Materials preparation to the practical classes

for the students of pharmaceutical faculty

LESSON № 21

Theme 29. Condensed heterocyclic systems. Purine. Notion about alkaloids.

In addition to these three diazines, the bicyclic tetraaza compound, purine, is an important heterocyclic system.

Purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle iature. Purines and pyrimidines make up the two groups of nitrogenous bases, including the two groups of nucleotide bases. Notable purines.

 

Method of receiving

 

 

 

 

Chemical properties of purine.

Purine is an amphoteric compound

Derivatives of purine

These ring systems, particularly that of pyrimidine, occur commonly in natural products. The pyrimidines, cytosine, thymine, and uracil are especially important because they are components of nucleic acids, as are the purine derivatives adenine and guanine.

   

The рurine nucleus also occurs in such compounds as caffeine (coffee and tea) and theobromine (cacao beans).

Uric acid is colorless crystal compound, bad soluble in water, ethanol and ether, soluble in dilute base solutions and glycerin. Uric acid is dibases acid.

Ø Uric acid (or urate) is an organic compound of carbon, nitrogen, oxygen and hydrogen with the formula C5H4N4O3. Uric acid is produced by xanthine oxidase from xanthine and hypoxanthine, which in turn are produced from purine. Uric acid is more toxic to tissues than either xanthine or hypoxanthine.

Ø In humans and higher primates, uric acid is the final oxidation (breakdown) product of purine metabolism and is excreted in urine. In most other mammals, the enzyme uricase further oxidizes uric acid to allantoin. The loss of uricase in higher primates parallels the similar loss of the ability to synthesize ascorbic acid. Both uric acid and ascorbic acid are strong reducing agents (electron donors) and potent antioxidants. In humans, over half the antioxidant capacity of blood plasma comes from uric acid.

Ø Salts of uric acid called urats. Urats is bad soluble in water, except  salts with litium (Li).

Ø In hydroxyform uric acid gives reactions of nucleophilic substitutions.

Murexidne’s reaction is the qualitative reaction on uric acid

By heating uric acid with nitrate acid and next adding of ammonium observe purpur-violet color:

purpure acid (enole form)                                  murexide

Reactions of reduction

Pteridine (pyrazino[2,3-d]pyrimidine)

Method of getting: condensation of 4,5-diaminopyrimidins with 1,2-dicarbonile compounds.

Pteridine is light yellow crystal compound, soluble in water, ethanol, less soluble in diethyl ether and benzole. Pteridine is stable to oxidation, by acting of acids and bases pteridine cycle decompose. Gives reaction of electrophilic substitution, protonate oitrogen atom in 1 location. 

Derivatives of pteridine

Folic acid

 

7-Membered rings

Sevenmember heterocyclic ring compounds have received much attention in the past few years owing to its wide range of biological activity.

With 7-membered rings, aromatic stabilization is not available. Compounds with one heteroatom include:

Heteroatom	Saturated	Unsaturated
Nitrogen	Azepane	Azepine
Oxygen	Oxepane	Oxepine
Sulfur	Thiepane	Thiepine

Those with two heteroatoms include:

Heteroatom	Saturated	Unsaturated
Nitrogen		Diazepine
Nitrogen/sulfur		Thiazepine

Images

	Saturated			Unsaturated
Heteroatom	Nitrogen	Oxygen	Sulfur	Nitrogen	Oxygen	Sulfur
7-Ring
Name	Azepane	Oxepane	Thiepane	Azepine	Oxepine	Thiepine
Structure

       Alkaloids

Alkaloids are naturally occurring chemical compounds containing basic nitrogen atoms. The name derives from the word alkaline and was used to describe any nitrogen-containing base. Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants, and animals and are part of the group of natural products (also called secondary metabolites). Many alkaloids can be purified from crude extracts by acid-base extraction. Many alkaloids are toxic to other organisms. They often have pharmacological effects and are used as medications and recreational drugs. Examples are the local anesthetic and stimulant cocaine, the stimulant caffeine, nicotine, the analgesic morphine, or the antimalarial drug quinine. Some alkaloids have a bitter taste.

Alkaloid classifications

Alkaloids are usually classified by their common molecular precursors, based on the metabolic pathway used to construct the molecule. Wheot much was known about the biosynthesis of alkaloids, they were grouped under the names of known compounds, even some non-nitrogenous ones (since those molecules’ structures appear in the finished product; the opium alkaloids are sometimes called “phenanthrenes”, for example), or by the plants or animals they were isolated from. When more is learned about a certain alkaloid, the grouping is changed to reflect the new knowledge, usually taking the name of a biologically-important amine that stands out in the synthesis process.

• Pyridine group: piperine, coniine, trigonelline, arecoline, arecaidine, guvacine, cytisine, lobeline, nicotine, anabasine, sparteine, pelletierine.

• Pyrrolidine group: hygrine, cuscohygrine, nicotine

• Tropane group: atropine, cocaine, ecgonine, scopolamine, catuabine

• Quinoline group: quinine, quinidine, dihydroquinine, dihydroquinidine, strychnine, brucine, veratrine, cevadine

• Isoquinoline group: opium alkaloids (papaverine, narcotine, narceine), sanguinarine, hydrastine, berberine, emetine, berbamine, oxyacanthine

• Phenanthrene alkaloids: opium alkaloids (morphine, codeine, thebaine)

• Phenethylamine group: mescaline, ephedrine, dopamine

• Indole group:

• Tryptamines: serotonin, DMT, 5-MeO-DMT, bufotenine, psilocybin

• Ergolines (the ergot alkaloids): ergine, ergotamine, lysergic acid

• Beta-carbolines: harmine, harmaline, tetrahydroharmine

• Yohimbans: reserpine, yohimbine

• Vinca alkaloids: vinblastine, vincristine

• Kratom (Mitragyna speciosa) alkaloids: mitragynine, 7-hydroxymitragynine

• Tabernanthe iboga alkaloids: ibogaine, voacangine, coronaridine

•  Strychnos nux-vomica alkaloids: strychnine, brucine

•  Purine group:

•  Xanthines: caffeine, theobromine, theophylline

4.Classification of alkaloids.

5. Alkaloids group of pyridine and piperine (nicotine, anabasine, lobeline);

6. Alkaloids group of quinoline (quinine);

7. Alkaloids of group of quinoline and phenanthreneisoquinoline (papaverine, morphine, codeine);

8. Alkaloids group of purinu (caffeine, theobromine, theophylline);

9. Alkaloids group of tropane (atropine, scopolamine, cocaine);

10. Alkaloids group of indole (reserpine, strychnine).

 Physicochemical properties

Low-molecular weight alkaloids without hydrogen bond donors such as hydroxy groups are often liquid at room temperature, examples are nicotine, sparteine, coniine, and phenethylamine.

The basicity of alkaloids depends on the lone pairs of electrons on their nitrogen atoms. As organic bases, alkaloids form salts with mineral acids such as hydrochloric acid and sulfuric acid and organic acids such as tartaric acid or maleic acid. These salts are usually more water-soluble than their free base form.

Nicotine
Systematic (IUPAC) name 3-[(2S)-1-methylpyrrolidin-2-yl]pyridine
Identifiers
CAS number	54-11-5
ATC code	N07BA01
PubChem	942
ChemSpider	80863
Chemical data
Formula	C10H14N2

 

Nicotine

Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae) which constitutes approximately 0.6–3.0% of dry weight of tobacco, with biosynthesis taking place in the roots, and accumulating in the leaves. It functions as an antiherbivore chemical with particular specificity to insects; therefore nicotine was widely used as an insecticide in the past, and currently nicotine analogs such as imidacloprid continue to be widely used.

History and name

Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after Jean Nicot de Villemain, French ambassador in Portugal, who sent tobacco and seeds from Brazil to Paris in 1560 and promoted their medicinal use. Nicotine was first isolated from the tobacco plant in 1828 by German chemists Posselt & Reimann.  Its chemical empirical formula was described by Melsens in 1843, its structure was discovered by Adolf Pinner in 1893, and it was first synthesized by A. Pictet and Crepieux in 1904.

Chemistry

Nicotine is a hygroscopic, oily liquid that is miscible with water in its base form. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble. Nicotine easily penetrates the skin. As shown by the physical data, free base nicotine will burn at a temperature below its boiling point, and its vapors will combust at 308 K (35 °C; 95 °F) in air despite a low vapor pressure. Because of this, most of the nicotine is burned when a cigarette is smoked; however, enough is inhaled to provide the desired effects. The amount of nicotine inhaled with tobacco smoke is a fraction of the amount contained in the tobacco leaves.

 Pharmacology

 Pharmacokinetics

As nicotine enters the body, it is distributed quickly through the bloodstream and can cross the blood-brain barrier. On average it takes about seven seconds for the substance to reach the brain when inhaled. The half life of nicotine in the body is around two hours. The amount of nicotine absorbed by the body from smoking depends on many factors, including the type of tobacco, whether the smoke is inhaled, and whether a filter is used. For chewing tobacco, dipping tobacco and snuff, which are held in the mouth between the lip and gum, or taken in the nose, the amount released into the body tends to be much greater than smoked tobacco. Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine.

 Pharmacodynamics

Nicotine acts on the nicotinic acetylcholine receptors, specifically the ganglion type nicotinic receptor and one CNS nicotinic receptor. The former is present in the adrenal medulla and elsewhere, while the latter is present in the central nervous system (CNS). In small concentrations, nicotine increases the activity of these receptors. Nicotine also has effects on a variety of other neurotransmitters through less direct mechanisms.

In CNS

By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters – acting as a sort of “volume control”. It is thought that the increased levels of dopamine in the reward circuits of the brain is what is responsible for the euphoria and relaxation and eventual addiction caused by nicotine consumption.

Tobacco smoke contains the monoamine oxidase inhibitors harman and norharman, and significantly decreases MAO activity in smokers. MAO enzymes break down monoaminergic neurotransmitters such as dopamine, norepinephrine, and serotonin.

Chronic nicotine exposure via tobacco smoking up-regulates alpha4beta2* nAChR in cerebellum and brainstem regions but not habenulopeduncular structures.

 In PNS

Nicotine also activates the sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulates the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts oicotinic acetylcholine receptors, causing the release of epinephrine (and norepinephrine) into the bloodstream.

 In adrenal medulla

By binding to ganglion type nicotinic receptors in the adrenal medulla nicotine increases flow of adrenaline (epinephrine), a stimulating hormone. By binding to the receptors, it causes cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream. The release of epinephrine (adrenaline) causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels. Cotinine is a byproduct of the metabolism of nicotine which remains in the blood for up to 48 hours. It can therefore be used as an indicator of a person’s exposure to smoke.

Anabasine is a pyridine alkaloid found in the Tree Tobacco (Nicotiana glauca) plant, a close relative of the common tobacco plant (Nicotiana tabacum). It is similar to nicotine. Its principal (historical) industrial use is as an insecticide. Anabasine is present in trace amounts in tobacco smoke, and can be used as an indicator of a person’s exposure to tobacco smoke.

Pharmacology

Anabasine is a nicotinic acetylcholine receptor agonist. In high doses, it produces a depolarizing block of nerve transmission, which can cause symptoms similar to those of nicotine poisoning and, ultimately, death by asystole.  In larger amounts it is thought to be teratogenic in swine.

Anabasine

 

 

Lobeline is a natural alkaloid found in “Indian tobacco” (Lobelia inflata), “Devil’s tobacco” (Lobelia tupa), “cardinal flower” (Lobelia cardinalis), “great lobelia” (Lobelia siphilitica), and Hippobroma longiflora. In its pure form it is a white amorphous powder which is freely soluble in water. Lobeline has been used as a smoking cessation aid, and may have application in the treatment of other drug addictions such as addiction to amphetamines or cocaine.

