, 20 times more toxic
  than cocaine alone
• Use of cocaine together with nicotine, doubles
  vasoconstriction and hypertension leading to
  increased risk of MI and other complications

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Possible Mechanisms of Cardiovascular
Complications of Cocaine
Cocaine
Membrane stabilization
Adrenergic Effects
Platelet aggregation
Direct Toxicity
Coronary Spasm
Myiocarditis, Focal Necrosis, Contraction Band
Necrosis
? Myocardial O2 Demand
Coronary Thrombosis
Arrhytmias
Cardiomiopathy
Myocardial Infarction
Myocardial Ishaemia
Adapted from Isner JM, Choski SK. Curr Probl
Cardiol 1991 m.
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Acute cocaine effects
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Cocaine and Myocardial Infarction

• People using cocaine are mainly hospitalized for
  cardiovascular diseases. The most frequent among
  them is acute MI.
• CAMI (Cocaine Associated Myocardial Infarction)
  study ( 136 cocaine related acute MI cases).
  Median age 38 yrs, 88 were using cocaine over
  the preceeding 24 hrs.
• Determinants of Myocardial Infarction Onset Study
  (3946 patients) risk for MI within 1 hour of
  cocaine use rises 23,7 time

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Cocaine and Myocarial Ischaemia

• Platelet aggregation increases in vitro (autopsy
  a lot of new thrombi rich in platelets both in
  healthy and atherosclerotic vessels)
• Increases Oxygen requirements of the myocardium
• Vasospasm (endothel1 concentration increases
  leading to ? receptor stimulation)
• Hyperplasia of intima in young patients
• The risk of MI dose not depend on the cocaine
  dose, route of adminsitration or frequency of
  use. In 33 of cocaine patients no pathology is
  visible by angiography

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Cocaine effects on coronary arteries
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Cocaine induced arhythmias
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Aritmiju atsiradimo mechanizmai

• Tiesioginis toksinis miokardo paeidimas
  daugybiniai miokardito idiniai, mikroidinine
  fibroze, kontraktiliniu skaidulu nekroze
• Autoreguliacijos mechanizmu sutrikimas del
  padidejusios neuromediatoriu koncentracijos
• Tiesioginis intraskilvelinio laidumo suletejimas
• Iemijos indukuoti laidumo sutrikimai
• Gritamojo sujaudinimo (reentry) mechanizmas

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Aortos disekacija

• Reta komplikacija
• Aortos disekacijos ar plyimo galimybe turi buti
  ivertinta, diagnozavus su kokaino vartojimu
  susijusi krutines skausma
• Galima prieastis - enklus AKS pakilimas
• Apraomi mikotiniu ir intracerebriniu aneurizmu
  plyimai

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Letiniai kokaino efektai
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Miokarditas ir kardiomiopatija

• Miokarditas kokaino vartotojams pasireikia 5
  kartus daniau, isivystymo mechanizmas dar nera
  visikai aikus, manoma, kad jis yra
  mikrovaskulinio paeidimo rezultatas
• Tranzitorine toksine kardiomiopatija isivysto
  del neigiamo inotropinio poveikio i irdies
  raumeni
• Retai nustatoma (nepakankama diagnostika?)

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Endokarditas

• Atsiranda daniau, nei kitus narkotikus
  vartojantiems asmenims
• kokaino imunosupresinis poveikis
• votuvu ir kraujagysliu paeidimas del
  padidejusiu AKS ir SD
• Daniau paeidia kairiosios irdies votuvus

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Diferencine diagnostika I

• Nemaa dalis apsinuodijimu kokainu net stacionare
  taip ir nediagnozuojami, nes
• nukenteje asmenys linke slepti anamneze
• sunku rutinikai nustatyti biologinese terpese
• klinika simuliuoja kitas patologijas

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Diferencine diagnostika II

• Umini apsinuodijima kokainu galima itarti esant
• euforijai, stipriam sujaudinimui, reciau -
  psichozei
• apsunkintam kvepavimui, krutines skausmui
• kraujavimui i nosies
• staiga prasidejus traukuliams
• sunkiai koreguojamai hipertermijai
• Gretutiniai kokaino vartojimo sukelti susirgimai
• tromboembolija, plauciu infarktas
• galvos smegenu infarktas, TIA
• ieminiai odos pakitimai
• nosies gleivines ar net pertvaros defektai

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Diferencine diagnostika III

• Tikslia kokaino sukelto MI diagnostika apsunkina
• EKG pakitimai galimi 56-84 krutines skausmu po
  kokaino vartojimo besiskundianciu pacientu, net
  jei jie neserga MI
• 43 kokaino vartotoju EKG pakitimai imituoja
  umini MI
• Serumo kreatinkinaze nera patikimas ymuo, jis
  pakiles madaug pusei kokaino vartotoju
  (vertinamas troponinas)
• Kokybinis testas bei kiekybiniai laboratoriniai
  tyrimai