Lobeline has multiple mechanisms of action, acting as a VMAT2 ligand,  which stimulates dopamine release to a moderate extent when administered alone, but reduces the dopamine release caused by methamphetamine. It also inhibits the reuptake of dopamine and serotonin,  and acts as a mixed agonist-antagonist at nicotinic acetylcholine receptors and an antagonist at μ-opioid receptors.

 

 

 

 

 

 

 

Quinine

Systematic (IUPAC) name (R)-(6-methoxyquinolin-4-yl)((2S,4S,8R)- 8-vinylquinuclidin-2-yl)methanol

Quinine is a natural white crystalline alkaloid having antipyretic (fever-reducing), antimalarial, analgesic (painkilling), and anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine.

Quinine was the first effective treatment for malaria caused by Plasmodium falciparum, appearing in therapeutics in the 17th century. It remained the antimalarial drug of choice until the 1940s, when other drugs took over. Since then, many effective antimalarials have been introduced, although quinine is still used to treat the disease in certain critical situations. Quinine is available with a prescription in the United States. Quinine is also used to treat nocturnal leg cramps and arthritis, and there have been attempts (with limited success) to treat prion diseases. It was once a popular heroin adulterant and is now not as popular in the world, although many countries (such as Scotland) still have quinine-contaminated heroin selling on the streets.

Originally discovered by the Quechua Indians of Peru, the bark of the cinchona tree was first brought to Europe by the Jesits.

Chemical structure

Quinine contains two major fused-ring systems: The aromatic quinoline and the bicyclic quinuclidine.

 History

Quinine is an effective muscle relaxant, long used by the Quechua Indians of Peru to halt shivering brought on by cold temperatures. Made from the bark of cinchona trees, the Peruvians would mix the ground up bark with sweetened water to offset the bark’s bitter taste, thus producing tonic water.

Quinine has been used in un-extracted form by Europeans since at least the early 1600s. Quinine was first used to treat malaria in Rome in 1631. During the 1600s, malaria was endemic to the swamps and marshes surrounding the city of Rome. Over time, malaria was responsible for the death of several popes, many cardinals and countless common citizens of Rome. Most of the priests trained in Rome had seen malaria victims and were familiar with the shivering brought on by the cold phase of the disease. The Jesuit brother Agostino Salumbrino (1561-1642), an apothecary by training who lived in Lima, observed the Quechua using the quinine-containing bark of the cinchona tree for that purpose. While its effect in treating malaria (and hence malaria-induced shivering) was entirely unrelated to its effect in controlling shivering from cold, it was still the correct medicine for malaria. At the first opportunity, he sent a small quantity to Rome to test in treating malaria. In the years that followed, cinchona bark became one of the most valuable commodities shipped from Peru to Europe.

The correct form of quinine best used to treat malaria was found by Charles Marie de La Condamine in 1737. Quinine was isolated and named in 1817 by French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou. The name was derived from the original Quechua (Inca) word for the cinchona tree bark, “quina” or “quina-quina”, which roughly means “bark of bark” or “holy bark”. Prior to 1820, the bark was first dried, ground to a fine powder and then mixed into a liquid (commonly wine) which was then drunk. Large scale use of quinine as a prophylaxis started around 1850.

Quinine also played a significant role in the colonization of Africa by Europeans. As the harbinger of modern pharmacology, quinine was the prime reason Africa ceased to be known as the white man’s grave. A historian has stated that “it was quinine’s efficacy that gave colonists fresh opportunities to swarm into the Gold Coast, Nigeria and other parts of west Africa”.

To maintain their monopoly on cinchona bark, Peru and surrounding countries began outlawing the exportation of cinchona seeds and saplings beginning in the early 19th century. The Dutch government persisted in their attempts to smuggle the seeds, and by the 1930s Dutch plantations in Java were producing 22 million pounds of cinchona bark, or 97% of the world’s quinine production. During World War II, Allied powers were cut off from their supply of quinine when the Germans conquered Holland and the Japanese controlled the Phillipines and Indonesia. The United States, however, had managed to obtain four million cinchona seeds from the Phillipines and begin operation of cinchona plantations in Costa Rica. It had come too late, however, and an estimated 60,000 US troops in Africa and the South Pacific died as a result of the lack of quinine.

Synthetic quinine

Cinchona trees remain the only practical source of quinine. However, under wartime pressure, research towards its artificial production was undertaken. A formal chemical synthesis was accomplished in 1944 by American chemists R.B. Woodward and W.E. Doering. Since then, several more efficient quinine total syntheses have been achieved, but none of them can compete in economic terms with isolation of the alkaloid from natural sources.

Dosing

Quinine is a basic amine and is therefore always presented as a salt. Various preparations that exist include the hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate. This makes quinine dosing very complicated, because each of the salts has a different weight.

The following amounts of each form are equal:

• quinine base 100 mg

• quinine bisulfate 169 mg

• quinine dihydrochloride 122 mg

• quinine hydrochloride 111 mg

• quinine sulfate (actually (quinine)₂H₂SO₄∙2H₂O) 121 mg

• quinine gluconate 160 mg.

All quinine salts may be given orally or intravenously (IV); quinine gluconate may also be given intramuscularly (IM) or rectally (PR). The main problem with the rectal route is that the dose can be expelled before it is completely absorbed; this can be corrected by giving a half dose again.

The IV dose of quinine is 8 mg/kg of quinine base every eight hours; the IM dose is 12.8 mg/kg of quinine base twice daily; the PR dose is 20 mg/kg of quinine base twice daily. Treatment should be given for seven days.

The preparations available in the UK are quinine sulfate (200 mg or 300 mg tablets) and quinine hydrochloride (300 mg/ml for injection). Quinine is not licensed for IM or PR use in the UK. The adult dose in the UK is 600 mg quinine dihydrochloride IV or 600 mg quinine sulfate orally every eight hours. For nocturnal leg cramps, the dosage is 200-300mg at night.

In the United States, quinine sulfate is available as 324-mg tablets under the brand name Qualaquin; the adult dose is two tablets every eight hours. There is no injectable preparation of quinine licensed in the U.S.: quinidine is used instead.

Quinine is not recommended for malaria prevention (prophylaxis) because of its side-effects and poor tolerability, not because it is ineffective. When used for prophylaxis, the dose of quinine sulfate is 300–324mg once daily, starting one week prior to travel and continuing for four weeks after returning.

Abortifacient

Despite popular belief, quinine is an ineffective abortifacient (in the US, quinine is listed as Pregnancy category C. Pregnant women who take toxic doses of quinine will suffer from renal failure before experiencing any kind of quinine-induced abortion.

Disease interactions

Quinine can cause hemolysis in G6PD deficiency, but again this risk is small and the physician should not hesitate to use quinine in patients with G6PD deficiency when there is no alternative. Quinine can also cause drug-induced immune thrombocytopenic purpura (ITP).

Quinine can cause abnormal heart rhythms and should be avoided if possible in patients with atrial fibrillation, conduction defects or heart block.

Quinine can worsen hemoglobinuria, myasthenia gravis and optic neuritis.

Hearing impairment

Some studies have related the use of quinine and hearing impairment, in particular high-frequency loss, but it has not been conclusively established whether such impairment is temporary or permanent.

Regulation by the United States Food and Drug Administration

From 1969 to 1992, the U.S. Food and Drug Administration (FDA) received 157 reports of health problems related to quinine use, including 23 which had resulted in death. In 1994, the FDA banned the use of over-the-counter (OTC) quinine as a treatment for nocturnal leg cramps. Pfizer Pharmaceuticals had been selling the brand name Legatrin for this purpose. Doctors may still prescribe quinine, but the FDA has ordered firms to stop marketing unapproved drug products containing quinine. As of 2008, pharmacists will not sell quinine even if the patient has used a prescription for it in the past. The FDA is also cautioning consumers about off-label use of quinine to treat leg cramps. Quinine is approved for treatment of malaria, but is also commonly prescribed to treat leg cramps and similar conditions. Because malaria is life-threatening, the risks associated with quinine use are considered acceptable when used to treat that condition. However, because of the drug’s risks the FDA believes it should not be used to prevent or treat leg cramps.

Non-medical uses of quinine

Tonic water, iormal light and UV.

Quinine is a flavour component of tonic water and bitter lemon. According to tradition, the bitter taste of anti-malarial quinine tonic led British colonials in India to mix it with gin, thus creating the gin and tonic cocktail, which is still popular today in many parts of the world, especially the U.K., United States, southern Canada, parts of Australia and even Lhasa, Tibet.

Bark of Remijia contains 0.5 – 2 % of quinine. The bark is cheaper than bark of Cinchona and as it has an intense taste, it is used for making tonic water. In some areas, non-medical use of quinine is regulated. For example, in the United States and in Germany, quinine is limited to between 83-85 parts per million. In order to achieve a therapeutic dose of quinine from tonic water, a person would have to drink between 6 and 12 litres in a 24-hour period. In France, quinine is an ingredient of an apéritif known as Quinquina. Because of its relatively constant and well-known fluorescence quantum yield, quinine is also used in photochemistry as a common fluorescence standard. Quinine (and quinidine) are used as the chiral moiety for the ligands used in Sharpless asymmetric dihydroxylation. Quinine is sometimes added to the recreational drugs cocaine, heroin and others in order to “cut” the product and make more profit. In Canada, quinine is an ingredient in the carbonated chinotto beverage called Brio. In the United Kingdom, Scottish company A.G. Barr’s uses quinine as an ingredient in the carbonated and caffeinated beverage Irn-Bru. In England, Australia, New Zealand and Egypt, quinine is an ingredient in Schweppes and other Indian tonic waters, at a concentration of 0.4 mg/l. In Uruguay and Argentina, quinine is an ingredient of a Pepsico Inc. Tonic water named Paso de los Toros. In South Africa, quinine is an ingredient of a Clifton Instant Drink named Chikree produced by Tiger Food Brands.

Papaverine is an opium alkaloid used primarily in the treatment of visceral spasm, vasospasm (especially those involving the heart and the brain), and occasionally in the treatment of erectile dysfunction. While it is found in the opium poppy, papaverine differs in both structure and pharmacological action from the other opium alkaloids (opiates). In 1979, a Food and Drug Administration Advisory Committee evaluated studies on papaverine and concluded that there was a lack of objective data to support the therapeutic use of papaverine for these conditions. Papaverine remains available despite the committee’s recommendation that it be withdrawn from the market.

Uses

Papaverine is approved to treat spasms of the gastrointestinal tract, bile ducts and ureter and for use as a cerebral and coronary vasodilator in subarachnoid hemorrhage (combined with balloon angioplasty) and coronary artery bypass surgery. Papaverine may also be used as a smooth muscle relaxant in microsurgery where it is applied directly to blood vessels. It is also commonly used in cryopreservation of blood vessels along with the other glycosaminoglycans and protein suspensions. Functions as a vasodilator during cryopreservation when used in conjunction with verapamil, phentolamine, nifedipine, tolazoline or nitroprusside. Papaverine is also being investigated as a topical growth factor in tissue expansion with some success.

Mechanism

The in vivo mechanism of action is not entirely clear, but an inhibition of the enzyme phosphodiesterase causing elevation of cyclic AMP levels is significant. It may also alter mitochondrial respiration.

Papaverine has also been demonstrated to be a selective phosphodiesterase inhibitor for the PDE_10A subtype found mainly in the striatum of the brain. When administered chronically to mice it produced motor and cognitive deficits and increased anxiety, but conversely may produce an antipsychotic effect.

Side effects

Frequent side effects of papaverine treatment include polymorphic ventricular tachycardia, constipation, interference with sulphobromophthalein retention test (used to determine hepatic function), increased transaminase levels, increased alkaline phosphatase levels, somnolence, and vertigo.

Rare side effects include flushing of the face, hyperhidrosis (excessive sweating), cutaneous eruption, arterial hypotension, tachycardia, loss of appetite, jaundice, eosinophilia, thrombopenia, mixed hepatitis, headache, allergic reaction, chronic active hepatitis, and paradoxical aggravation of cerebral vasospasm.

Formulations and trade names

Papaverine is available as a conjugate of hydrochloride, codecarboxylate, adenylate, and teprosylate. It was also once available as a salt of hydrobromide, camsylate, cromesilate, nicotinate, and phenylglycolate. The hydrochloride salt is available for intramuscular, intravenous, rectal and oral administration. The teprosylate is available in intravenous, intramuscular, and orally administered formulations. The codecarboxylate is available in oral form, only, as is the adenylate.

Papaverine Systematic (IUPAC) name 1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline
Identifiers
CAS number	58-74-2 61-25-6 (hydrochloride)
ATC code	A03AD01 G04BE02
PubChem	4680
DrugBank	APRD00628
Chemical data
Formula	C20H21NO4
Mol. mass	339.385 g/mol
Pharmacokinetic data
Bioavailability	80%
Protein binding	~90%
Metabolism	Hepatic
Half life	1.5–2 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	USA: C
Legal status

The codecarboxylate is sold under the name Albatran, the adenylate as Dicertan, and the hydrochloride salt is sold variously as Artegodan (Germany), Cardioverina (countries outside Europe and the United States), Dispamil (countries outside Europe and the United States), Opdensit (Germany), Panergon (Germany), Paverina Houde (Italy, Belgium), Pavacap (United States), Pavadyl (United States), Papaverin–Hamelin (Germany), Paveron (Germany), Spasmo–Nit (Germany),Cardiospan, Papaversan, Cepaverin, Cerespan, Drapavel, Forpaven, Papalease, Pavatest, Paverolan, Therapav (France), Vasospan, Cerebid, Delapav, Dilaves, Durapav, Dynovas, Optenyl, Pameion, Papacon, Pavabid, Pavacen, Pavakey, Pavased, Pavnell, Alapav, Myobid, Vasal, Pamelon, Pavadel, Pavagen, Ro–Papav, Vaso–Pav, Papanerin–hcl, Qua bid, Papital T.R., Paptial T.R., Pap–Kaps-150.. In Hungary papaverine and homatropine-methylbromide are used in mild drugs that help “flush” the bile (e.g. Neo-Bilagit).

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Morphine (INN) is a highly potent opiate analgesic drug, is the principal active agent in opium, and is considered to be the prototypical opioid. Morphine was in 1803 the first alkaloid isolated from a plant source. Like other opioids, e.g. oxycodone, hydromorphone, and diacetylmorphine (heroin), morphine acts directly on the central nervous system (CNS) to relieve pain, particularly at the synapses of the nucleus accumbens. Morphine has a high potential for addiction; tolerance and both physical and psychological dependence develop rapidly.

History

Advertisement for curing Morphine Addictions ca. 1900^[1]

An ampoule of morphine with integral needle for immediate use. From WWII. On display at the Army Medical Services Museum.

Morphine was first isolated, which was the first active principle chemically isolated from any plant, in the autumn of 1803 in Paderborn, Germany, by the German pharmacist Friedrich Wilhelm Adam Sertürner, who named it morphium after Morpheus, the Greek god of dreams. But it was not until the development of the hypodermic needle in 1853 that its use spread. It was used for pain relief, and as a “cure” for opium and alcohol addiction. Later it was found out that morphine was even more addictive than either alcohol or opium, and its extensive use during the American Civil War allegedly resulted in over 400,000 sufferers from the “soldier’s disease” of morphine addiction. This idea has been a subject of controversy, as there have been suggestions that such a disease was in fact a hoax.

Diacetylmorphine (better known as heroin) was synthesized from morphine in 1874 and brought to market by Bayer in 1898. Heroin is approximately 1.5–2 times more potent than morphine on a milligram-for-milligram basis. Using a variety of subjective and objective measures, one study estimated the relative potency of heroin to morphine administered intravenously to post-addicts to be 1.80–2.66 mg of morphine sulfate to 1 mg of diamorphine hydrochloride (heroin).

Morphine became controlled substances in the U.S. under the Harrison Narcotics Tax Act of 1914, and possession without a prescription in the U.S. is a criminal offense.

The structural formula of morphine was determined by 1925. At least three methods of total synthesis of morphine from starting materials such as coal tar and petroleum distillates have been patented, the first of which was announced in 1952, by Dr. Marshall D. Gates, Jr at the University of Rochester. . Still, the vast majority of morphine is derived from the opium poppy by either the traditional method of gathering latex from the scored unripe pods of the poppy, or processes using poppy straw, the dried pods and stems of the plant, the most widespread of which was invented in Hungary in 1925 and announced in 1930 by chemist János Kábay.

Morphine was the most commonly abused narcotic analgesic in the world up until heroin was synthesized and came into use. Until the synthesis of dihydromorphine (c.a. 1900), the dihydromorphinone class of opioids (1920s), and oxycodone (1916) and similar drugs, there generally were no other drugs in the same efficacy range as opium, morphine and heroin, with synthetics still several years away (pethidine was invented in Germany in 1937) and opioid agonists amongst the semi-synthetics were analogues and derivatives of codeine such as dihydrocodeine (Paracodin), ethylmorphine (Dionine), and benzylmorphine (Peronine). Even today, morphine is the most sought after prescriptioarcotic by heroin addicts when heroin is scarce, all other things being equal; local conditions and user preference may cause hydromorphone, oxymorphone, high-dose oxycodone, or methadone as well as dextromoramide in specific instances such as 1970s Australia, to top that particular list. The stop-gap drugs used by the largest absolute number of heroin addicts is probably codeine, with significant use also of dihydrocodeine, poppy straw derivatives like poppy pod and poppy seed tea, propoxyphene, and tramadol

Indications

Morphine can be used:

• as an analgesic in hospital settings to relieve

• pain in myocardial infarction

• pain in sickle cell crisis

• pain associated with surgical conditions, pre- and postoperatively

• pain associated with trauma

• in the relief of severe chronic pain, e.g.,

• cancer

• pain from kidney stones (renal colic, ureterolithiasis)

• severe back pain

• as an adjunct to general anesthesia

• in epidural anesthesia or intrathecal analgesia

• for palliative care (i.e., to alleviate pain without curing the underlying reason for it, usually because the latter is found impossible)

• as an antitussive for severe cough

• iebulized form, for treatment of dyspnea, although the evidence for efficacy is slim. Evidence is better for other routes.

• as an antidiarrheal in chronic conditions (e.g., for diarrhea associated with AIDS, although loperamide (a non-absorbed opioid acting only on the gut) is the most commonly used opioid for diarrhea).

Constipation

Like loperamide and other opioids, morphine acts on the myenteric plexus in the intestinal tract, reducing gut motility, causing constipation. The gastrointestinal effects of morphine are mediated primarily by μ-opioid receptors in the bowel. By inhibiting gastric emptying and reducing propulsive peristalsis of the intestine, morphine decreases the rate of intestinal transit. Reduction in gut secretion and increases in intestinal fluid absorption also contribute to the constipating effect. Opioids also may act on the gut indirectly through tonic gut spasms after inhibition of nitric oxide generation. This effect was shown in animals when a nitric oxide precursor reversed morphine-induced changes in gut motility.

Addiction

Morphine is a potentially highly addictive substance, as it can cause psychological dependence and physical dependence as well as tolerance, with an addiction potential identical to that of heroin. When used illicitly, a very serious narcotic habit can develop in a matter of weeks whereas iatrogenic morphine addiction rates have, according to a number of studies, remained nearly constant at one case in 150 to 200 for at least two centuries.^] In the presence of pain and the other disorders for which morphine is indicated for use, a combination of psychological and physiological factors tend to prevent true addiction from developing, although physical dependence and tolerance will develop with protracted opioid therapy, and these two factors do not add up to addiction without psychological dependence which manifests primarily as a morbid seek orientation for the drug.

In controlled studies comparing the physiological and subjective effects of injected heroin and morphine in individuals formerly addicted to opiates, subjects showed no preference for one drug over the other. Equipotent, injected doses had comparable action courses, with no difference in subjects’ self-rated feelings of euphoria, ambition, nervousness, relaxation, drowsiness, or sleepiness. Short-term addiction studies by the same researchers demonstrated that tolerance developed at a similar rate to both heroin and morphine. When compared to the opioids hydromorphone, fentanyl, oxycodone, and pethidine/meperidine, former addicts showed a strong preference for heroin and morphine, suggesting that heroin and morphine are particularly susceptible to abuse and addiction. Morphine and heroin were also much more likely to produce euphoria and other positive subjective effects when compared to these other opioids.

Other studies such as the Rat Park experiments suggest that morphine is less physically addictive than others suggest, and most studies on morphine addiction merely show that “severely distressed animals, like severely distressed people, will relieve their distress pharmacologically if they can.” In these studies rats with a morphine “addiction” overcome their addiction themselves when placed in decent living environments with enough space, good food, companionship, areas for exercise, areas for privacy. More recent research has shown that an enriched environment may decrease morphine addiction in mice.

Withdrawal symptoms

The withdrawal symptoms associated with morphine addiction are usually experienced shortly before the time of the next scheduled dose, sometimes within as early as a few hours (usually between 6–12 hours) after the last administration. Early symptoms include watery eyes, insomnia, diarrhea, runny nose, yawning, dysphoria, and sweating and in some cases a strong drug craving. Severe headache, restlessness, irritability, loss of appetite, body aches, severe abdominal pain, nausea and vomiting, tremors, and even stronger and more intense drug craving appear as the syndrome progresses. Severe depression and vomiting are very common. The heart rate and blood pressure are elevated and can lead to a heart attack, blood clot or stroke. Chills or cold flashes with goose bumps (“cold turkey”) alternating with flushing (hot flashes), kicking movements of the legs (“kicking the habit”) and excessive sweating are also characteristic symptoms.Severe pains in the bones and muscles of the back and extremities occur, as do muscle spasms. At any point during this process, a suitable narcotic can be administered that will dramatically reverse the withdrawal symptoms. Major withdrawal symptoms peak between 48 and 96 hours after the last dose and subside after about 8 to 12 days. Sudden withdrawal by heavily dependent users who are in poor health is very rarely fatal. Morphine withdrawal is considered less dangerous than alcohol, barbiturate, or benzodiazepine withdrawal.

The psychological dependence associated with morphine addiction is complex and protracted. Long after the physical need for morphine has passed, the addict will usually continue to think and talk about the use of morphine (or other drugs) and feel strange or overwhelmed coping with daily activities without being under the influence of morphine. Psychological withdrawal from morphine is a very long and painful process. Addicts often suffer severe depression, anxiety, insomnia, mood swings, amnesia (forgetfulness), low self-esteem, confusion, paranoia, and other psychological disorders. The psychological dependence on morphine can, and usually does, last a lifetime. There is a high probability that relapse will occur after morphine withdrawal wheeither the physical environment nor the behavioral motivators that contributed to the abuse have been altered. Testimony to morphine’s addictive and reinforcing nature is its relapse rate. Abusers of morphine (and heroin), have one of the highest relapse rates among all drug users.