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Kokainui budinga klinika

• I faze ankstyva stimuliacija
• CNS midriaze, galvos skausmas, svaigimas,
  vemimas, tremoras
• Kraujotaka hipertenzija, tachikardija ar
  bradikardija, blykumas
• Kvepavimas padideje danis ir turis
• Termoreguliacija hipertermija
• Elgesys euforija, baimingumas, nuovargio
  nebuvimas
• II faze velyva stimuliacija
• CNS encefalopatija, generalizuoti traukuliai
• Kraujotaka hipertenzija, tachikardija,
  aritmijos
• Kvepavimas tachipneja, dusulys, nereguliarus
  kvepavimas
• Termoreguliacija sunki hipertermija
• III faze slopinimas ir agonija
• CNS koma, arefleksija, platus fiksuoti
  vyzdiai, paralyius
• Kraujotaka irdies sustojimas (skilveliu
  virpejimas ar asistolija)
• Kvepavimas plauciu edema, agonikas kvepavimas

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Pagal Vilniaus toksikologijos klinika.
Standartizuotas apsvaigimo ivertinimas 2003
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Gydymo ypatumai I

• VISI kokainu apsinuodije pacientai turi buti
  gydomi ir pastoviai monitoruojami ITP
• Gyvybiniu funkciju stabilizavimas ir palaikymas
• Pirmoji pagalba
• Oksigenoterapija
• BZD (diazepamas) - tik i/v 5-10 mg, kartojant po
  5 min. iki efekto
• Hipertermija gydoma iorinemis aldymo
  priemonemis
• Koreguojami V-E, -R balanso sutrikimai,
  hipoglikemija
• Skrandio plovimas ir enterosorbcija tikslinga
  tik esant masyviam peroraliniam apsinuodijimui
  (body packing fenomenas)

Sujaudinimas apsunkina pagalbos teikima!
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Gydymo ypatumai II

• Nitratai sumaina kokaino sukelta
  vazokonstrikcija tiek aterosklerozinese, tiek
  sveikose VA
• Antrojo pasirinkimo vaistas vazokonstrikcijos
  korekcijai yra ? antagonistas fentolaminas
• Kontraindikuotinas neselektyviu ? blokatoriu
  skyrimas del nekontroliuojamos ? receptoriu
  aktyvacijos galima nekoreguojama hipertenzija ir
  VA vazokonstrikcija
• Kai kurie autoriai rekomenduoja esmololi,
  selektyvu ?1 blokatoriu, tachikardijai ir
  hipertenzijai koreguoti
• Skiriamos tik maos morfino dozes (2-8 mg i/v)

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Recommendations of the American Heart Association
for the treatment of Cocaine related Myocardial
ishaemia or Infarction

• Second-line agents
• Verapamil
• Phentolamin
• Thrombolytic agent or primary angioplasty (after
  demonstration by arteriography of an occluded
  coronary artery)
• Agents to be avoided Propranolol

• First-line agents
• Oxygen
• Aspirin
• Nitroglycerin
• Benzodiazepines
• Guidelines 2000

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Ivados I

• Kokaino vartojimas gali sukelti sunkias, net
  mirtinas kardiovaskulines komplikacijas
• Kardiotoksinio veikimo mechanizmai nera pilnai
  aikus
• Augantis kokaino vartojimas susijes su
  padidejusiu komplikaciju kiekiu, padanejusia
  hospitalizacija, didejanciu mirtamumu

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Ivados II

• Gydymas ilieka problematikas, nes neatliekamos
  prospektyvines, randomizuotos studijos.
  Tikslinga
• BZD slopina kokaino efektus CNS ir
  kardiovaskulinei sistemai, maindami sujaudinima,
  AKS bei SD
• Antitrombotine terapija aspirinu yra
  pateisinama, jei nera kontraindikaciju, nors nera
  tai patvirtinanciu tyrimu
• Siekiant slopinti iemijos sukelta skausma bei
  paalinti kokaino sukelta VA spazma, gali buti
  skiriami nitratai
• Tolesniu isamiu tyrimu galimybe labai riboja
  etiniai motyvai bei pacientu nenoras bendrauti su
  tyrejais

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Ivados III

• Kokaino vartojimo komplikaciju galimybe turi buti
  rimtai svarstoma visiems jauniems pacientams,
  turintiems maa kardiologiniu komplikaciju
  rizika, bet sergantiems uminiu MI, diliatacine
  kardiomiopatija, miokarditais bei ivairiomis
  aritmijomis