Hepatitis C and morphine withdrawal

Researchers at the University of Pennsylvania have demonstrated that morphine withdrawal complicates hepatitis C by suppressing IFN-alpha-mediated immunity and enhancing virus replication. Hepatitis C virus (HCV) is common among intravenous drug users. This high association has piqued interest in determining the effects of drug abuse, specifically morphine and heroin, on progression of the disease. The discovery of such an association would impact treatment of both HCV infection and drug abuse.

Contraindications

The following conditions are relative contraindications for morphine:

• acute respiratory depression

• renal failure (due to accumulation of the metabolite morphine-6-glucuronide)

• chemical toxicity (potentially lethal in low tolerance subjects)

• raised intracranial pressure, including head injury (exacerbation due pCO2 increases from respiratory depression)

Older literature, based upon studies of animals with acute pancreatitis, claimed that morphine caused significant spasm of the sphincter of Oddi and could therefore worsen the pain of the disease.

 Pharmacology

Morphine is the prototype narcotic drug and is the standard against which all other opioids are tested. It interacts predominantly with the μ-opioid receptor. These μ-binding sites are discretely distributed in the human brain, with high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve.

Morphine is a phenanthrene opioid receptor agonist – its main effect is binding to and activating the μ-opioid receptors in the central nervous system. In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system and gastrointestinal tract. Its primary actions of therapeutic value are analgesia and sedation. Activation of the μ-opioid receptors is associated with analgesia, sedation, euphoria, physical dependence, and respiratory depression. Morphine is a rapid-acting narcotic, and it is known to bind very strongly to the μ-opioid receptors, and for this reason, it often has a higher incidence of euphoria/dysphoria, respiratory depression, sedation, pruritus, tolerance, and physical and psychological dependence when compared to other opioids at equianalgesic doses. Morphine is also a κ-opioid and δ-opioid receptor agonist, κ-opioid’s action is associated with spinal analgesia, miosis (pinpoint pupils) and psychotomimetic effects. δ-opioid is thought to play a role in analgesia.

The effects of morphine can be countered with opioid antagonists such as naloxone and naltrexone; the development of tolerance to morphine may be inhibited by NMDA antagonists such as ketamine or dextromethorphan. The rotation of morphine with chemically dissimilar opioids in the long-term treatment of pain will slow down the growth of tolerance in the longer run, particularly agents known to have significantly incomplete cross-tolerance with morphine such as levorphanol, ketobemidone, piritramide, and methadone and its derivatives; all of these drugs also have NMDA antagonist properties. It is believed that the strong opioid with the most incomplete cross-tolerance with morphine is either methadone or dextromoramide.

Gene expression

Studies have shown that morphine can alter the expression of a number of genes. A single injection of morphine has been shown to alter the expression of two major groups of genes, for proteins involved in mitochondrial respiration and for cytoskeleton-related proteins.

Effects on the immune system

Morphine has long been known to act on receptors expressed on cells of the central nervous system resulting in pain relief and analgesia. In the 1970s and ’80s, evidence suggesting that opiate drug addicts show increased risk of infection (such as increased pneumonia, tuberculosis, and HIV) led scientists to believe that morphine may also affect the immune system. This possibility increased interest in the effect of chronic morphine use on the immune system.

The first step of determining that morphine may affect the immune system was to establish that the opiate receptors known to be expressed on cells of the central nervous system are also expressed on cells of the immune system. One study successfully showed that dendritic cells, part of the innate immune system, display opiate receptors. Dendritic cells are responsible for producing cytokines, which are the tools for communication in the immune system. This same study showed that dendritic cells chronically treated with morphine during their differentiation produce more interleukin-12 (IL-12), a cytokine responsible for promoting the proliferation, growth, and differentiation of T-cells (another cell of the adaptive immune system) and less interleukin-10 (IL-10), a cytokine responsible for promoting a B-cell immune response (B cells produce antibodies to fight off infection).

This regulation of cytokines appear to occur via the p38 MAPKs (mitogen activated protein kinase) dependent pathway. Usually, the p38 within the dendritic cell expresses TLR 4 (toll-like receptor 4), which is activated through the ligand LPS (lipopolysaccharide). This causes the p38 MAPK to be phosphorylated. This phosphorylation activates the p38 MAPK to begin producing IL-10 and IL-12. When the dendritic cell is chronically exposed to morphine during their differentiation process then treated with LPS, the production of cytokines is different. Once treated with morphine, the p38 MAPK does not produce IL-10, instead favoring production of IL-12. The exact mechanism through which the production of one cytokine is increased in favor over another is not known. Most likely, the morphine causes increased phosphorylation of the p38 MAPK. Transcriptional level interactions between IL-10 and IL-12 may further increase the production of IL-12 once IL-10 is not being produced. Future research may target the exact mechanism that increases the production of IL-12 in morphine treated dendritic cells. This increased production of IL-12 causes increased T-cell immune response. This response is due to the ability of IL-12 to cause T helper cells to differentiate into the Th1 cell, causing a T cell immune response.

Pharmacokinetics

Morphine is primarily metabolized into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) via glucuronidation by phase II metabolism enzyme UDP-glucuronosyl transferase-2B7 (UGT2B7). The cytochrome P450 (CYP) family of enzymes involved in phase I metabolism plays a lesser role. Not only does the metabolism occur in the liver but it may also take place in the brain and the kidneys. M6G has been found to be a far more potent analgesic than morphine when dosed to rodents, but crosses the blood-brain barrier with difficulty. M6G has been shown to be relatively more selective for mu-receptors than for delta- and kappa-receptors, whereas M3G does not appear to compete for opioid receptor binding. The significance of M6G formation on the observed effect of a dose of morphine is the subject of extensive debate among pharmacologists.

Chemistry

 

Chemical structure of morphine in correct 3D configuration. The benzylisoquinoline backbone is shown in blue. Morphine is a benzylisoquinoline alkaloid with two additional ring closures. Most of the licit morphine produced is used to make codeine by methylation. It is also a precursor for many drugs including heroin (diacetylmorphine), hydromorphone, and oxymorphone. Replacement of the N-methyl group of morphine with an N-phenylethyl group results in a product that is 18 times more powerful than morphine in its opiate agonist potency. Combining this modification with the replacement of the 6-hydroxyl with a 6-methylene produces a compound some 1,443 times more potent than morphine, stronger than the Bentley compounds such as etorphine.

The structure-activity relationship of morphine has been extensively studied. As a result, more than 100 morphine derivatives (also counting codeine and related drugs) have been developed since the last quarter of the 19th Century. These drugs range from 25 per cent the strength of codeine or a little over 2 per cent of the strength of morphine, to several hundred times the strength of morphine to several powerful opioid antagoinsts including naloxone (Narcan®), naltrexone (Trexan®), and nalorphine (Nalline®) for human use and also the amongst strongest antagonists known, such as diprenorphine (M5050), the reversing agent in the Immobilon® large animal tranquilliser dart kit; the tranquilliser is another ultra-potent morphine derivative/structural analogue, viz., etorphine (M99). Morphine-derived agonist-antagonist drugs have also been developed.

Most semi-synthetic opioids, both of the morphine and codeine subgroups, are created by modifying one or more of the following:

• Saturating, opening, or other changes to the bond betwixt positions 7 and 8 on the morphine carbon skeleton, as well as adding, removing, or modifying functional groups to these positions; saturating, reducing, eliminating, or otherwise modifying the 7-8 bond and attaching a functional group at 14 yields hydromorphinol; the oxidation of the hydroxyl group to a carbonyl and changing the 7-8 bond to single from double changes codeine into oxycodone.

• Attachment, removal or modification of functional groups to positions 3 and/or 6 (dihydrocodeine and related, hydrocodone, nicomorphine); in the case of moving the methyl functional group from position 3 to 6, codeine becomes heterocodeine which is 72 times stronger, and therefore six times stronger than morphine

• Attachment of functional groups or other modification at position 14 (oxymorphone, oxycodone, naloxone)

• Modifications at positions 2, 4, 5 or 17, usually along with other changes to the molecule elsewhere on the morphine skeleton.

Both morphine and its hydrated form, C₁₇H₁₉NO₃H₂O, are sparingly soluble in water. In five liters of water, only one gram of the hydrate will dissolve. For this reason, pharmaceutical companies produce sulfate and hydrochloride salts of the drug, both of which are over 300 times more water-soluble than their parent molecule. Whereas the pH of a saturated morphine hydrate solution is 8.5, the salts are acidic. Since they derive from a strong acid but weak base, they are both at about pH = 5; as a consequence, the morphine salts are mixed with small amounts of NaOH to make them suitable for injection. A number of salts of morphine are used, and the opioids Morphine-N-Oxide (Genomorphine) which is a pharmaceutical which is no longer in common use; and Pseudomorphine, an alkaloid which exists in opium, form as degradation products of morphine. The salts listed by the United States Drug Enforcement Administration, in addition to a few others, are as follows:

Production

A Hungarian chemist, János Kabay, found and internationally patented a method to extract morphine from “poppy straw”: dried poppy pods and stem, and other parts of the dry plant, except for seeds and root. In natural form, in poppy plant, the alkaloids are bound to meconic acid. The method is to extract from the crushed plant with diluted sulfuric acid, which is a stronger acid than meconic acid, but not so strong to react with alkaloid molecules. The extraction is performed in many steps (one amount of crushed plant is at least six to ten times extracted, so practically every alkaloid goes into the solution). From the solution obtained at the last extraction step, the alkaloids are precipitated by either ammonium hydroxide or sodium carbonate. The last step is purifying and separating morphine from other opium alkaloids (opium poppy contains at least 15–20 different alkaloids, but most of them are of very low concentration). In the 1950s and 1960s, Hungary supplied nearly 60% of Europe‘s total medication-purpose morphine production. To this day, poppy farming is legal in Hungary, but poppy farms are limited by law to 2 acres (8,100 m²). It is also legal to sell dried poppy in flower shops for use in floral arrangements.

It was announced in 1973 that a team at the National Institutes of Health in the United States had developed a method for total synthesis of morphine, codeine, and thebaine using coal tar as a starting material. A shortage in codeine-hydrocodone class cough suppressants (all of which can be made from morphine in one or more steps, as well as from codeine or thebaine) was the initial reason for the research.

The UN Office On Drugs & Crime Bulletin On Narcotics, issue II of 1952, describes the process which led to the final determination of the structural formula of morphine in 1925 and the invention of two methods of total synthesis of morphine.

Most morphine produced for pharmaceutical use around the world is actually converted into codeine as the concentration of the latter in both raw opium and poppy straw is much lower than that of morphine; in most countries the usage of codeine (both as end-product and precursor) is at least an order of magnitude greater than that of morphine on a weight basis and codeine is by far the most commonly-used opioid in the world. Whilst strains of poppies have been engineered to produce much higher yields of the other useful opioid pharmaceutical precursors thebaine and oripavine, no known strain of P. somniferum will produce more codeine than morphine under most or all possible conditions.

 

Illicit use

The euphoria, comprehensive alleviation of distress and therefore all aspects of suffering, promotion of sociability and empathy, “body high”, and anxiolysis provided by narcotic drugs including the opioids can cause the use of high doses in the absence of pain for a protracted period, which can impart a morbid craving for the drug in the user. Being the prototype of the entire opioid class of drugs means that morphine has properties that may lend it to misuse. Morphine addiction is the model upon which the current perception of addiction is based.

Animal and human studies and clinical experience back up the contention that morphine is one of the most euphoric of drugs, and via all but the IV route heroin and morphine cannot be distinguished according to studies. More significant chemical changes or the synthesis of totally new drugs yield other powerful euphorigenics such as hydromorphone (Dilaudid®, Hydal®) and oxymorphone (Numorphan®, Opana®) as well as the methylated equivalents hydrocodone and oxycodone respectively, dextromoramide (Palfium®), and piritramide (Dipidolor®), and other members of the 3,6 morphine diester category like nicomorphine.

Misuse of morphine generally entails taking more than prescribed or outside of medical supervision, injecting oral formulations, mixing it with unapproved potentiators such as alcohol, cocaine, and the like, and/or defeating the extended-release mechanism by chewing the tablets or turning into a powder for snorting or preparing injectables. The latter method can be every bit as time-consuming and involved as traditional methods of smoking opium. This and the fact that the liver destroys a large percentage of the drug on the first pass impacts the demand side of the equation for clandestine re-sellers, as many customers are not needle users and may have been disappointed with ingesting the drug orally. As morphine is generally as hard or harder to divert than oxycodone in a lot of cases, morphine in any form is uncommon on the street, although ampoules and phials of morphine injection, pure pharmaceutical morphine powder, and soluble multi-purpose tablets are very popular where available.

Slang terms for morphine include M, Big M, Vitamin M, Miss Emma, morph, morpho, Murphy, cube, cube juice, White Nurse, Red Cross, mojo, hocus, 13, Number 13, mofo, unkie, happy powder, joy powder, first line, Aunt Emma, coby, em, emsel, morf, dope, glad stuff, goody, God’s Medicine, God’s Own Medicine, hard stuff, morfa, morphia, morphy, mud, sister, Sister Morphine, stuff, white stuff, white merchandise and others. MS-Contin and its equivalents in other countries are known as misties, blockbusters, and the 100 mg tablets as greys.

Precursor to other opioids, Phamaceutical Manufacturing Setting

Morphine is a precursor in the manufacture in a large number of opioids such as dihydromorphine, hydromorphone, nicomorphine, and heroin as well as codeine, which itself has a large family of semi-synthetic derivatives.Morphine is commonly treated with acetic anhydride and ignited to yield heroin. The pharmacology of heroin and morphine is identical except the two acetyl groups increase the lipid solubility of the heroin molecule, causing it to cross the blood-brain barrier and enter the brain more rapidly. Once in the brain, these acetyl groups are removed to yield morphine, which causes the subjective effects of heroin. Thus, heroin may be thought of as a more rapidly acting form of morphine.

Precursor to other opioids, Underground & Illicit

Illicit morphine is rarely produced from codeine found in over the counter cough and pain medicines. This demethylation reaction is often performed using pyridine and hydrochloric acid.

Another source of illicit morphine comes from the extraction of morphine from extended release morphine products, such as MS-Contin. Morphine can be extracted from these products with simple extraction techniques to yield a morphine solution that can be injected. Alternatively, the tablets can be crushed and snorted, injected or swallowed, although this provides much less euphoria although retaining some of the extended-release effect and the extended-release property is why MS-Contin is used in some countries alongside methadone, dihydrocodeine, buprenorphine, dihydroetorphine, piritramide, levo-alpha-acetylmethadol (LAAM) and special 24-hour formulations of hydromorphone for maintenance and detoxification of those physically dependent on opioids.

Another means of using or misusing morphine is to use chemical reactions to turn it into heroin or another stronger opioid. Morphine can, using a technique reported in New Zealand (where the initial precursor is codeine) and elsewhere known as home-bake, be turned into what is usually a mixture of morphine, heroin, 3-monoacetylmorphine, 6-monoacetylmorphine, and codeine derivatives like acetylcodeine if the process is using morphine made from demethylating codeine by mixing acetic anhydride with the morphine and cooking it in an oven between 80 and 85°C for several hours. Since heroin is one of a series of 3,6 diesters of morphine, it is possible to convert morphine to nicomorphine (Vilan®) using nicotinic anhydride, dipropanoylmorphine with propionic anhydride. Acetic acid can be used to obtain a mixture high in 3-monoacetylmorphine, nicotinic acid (Vitamin B3) in some form would be precursor to 3-nicotinylmorphine, and so on.

The clandestine conversion of morphine to ketones of the hydromorphone class or other derivatives like dihydromorphine (Paramorfan®), desomorphine (Permonid®), metopon &c. and codeine to hydrocodone (Dicodid®), dihydrocodeine (Paracodin®) &c. is more involved, time consuming, requires lab equipment of various types, and usually requires expensive catalysts and large amounts of morphine at the outset and is less common but still has been discovered by authorities in various ways during the last 20 years or so. Dihydromorphine can be acetylated into another 3,6 morphine diester, namely diacetyldihydromorphine (Paralaudin®), and hydrocodone into thebacon.

Morphine

Systematic (IUPAC) name (5α,6α)-7,8-didehydro-
4,5-epoxy-17-methylmorphinan-3,6-diol

 

Codeine

Codeine (INN) or methylmorphine is an opiate used for its analgesic, antitussive and antidiarrheal properties. It is by far the most widely used opiate in the world and probably the most commonly used drug overall according to numerous reports over the years by organizations such as the World Health Organization and its League of Nations predecessor agency and others. It is one of the most effective orally-administered opioid analgesics and has a wide safety margin. It is from 8 to 12 percent of the strength of morphine in most people; differences in metabolism can change this figure as can other medications.

History

Codeine is an alkaloid found in opium and other poppy saps like Papaver bracteatum, the Iranian poppy, in concentrations ranging from 0.3 to 3.0 percent. While codeine can be extracted from opium, most codeine is synthesized from morphine through the process of O-methylation. It was first isolated in 1830 in France by Jean-Pierre Robiquet.

The effects of the Nixon War On Drugs by 1972 or so had caused across-the-board shortages of illicit and licit opiates because of a scarcity of natural opium, poppy straw and other sources of opium alkaloids, and the geopolitical situation was getting less helpful for the United States. After a large percentage of the opium and morphine in the US National Stockpile of Strategic & Critical Materials had to be tapped in order to ease severe shortages of medicinal opiates — the codeine-based antitussives in particular — in late 1973, researchers were tasked with and quickly succeeded in finding a way to synthesize codeine and its derivatives and precursors from scratch from petroleum or coal tar using a process developed at the United States’ National Institutes of Health.

Numerous codeine salts have been prepared since the drug was discovered. The most commonly used are the hydrochloride (freebase conversion ratio 0.805), phosphate (0.736), sulphate (0.859) and citrate (0.842). Others include a salicylate NSAID, codeine salicylate (0.686), and at least four codeine-based barbiturates, the cyclohexenylethylbarbiturate (0.559), cyclopentenylallylbarbiturate (0.561), diallylbarbiturate (0.561), and diethylbarbiturate (0.619).

Pharmacology

Codeine is considered a prodrug, since it is metabolised in vivo to the primary active compounds morphine and codeine-6-glucuronide. Roughly 5-10% of codeine will be converted to morphine, with the remainder either free, conjugated to form codeine-6-glucuronide (~70%), or converted to norcodeine (~10%) and hydromorphone (~1%). It is less potent than morphine and has a correspondingly lower dependence-liability than morphine. Like all opioids, continued use of codeine induces physical dependence and can be psychologically addictive. However, the withdrawal symptoms are relatively mild and as a consequence codeine is considerably less addictive than the other opiates.

A dose of approximately 200 mg (oral) of codeine must be administered to give analgesia approximately equivalent to 30 mg (oral) of morphine (Rossi, 2004). However, codeine is generally not used in single doses of greater than 60 mg (and no more than 240 mg in 24 hours). When analgesia beyond this is required, stronger opioids such as hydrocodone or oxycodone are favored. Because codeine needs to be metabolized to an active form, there is a ceiling effect around 400-450 mg. This low ceiling further contributes to codeine being less addictive than the other opiates. The ceiling dose can be more accurately calculated by using 7 mg per 1 kg of bodyweight, taking into consideration the BMI to not over or under calculate in cases of obese or underweight people (this rule does not take into consideration the usage of other CYP2D6 inhibiting drugs, alcohol or naturally low or high enzyme presence).

Pharmacokinetics

The conversion of codeine to morphine occurs in the liver and is catalysed by the cytochrome P450 enzyme CYP2D6. CYP3A4 produces norcodeine and UGT2B7 conjugates codeine, norcodeine and morphine to the corresponding 3- and 6- glucuronides. Approximately 6–10% of the Caucasian population, 2% of Asians, and 1% of Arabs are “poor metabolizers”; they have little CYP2D6 and codeine is less effective for analgesia in these patients (Rossi, 2004), although it is speculated that codeine-6-glucuronide is responsible for a large percentage of the analgesia of codeine and thus these patients should experience some analgesia. Many of the adverse effects will still be experienced in poor metabolizers. Conversely, 0.5-2% of the population are “extensive metabolizers”; multiple copies of the gene for 2D6 produce high levels of CYP2D6 and will metabolize drugs through that pathway more quickly than others.

Some medications are CYP2D6 inhibitors and reduce or even completely block the conversion of codeine to morphine. The most well-known of these are two of the selective serotonin reuptake inhibitors, paroxetine (Paxil) and fluoxetine (Prozac) as well as the antidepressant, buproprion (Wellbutrin, also known as Zyban). Other drugs, such as rifampicin and dexamethasone, induce CYP450 isozymes and thus increase the conversion rate.

While a CYP2D6 extensive metaboliser (EM) needs higher doses of drugs metabolized by CYP2D6 to maintain sufficient plasma levels for therapeutic effect and a poor metaboliser (PM) may suffer from drug toxicity due to slow drug clearance and excessive plasma concentration, prodrugs like codeine have the opposite effect. Thus an EM may have adverse effects from a rapid buildup of codeine metabolites while a PM may get little or no pain relief.

The active metabolites of codeine, notably morphine, exert their effects by binding to and activating the μ-opioid receptor.

Indications

Approved indications for codeine include:

• Cough, though its efficacy in low dose over the counter formulations has been disputed.

• Diarrhea

• Mild to severe pain

• Irritable bowel syndrome

Codeine is sometimes marketed in combination preparations with the analgesic acetaminophen (paracetamol), as co-codamol, paracod, panadeine, or Tylenol 3; with the analgesic acetylsalicylic acid (aspirin), as co-codaprin; or with the NSAID (non-steroidal anti-inflammatory drug) ibuprofen, as Nurofen Plus. These combinations provide greater pain relief than either agent alone (drug synergy). Codeine is also commonly compounded with other pain killers or muscle relaxers such as Fioricet with Codeine, Soma Compound/Codeine, etc. Codeine-only products can be obtained with a prescription as a time release tablet (e.g. Codeine Contin(r) 100 mg and Perduretas 50 mg).

The narcotic content number in the US names of codeine tablets and combination products like Tylenol With Codeine No. 3, Emprin With Codeine No. 4 are as follows: No. 1 – 7½ or 8 mg (1/8 grain), No. 2 – 15 or 16 mg (1/4 grain), No. 3 – 30 or 32 mg (1/2 grain), No. 4 – 60 or 64 mg (1 grain). The Canadian 222 series is identical to the above list 222=1/8 grain, 292=1/4 grain, 293=1/2 grain, and 294=1 grain of codeine.

Injectable codeine is available for subcutaneous or intramuscular injection; intravenous injection can cause a serious reaction which can progress to anaphylaxis. Codeine suppositories are also marketed in some countries.

Availability

Codeine phosphate and sulphate are marketed in the United States and Canada. Codeine hydrochloride is more commonly marketed in continental Europe and other regions, and codeine hydroiodide and codeine citrate round out the top five most-used codeine salts worldwide. Codeine is usually present in raw opium as free alkaloid in addition to codeine meconate, codeine pectinate, and possibly other naturally-occurring codeine salts. Codeine bitartrate, tartrate, nitrate, picrate, acetate, hydrobromide and others are occasionally encountered on the pharmaceutical market and in research.

In certain jurisdictions, codeine is available over-the-counter in combination with guaifenesin or promethazine to be sold at the pharmacist’s discretion, though many pharmacists decline to do so

Relation to other opiates

Codeine is the starting material and prototype of a large class of mainly mild to moderately strong opioids such as hydrocodone, dihydrocodeine and its derivatives such as nicocodeine. Related to codeine in other ways are Codeine-N-Oxide (Genocodeine), related to the nitrogen morphine derivatives as is codeine methobromide, and heterocodeine which is a drug six times stronger than morphine and 72 times stronger than codeine due to a small re-arrangement of the molecule, viz. moving the methyl group from the 3 to the 6 position on the morphine carbon skeleton. Drugs bearing resemblance to codeine in effects due to close structural relationship are variations on the methyl groups at the 3 position including ethylmorphine a.k.a. codethyline (Dionine) and benzylmorphine (Peronine). While having no narcotic effects of its own, the important opioid precursor thebaine differs from codeine only slightly in structure. Pseudocodeine and some other similar alkaloids not currently used in medicine are found in trace amounts in opium as well.

Adverse effects

Common adverse drug reactions associated with the use of codeine include euphoria, itching, nausea, vomiting, drowsiness, dry mouth, miosis, orthostatic hypotension, urinary retention, depression and constipation. Another side effect commonly noticed is the lack of sexual drive and increased complications in erectile dysfunction. Some people may also have an allergic reaction to codeine, such as the swelling of skin and rashes.

Tolerance to many of the effects of codeine develops with prolonged use, including therapeutic effects. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance.

A potentially serious adverse drug reaction, as with other opioids, is respiratory depression. This depression is dose-related and is the mechanism for the potentially fatal consequences of overdose. As codeine is metabolized to morphine, morphine can be passed through breast milk in potentially lethal amounts, fatally depressing the respiration of a breastfed baby.

Withdrawal effects

As with other opiate based pain killers chronic use of codeine can cause a physical dependence to develop. When physical dependence has developed to codeine it means if a person stops the medication too quickly they may experience withdrawal symptoms including craving, runny nose, yawning, sweating, restless sleep, weakness, stomach cramps, nausea, vomiting, diarrhea, muscle spasms, chills, irritability and pain. To minimise withdrawal symptoms long term users need to gradually reduce their codeine medication under the supervision of a healthcare professional. A support group called CodeineFree exists to help people who have found themselves dependent on codeine.

Atropine is a tropane alkaloid extracted from deadly nightshade (Atropa belladonna), jimsonweed (Datura stramonium), mandrake (Mandragora officinarum) and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects. It is a competitive antagonist for the muscarinic acetylcholine receptor. It is classified as an anticholinergic drug. Being potentially deadly, it derives its name from Atropos, one of the three Fates who, according to Greek mythology, chose how a person was to die. Atropine is a core medicine in the World Health Organization’s “Essential Drugs List”, which is a list of minimum medical needs for a basic health care system.

Physiological effects and uses

Increases firing of the sinoatrial node (SA) and conduction through the atrioventricular node (AV) of the heart, opposes the actions of the vagus nerve, blocks acetylcholine receptor sites, and decreases bronchiole secretions.

Generally, atropine lowers the parasympathetic activity of all muscles and glands regulated by the parasympathetic nervous system. This occurs because atropine is a competitive antagonist of the muscarinic acetylcholine receptors (Acetylcholine is the maieurotransmitter used by the parasympathetic nervous system). Therefore, it may cause swallowing difficulties and reduced secretions.

 

Ophthalmic use

Topical atropine is used as a cycloplegic, to temporarily paralyze the accommodation reflex; and as a mydriatic, to dilate the pupils. Atropine degrades slowly, typically wearing off in 7 to 14 days, so it is generally used as a therapeutic mydriatic, whereas tropicamide (a shorter-acting cholinergic antagonist) or phenylephrine (an α-adrenergic agonist) are preferred as an aid to ophthalmic examination. Atropine induces mydriasis by blocking contraction of the circular pupillary sphincter muscle, which is normally stimulated by acetylcholine release, thereby allowing the radial pupillary dilator muscle to contract and dilate the pupil. Atropine induces cycloplegia by paralyzing the ciliary muscles, which inhibits accommodation to allow accurate refraction in children, helps to relieve pain associated with iridocyclitis, and treats ciliary block (malignant) glaucoma. Atropine is contraindicated in patients pre-disposed to narrow angle glaucoma.

Atropine can be given to patients who have direct globe trauma.

Resuscitation

Injections of atropine are used in the treatment of bradycardia (an extremely low heart rate), asystole and pulseless electrical activity (PEA) in cardiac arrest. This works because the main action of the vagus nerve of the parasympathetic system on the heart is to slow it down. Atropine blocks that action and therefore may speed up the heart rate. The usual dosage of atropine in bradyasystolic arrest is 0.5 to 1 mg IV push every three to five minutes, up to a maximum dose of 0.04mg/kg. For symptomatic bradycardia the usual dosage is 0.5 to 1.0 mg IV push, may repeat every 3 to 5 minutes up to a maximum dose of 3.0 mg.

Atropine is also useful in treating second degree heart block Mobitz Type 1 (Wenckebach block), and also third degree heart block with a high Purkinje or AV-nodal escape rhythm. It is usually not effective in second degree heart block Mobitz type 2, and in third degree heart block with a low Purkinje or ventricular escape rhythm. Atropine is contraindicated in ischemia-induced conduction block, because the drug increases oxygen demand of the AV nodal tissue, thereby aggravating ischemia and the resulting heart block.

One of the main actions of the parasympathetic nervous system is to stimulate the M₂ muscarinic receptor in the heart, but atropine inhibits this action.

Secretions and bronchoconstriction

Atropine’s actions on the parasympathetic nervous system inhibits salivary, sweat, and mucus glands. This can be useful in treating hyperhidrosis and can prevent the death rattle of dying patients. Even though it has not been officially indicated for either of these purposes by the FDA, it has been used by physicians for these purposes.

Chemistry and pharmacology

Atropine is a racemic mixture of D-hyoscyamine and L-hyoscyamine, with most of its physiological effects due to L-hyoscyamine. Its pharmacological effects are due to binding to muscarinic acetylcholine receptors. It is an antimuscarinic agent.

The most common atropine compound used in medicine is atropine sulfate (C₁₇H₂₃NO₃)₂·H₂SO₄·H₂O, the full chemical name is 1α H, 5α H-Tropan-3-α ol (±)-tropate(ester), sulfate monohydrate.

History

Mandragora (mandrake) was described by Theophrastus in the fourth century B.C. for treatment of wounds, gout, and sleeplessness, and as a love potion. By the first century A.D. Dioscorides recognized wine of mandrake as an anaesthetic for treatment of pain or sleeplessness, to be given prior to surgery or cautery. The use of Solanaceae containing tropane alkaloids for anesthesia, often in combination with opium, persisted throughout the Roman and Islamic Empires and continued in Europe until superseded by the use of ether, chloroform, and other modern anesthetics.

Atropine extracts from the Egyptian henbane were used by Cleopatra in the last century B.C. to dilate her pupils, in the hope that she would appear more alluring. In the Renaissance, women used the juice of the berries of Atropa belladonna to enlarge the pupils of their eyes, for cosmetic reasons; “bella donna” is Italian for “beautiful lady”. This practice resumed briefly in the late nineteenth- and early twentieth-century in Paris.

The mydriatic effects of atropine were studied among others by the German chemist Friedrich Ferdinand Runge (1795–1867). In 1831 the pharmacist Mein succeeded the pure crystalline isolation of atropine. The substance was first synthesized by German chemist Richard Willstätter in 1901.

Atropinic shock therapy, also known as atropinic coma therapy, is an old and rarely used method. It consists of induction of atropinic coma by rapid intravenous infusion of atropine. Atropinic shock treatment is considered safe with careful monitoring and preparation, but it entails prolonged coma (between four and five hours) and it has many unpleasant side effects, such as blurred vision.

Atropine is found in many members of the Solanaceae family. The most commonly found sources are Atropa belladonna, Datura inoxia, D. metel, and D. stramonium. Other sources include members of the Brugmansia and Hyoscyamus genera. The Nicotiana genus (including the tobacco plant, N. tabacum) is also found in the Solanaceae family, but these plants do not contain atropine or other tropane alkaloids.

Atropine

Systematic (IUPAC) name (8-methyl-8-azabicyclo[3.2.1]oct-3-yl) 3-hydroxy-2-phenylpropanoate

 

Cocaine (benzoylmethyl ecgonine) is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from “coca” in addition to the alkaloid suffix -ine, forming cocaine. It is both a stimulant of the central nervous system and an appetite suppressant. Specifically, it is a dopamine reuptake inhibitor, a norepinephrine reuptake inhibitor and a serotonin reuptake inhibitor which mediates functionality of such as an exogenous DAT ligand. Because of the way it affects the mesolimbic reward pathway, cocaine is addictive. Its possession, cultivation, and distribution are illegal for non-medicinal and non-government sanctioned purposes in virtually all parts of the world. Although its free commercialization is illegal and has been severely penalized in virtually all countries, its use worldwide remains widespread in many social, cultural, and personal settings.

Cocaine

Systematic (IUPAC) name methyl (1R,2R,3S,5S)-3- (benzoyloxy)-8-methyl-8-azabicyclo[3.2.1] octane-2-carboxylate Identifiers

History

Coca leaf

For over a thousand years South American indigenous peoples have chewed the coca leaf (Erythroxylon coca), a plant that contains vital nutrients as well as numerous alkaloids, including cocaine. The leaf was, and is, chewed almost universally by some indigenous communities—ancient Peruvian mummies have been found with the remains of coca leaves, and pottery from the time period depicts humans, cheeks bulged with the presence of something on which they are chewing. There is also evidence that these cultures used a mixture of coca leaves and saliva as an anesthetic for the performance of trepanation.

The coca plant, Erythroxylon coca.

When the Spaniards conquered South America, they at first ignored aboriginal claims that the leaf gave them strength and energy, and declared the practice of chewing it the work of the Devil. But after discovering that these claims were true, they legalized and taxed the leaf, taking 10% off the value of each crop.  In 1569, Nicolás Monardes described the practice of the natives of chewing a mixture of tobacco and coca leaves to induce “great contentment”

Isolation

Although the stimulant and hunger-suppressant properties of coca had been known for many centuries, the isolation of the cocaine alkaloid was not achieved until 1855 . Many scientists had attempted to isolate cocaine, but none had been successful for two reasons: the knowledge of chemistry required was insufficient at the time, and the cocaine was worsened because coca does not grow in Europe and ruins easily during travel.

The cocaine alkaloid was first isolated by the German chemist Friedrich Gaedcke in 1855. Gaedcke named the alkaloid “erythroxyline”, and published a description in the journal Archiv der Pharmazie.

In 1856, Friedrich Wöhler asked Dr. Carl Scherzer, a scientist aboard the Novara (an Austrian frigate sent by Emperor Franz Joseph to circle the globe), to bring him a large amount of coca leaves from South America. In 1859, the ship finished its travels and Wöhler received a trunk full of coca. Wöhler passed on the leaves to Albert Niemann, a Ph.D. student at the University of Göttingen in Germany, who then developed an improved purification process.

Niemann described every step he took to isolate cocaine in his dissertation titled Über eine neue organische Base in den Cocablättern (On a New Organic Base in the Coca Leaves), which was published in 1860—it earned him his Ph.D. and is now in the British Library. He wrote of the alkaloid’s “colourless transparent prisms” and said that, “Its solutions have an alkaline reaction, a bitter taste, promote the flow of saliva and leave a peculiar numbness, followed by a sense of cold when applied to the tongue.” Niemanamed the alkaloid “cocaine”—as with other alkaloids its name carried the “-ine” suffix (from Latin -ina).

The first synthesis and elucidation of the structure of the cocaine molecule was by Richard Willstätter in 1898. The synthesis started from tropinone, a related natural product and took five steps.

Medicalization

With the discovery of this new alkaloid, Western medicine was quick to exploit the possible uses of this plant.

In 1879, Vassili von Anrep, of the University of Würzburg, devised an experiment to demonstrate the analgesic properties of the newly-discovered alkaloid. He prepared two separate jars, one containing a cocaine-salt solution, with the other containing merely salt water. He then submerged a frog’s legs into the two jars, one leg in the treatment and one in the control solution, and proceeded to stimulate the legs in several different ways. The leg that had been immersed in the cocaine solution reacted very differently than the leg that had been immersed in salt water.

Carl Koller (a close associate of Sigmund Freud, who would write about cocaine later) experimented with cocaine for ophthalmic usage. In an infamous experiment in 1884, he experimented upon himself by applying a cocaine solution to his own eye and then pricking it with pins. His findings were presented to the Heidelberg Ophthalmological Society. Also in 1884, Jellinek demonstrated the effects of cocaine as a respiratory system anesthetic. In 1885, William Halsted demonstrated nerve-block anesthesia, and James Corning demonstrated peridural anesthesia. 1898 saw Heinrich Quincke use cocaine for spinal anaesthesia.

Popularization

In 1859, an Italian doctor, Paolo Mantegazza, returned from Peru, where he had witnessed first-hand the use of coca by the natives. He proceeded to experiment on himself and upon his return to Milan he wrote a paper in which he described the effects. In this paper he declared coca and cocaine (at the time they were assumed to be the same) as being useful medicinally, in the treatment of “a furred tongue in the morning, flatulence, [and] whitening of the teeth.”

Pope Leo XIII purportedly carried a hipflask of Vin Mariani with him, and awarded a Vatican gold medal to Angelo Mariani.

Pharmacology

Appearance

A pile of cocaine hydrochloride

A piece of compressed cocaine powder

Cocaine in its purest form is a white, pearly product. Cocaine appearing in powder form is a salt, typically cocaine hydrochloride (CAS 53-21-4). Street market cocaine is frequently adulterated or “cut” with various powdery fillers to increase its weight; the substances most commonly used in this process are baking soda; sugars, such as lactose, dextrose, inositol, and mannitol; and local anesthetics, such as lidocaine or benzocaine, which mimic or add to cocaine’s numbing effect on mucous membranes. Cocaine may also be “cut” with other stimulants such as methamphetamine. Adulterated cocaine is often a white, off-white or pinkish powder.

The color of “crack” cocaine depends upon several factors including the origin of the cocaine used, the method of preparation – with ammonia or baking soda – and the presence of impurities, but will generally range from white to a yellowish cream to a light brown. Its texture will also depend on the adulterants, origin and processing of the powdered cocaine, and the method of converting the base. It ranges from a crumbly texture, sometimes extremely oily, to a hard, almost crystalline nature.

Forms of cocaine

Cocaine sulfate

Cocaine sulfate is produced by macerating coca leaves along with water that has been acidulated with sulfuric acid, or an aromatic-based solvent, like kerosene or benzene. This is often accomplished by placing the ingredients into a vat and stomping on them, in a manner similar to the traditional method for crushing grapes. A more popular method in modern times is to form a makeshift “vat” by spreading a heavy nylon tarp on the floor of an enclosed area and shred the leaves with a gas-powered weed trimmer. This method is fast, and not only shreds the leaves, but results in bruising and fragmenting of the remaining pieces, aiding the extraction process. After the maceration is completed, the water is evaporated to yield a pasty mass of impure cocaine sulfate. The sulfate salt itself is an intermediate step to producing cocaine hydrochloride.

Freebase

Main article: Freebase (chemistry)

As the name implies, “freebase” is the base form of cocaine, as opposed to the salt form of cocaine hydrochloride. Whereas cocaine hydrochloride is extremely soluble in water, cocaine base is insoluble in water and is therefore not suitable for drinking, snorting or injecting. Whereas cocaine hydrochloride is not well-suited for smoking because the temperature at which it vaporizes is very high and close to the temperature at which it burns; cocaine base vaporizes at a much lower temperature, which makes it suitable for inhalation.

Smoking freebase cocaine has the additional effect of releasing methylecgonidine into the user’s system due to the pyrolysis of the substance (a side effect which insufflating or injecting powder cocaine does not create). Some research suggests that smoking freebase cocaine can be even more cardiotoxic than other routes of administration because of methylecgonidine’s effects on lung tissue and liver tissue.

When smoked, cocaine is sometimes combined with other drugs, such as cannabis, often rolled into a joint or blunt. Powdered cocaine is also sometimes smoked, though heat destroys much of the chemical; smokers often sprinkle it on marijuana.

The language referring to paraphernalia and practices of smoking cocaine vary, as do the packaging methods in the street level sale.

Physical mechanisms

The difference between cocaine & amphetamine with regard to DAT1 receptor reuptake blocking. Cocaine binds directly to the DAT1 transporter, whereas amphetamines phosphorylate and invert the transporter causing it to internalize.

The pharmacodynamics of cocaine involve the complex relationships of neurotransmitters (inhibiting monoamine uptake in rats with ratios of about: serotonin:dopamine = 2:3, serotonin:norepinephrine = 2:5) The most extensively studied effect of cocaine on the central nervous system is the blockade of the dopamine transporter protein. Dopamine transmitter released during neural signaling is normally recycled via the transporter; i.e., the transporter binds the transmitter and pumps it out of the synaptic cleft back into the presynaptic neuron, where it is taken up into storage vesicles. Cocaine binds tightly at the dopamine transporter forming a complex that blocks the transporter’s function. The dopamine transporter cao longer perform its reuptake function, and thus dopamine accumulates in the synaptic cleft. This results in an enhanced and prolonged postsynaptic effect of dopaminergic signaling at dopamine receptors on the receiving neuron. Prolonged exposure to cocaine, as occurs with habitual use, leads to homeostatic dysregulation of normal (i.e. without cocaine) dopaminergic signaling via down-regulation of dopamine receptors and enhanced signal transduction. The decreased dopaminergic signaling after chronic cocaine use may contribute to depressive mood disorders and sensitize this important brain reward circuit to the reinforcing effects of cocaine (e.g. enhanced dopaminergic signalling only when cocaine is self-administered). This sensitization contributes to the intractable nature of addiction and relapse.

Dopamine-rich brain regions such as the ventral tegmental area, nucleus accumbens, and prefrontal cortex are frequent targets of cocaine addiction research. Of particular interest is the pathway consisting of dopaminergic neurons originating in the ventral tegmental area that terminate in the nucleus accumbens. This projection may function as a “reward center”, in that it seems to show activation in response to drugs of abuse like cocaine in addition to natural rewards like food or sex. While the precise role of dopamine in the subjective experience of reward is highly controversial among neuroscientists, the release of dopamine in the nucleus accumbens is widely considered to be at least partially responsible for cocaine’s rewarding effects. This hypothesis is largely based on laboratory data involving rats that are trained to self-administer cocaine. If dopamine antagonists are infused directly into the nucleus accumbens, well-trained rats self-administering cocaine will undergo extinction (i.e. initially increase responding only to stop completely) thereby indicating that cocaine is no longer reinforcing (i.e. rewarding) the drug-seeking behavior.

In addition to the mechanism shown on the above chart, cocaine has been demonstrated to bind as to directly stabilize the DAT transporter on the open outward-facing conformation whereas other stimulants (namely phenethylamines) stabilize the closed conformation. Further, cocaine binds in such a way as to inhibit a hydrogen bond innate to DAT that otherwise still forms when amphetamine and similar molecules are bound. Cocaine’s binding properties are such that it attaches so this hydrogen bond will not form and is blocked from formation due to the tightly locked orientation of the cocaine molecule. Research studies have suggested that the affinity for the transporter is not what is involved in habituation of the substance so much as the conformation and binding properties to where & how on the transporter the molecule binds.

Sigma receptors are effected by cocaine, as cocaine functions as a sigma ligand agonist.  Further specific receptors it has been demonstrated to function on are NMDA and the D1 dopamine receptor.^[

In addition to irritability, mood disturbances, restlessness, paranoia, and auditory hallucinations, cocaine use can cause several dangerous physical conditions. It can lead to disturbances in heart rhythm and heart attacks, as well as chest pains or even respiratory failure. In addition, strokes, seizures and headaches are common in heavy users.

Cocaine can often cause reduced food intake, many chronic users lose their appetite and can experience severe malnutrition and significant weight loss. Cocaine effects, further, are shown to be potentiated for the user when used in conjunction with new surroundings and stimuli, and otherwise novel environs.

Metabolism and excretion

Cocaine is extensively metabolized, primarily in the liver, with only about 1% excreted unchanged in the urine. The metabolism is dominated by hydrolytic ester cleavage, so the eliminated metabolites consist mostly of benzoylecgonine (BE), the major metabolite, and other significant metabolites in lesser amounts such as ecgonine methyl ester (EME) and ecgonine. Further minor metabolites of cocaine include norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE), and m-hydroxybenzoylecgonine. These do not include metabolites created beyond the standard metabolism of the drug in the human body, like for example by the process of pyrolysis such as is the case with methylecgonidine. Depending on liver and kidney function, cocaine metabolites are detectable in urine. Benzoylecgonine can be detected in urine within four hours after cocaine intake and remains detectable in concentrations greater than 150 ng/ml typically for up to eight days after cocaine is used. Detection of accumulation of cocaine metabolites in hair is possible in regular users until the sections of hair grown during use are cut or fall out. If consumed with alcohol, cocaine combines with alcohol in the liver to form cocaethylene. Studies have suggested cocaethylene is both more euphorigenic, and has a higher cardiovascular toxicity than cocaine by itself.

Effects and health issues

Acute

Data from The Lancet shows Cocaine to be the 2nd most dependent and 2nd most harmful of 20 drugs.

Cocaine is a potent central nervous system stimulant. Its effects can last from 20 minutes to several hours, depending upon the dosage of cocaine taken, purity, and method of administration.

The initial signs of stimulation are hyperactivity, restlessness, increased blood pressure, increased heart rate and euphoria. The euphoria is sometimes followed by feelings of discomfort and depression and a craving to experience the drug again. Sexual interest and pleasure can be amplified. Side effects can include twitching, paranoia, and impotence, which usually increases with frequent usage.

Cocaine can cause coronary artery spasms which lead to a myocardial infarction. This effect can happen randomly to any user. The coronary artery spasms can occur on the user’s first usage or any other usage after. The coronary spasms cause the ectopic ventricular foci of the heart to become hypoxic and the extreme irritability can trigger life-threatening ventricular arrhythmias.

Chronic

Main effects of chronic cocaine use.

Chronic cocaine intake causes brain cells to adapt functionally to strong imbalances of transmitter levels in order to compensate extremes. Thus, receptors disappear from the cell surface or reappear on it, resulting more or less in an “off” or “working mode” respectively, or they change their susceptibility for binding partners (ligands) – mechanisms called down-/upregulation. However, studies suggest cocaine abusers do not show normal age-related loss of striatal DAT sites, suggesting cocaine has neuroprotective properties for dopamine neurons. The experience of insatiable hunger, aches, insomnia/oversleeping, lethargy, and persistent runny nose are often described as very unpleasant. Depression with suicidal ideation may develop in very heavy users. Finally, a loss of vesicular monoamine transporters, neurofilament proteins, and other morphological changes appear to indicate a long term damage of dopamine neurons. All these effects contribute a rise in tolerance thus requiring a larger dosage to achieve the same effect.

The lack of normal amounts of serotonin and dopamine in the brain is the cause of the dysphoria and depression felt after the initial high. Physical withdrawal is not dangerous, and is in fact restorative. The diagnostic criteria for cocaine withdrawal are characterized by a dysphoric mood, fatigue, unpleasant dreams, insomnia or hypersomnia, erectile dysfunction, increased appetite, psychomotor retardation or agitation, and anxiety.

         Scopolamine, known by the names levo-duboisine and hyoscine, is a tropane alkaloid drug with muscarinic antagonist effects. It is obtained from plants of the family Solanaceae (nightshades), such as henbane, jimson weed and Angel’s Trumpets (Datura resp. Brugmansia spec.), and corkwood (Duboisia species ). It is among the secondary metabolites of these plants. Therefore, scopolamine is one of three main active components of belladonna and stramonium tinctures and powders used medicinally along with atropine and hyoscyamine. Scopolamine was isolated from plant sources by scientists in 1881 in Germany and description of its structure and activity followed shortly thereafter and much knowledge was acquired prior to 1881 as the alkaloid was known for a number of years as levo-duboisine.

Scopolamine has anticholinergic properties and has legitimate medical applications in very minute doses. As an example, in the treatment of motion sickness, the dose, gradually released from a transdermal patch, is only 330 microgrammes (µg) per day. An overdose can cause delirium, delusions, dangerous elevations of body temperature, stupor and death.

Etymology

Scopolamine is named after the plant genus Scopolia. The name “hyoscine” is from the scientific name for henbane, Hyoscyamus niger.

Physiology

Scopolamine acts as a competitive antagonist at muscarinic acetylcholine receptors, specifically M1 receptors; it is thus classified as an anticholinergic,anti-muscarinic drug. (See the article on the parasympathetic nervous system for details of this physiology.)

Medical use

In medicine, scopolamine has these uses:

• Primary:

• Treatment of nausea and motion sickness

• Treatment of intestinal cramping

• For ophthalmic purposes.

• As a general depressant and adjunct to narcotic painkillers

• Less often:

• As a preanesthetic agent

• As a drying agent for sinuses, lungs, and related areas.

• To reduce motility and secretions in the GI tract — most frequently in tinctures or other belladonna or stramonium preparations, often used in conjunction with other drugs as in Donnagel original forumulation,

Addiction

Scopolamine has been used in the past to treat addiction to drugs such as heroin and cocaine. The patient was given frequent doses of scopolamine until they were delirious. This treatment was maintained for 2 to 3 days after which they were treated with pilocarpine. After recovering from this they were said to have lost the acute craving to the drug to which they were addicted. Currently, scopolamine is being investigated for its possible usefulness alone or in conjunction with other drugs in assisting people in breaking the nicotine habit. The mechanism by which it mitigates withdrawal symptoms is different from that of clonidine meaning that the two drugs can be used together without duplicating or canceling out the effects of each other.

Other medical uses

• It can be used as a depressant of the central nervous system, and was formerly used as a bedtime sleep aid.

• Anesthetic; Its use in general anesthesia is favored by some due to its amnesic effect. Scopolamine causes memory impairments to a similar degree as diazepam.

• In otolaryngology it is used to dry the upper airway (anti-sialogogue action) prior to instrumentation of the airway.

• In October 2006 researchers at the US National Institute of Mental Health found that scopolamine reduced symptoms of depression within a few days, and the improvement lasted for at least a week after switching to a placebo.

• Due to its effectiveness against sea-sickness it has become commonly used by scuba divers.

Recreational use

The use of medical scopolamine by itself or in opioid combination preparations for euphoria is uncommon but does exist and can be seen in conjunction with opioid use.

Another separate group of users prefer dangerously high doses, especially in the form of datura preparations, for the deliriant and hallucinogenic effects. The hallucinations produced by scopolamine, in common with other potent anticholinergics, are especially real-seeming, repetitive, boring and unpleasant. An overdose of scopolamine is also physically exceedingly unpleasant and can be fatal, unlike the effect of other more commonly used hallucinogens. For these reasons, naturally occurring anticholinergics are rarely used for recreational purposes.

Scopolamine in transdermal, oral, sublingual, and injectable formulations can produce a cholinergic rebound effect when high doses are stopped. This is the opposite of scopolamine’s therapeutic effects: sweating, runny nose, abdominal cramps, nausea, vomiting, vertigo, dizziness, irritability, and diarrhea. Psychological dependence is also possible when the drug is taken for its tranquilizing effects.

         Reserpine is an indole alkaloid^] antipsychotic and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic behaviors, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely used today. The antihypertensive actions of Reserpine are a result of its ability to deplete catecholamines (among the others) from peripheral sympathetic nerve endings. These substances are normally involved in controlling heart rate, force of cardiac contraction and peripheral resistance.  Reserpine depletion of monoamine neurotransmitters in the synapses is often cited as evidence to the theory that depletion of the neurotransmitters causes subsequent depression in humans. Moreover, reserpine has a peripheral action in many parts of the body, resulting in a preponderance of the cholinergic part of the nervous system (GI-Tract, smooth muscles vessels).

Reserpine has been discontinued in the UK for some years due to its vast interactions and side effects.

Reserpine was also highly influential in promoting the thought of a biogenic-amine hypothesis of depression – see Everett & Tolman, 1959.

Uses today

Reserpine is one of the few antihypertensive medications that have been shown in randomized controlled trials to reduce mortality: The Hypertension Detection and Follow-up Program, the Veterans Administration Cooperative Study Group in Anti-hypertensive Agents, and the Systolic Hypertension in the Elderly Program.

Reserpine is listed as a second line choice by the JNC 7. Reserpine is a second-line adjunct agent for patients who are uncontrolled on a diuretic when cost is an issue.

It is also used to treat symptoms of dyskinesia in patients suffering from Huntington’s disease.

In some countries reserpine is still available as part of combination drugs for the treatment of hypertension, in most cases they contain also a diuretic and/or a vasodilator like hydralazine. These combinations are currently regarded as second choice drugs. The daily dose of reserpine in antihypertensive treatment is as low as 0.1 to 0.25mg. The use of reserpine as an antipsychotic drug has beeearly completely abandoned. Originally, doses of 0.5mg to 40mg daily were used to treat psychotic diseases. Doses in excess of 3mg daily often required use of an anticholinergic drug to combat excessive cholinergic activity in many parts of the body as well as parkinsonism. Reserpine may be used as a sedative for horses.

Side effects

At doses of less than 0.2 mg/day, reserpine has few side effects, most commonly is nasal congestion.

There has been much concern about reserpine causing depression leading to suicide. However, this was reported in uncontrolled studies using doses averaging 0.5 mg per day.

Reserpine can cause: nasal congestion, nausea, vomiting, weight gain, gastric intolerance, gastric ulceration (due to increased cholinergic activity in gastric tissue and impaired mucosal quality), stomach cramps and diarrhea are noted. The drug causes hypotension and bradycardia and may worsen asthma. Congested nose and erectile dysfunction are other consequences of alpha-blockade. Depression can occur at any dose and may be severe enough to lead to suicide. Other central effects are a high incidence of drowsiness, dizziness, and nightmares. Parkinsonism occurs in a dose dependent manner. General weakness or fatigue is quite often encountered. High dose studies in rodents found reserpine to cause fibroadenoma of the breast and malignant tumors of the seminal vesicles among others. Early suggestions that reserpine causes breast cancer in women (risk approximately doubled) were not confirmed. It may also cause hyperprolactinemia.

Strychnine is a very toxic (LD₅₀ = 10 mg approx.), colorless crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine causes muscular convulsions and eventually death through asphyxia or sheer exhaustion. The most common source is from the seeds of the Strychnos nux vomica tree. Strychnine is one of the most bitter substances known. Its taste is detectable in concentrations as low as 1 ppm.

Pharmacology

Strychnine acts as a blocker or antagonist at the inhibitory or strychnine-sensitive glycine receptor (GlyR), a ligand-gated chloride channel in the spinal cord and the brain.

Although it is best known as a poison, small doses of strychnine were once used in medications as a stimulant, a laxative and as a treatment for other stomach ailments. A 1934 drug guide for nurses described it as “among the most valuable and widely prescribed drugs”.  Strychnine’s stimulant effects also led to its use historically for enhancing performance in sports. Because of its high toxicity and tendency to cause convulsions, the use of strychnine in medicine was eventually abandoned once safer alternatives became available.

The dosage for medical use was cited as between “1/60th grain–1/10th grain”, which is between 1.1 milligrams and 6.4 milligrams in modern measures. Normally the maximum dosage used was 3.2 mg, half of a “full dose”. A lethal dose was cited as 1/2 a grain (32 mg), but people have been known to die from as little as 5 mg of strychnine.

Strychnine  

 

 

Xanthine is a product on the pathway of purine degradation.

• It is created from guanine by guanine deaminase.

• It is created from hypoxanthine by xanthine oxidoreductase.

Xanthine is subsequently converted to uric acid by the action of the xanthine oxidase enzyme.

Pathology

People with the rare genetic disorder xanthinuria lack sufficient xanthine oxidase and cannot convert xanthine to uric acid.

 Clinical significance of xanthine derivatives

Derivatives of xanthine, known collectively as xanthines, are a group of alkaloids commonly used for their effects as mild stimulants and as bronchodilators, notably in treating the symptoms of asthma. In contrast to other, more potent stimulants, they only inhibit the actions of sleepiness-inducing adenosine, making them somewhat less effective as stimulants than sympathomimetic amines. Due to widespread effects, the therapeutic range of xanthines is narrow, making them merely a second-line asthma treatment. The therapeutic level is 10-20 micrograms/mL blood; signs of toxicity include tremor, nausea, nervousness, and tachycardia/arrhythmia.

Methylated xanthine derivatives include caffeine, paraxanthine, theophylline, and theobromine. These drugs inhibit phosphodiesterase and antagonise adenosine. Xanthines are also found very rarely as constituents of nucleic acids.

Caffeine: R₁ = R₂ = R₃ = CH₃
Theobromine: R₁ = H, R₂ = R₃ = CH₃
Theophylline: R₁ = R₂ = CH₃, R₃ = H

         Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a psychoactive stimulant drug and a mild diuretic. Caffeine was discovered by a German chemist, Friedrich Ferdinand Runge, in 1819. He coined the term “kaffein”, a chemical compound in coffee, which in English became caffeine.^[4] Caffeine is also part of the chemical mixtures and insoluble complexes guaranine found in guarana, mateine found in mate, and theine found in tea; all of which contain additional alkaloids such as the cardiac stimulants theophylline and theobromine, and often other chemicals such as polyphenols which can form insoluble complexes with caffeine.

Caffeine is found in varying quantities in the beans, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants. It is most commonly consumed by humans in infusions extracted from the cherries of the coffee plant and the leaves of the tea bush, as well as from various foods and drinks containing products derived from the kola nut. Other sources include yerba mate, guarana berries, and the Yaupon Holly.

In humans, caffeine is a central nervous system (CNS) stimulant, having the effect of temporarily warding off drowsiness and restoring alertness. Beverages containing caffeine, such as coffee, tea, soft drinks and energy drinks enjoy great popularity. Caffeine is the world’s most widely consumed psychoactive substance, but unlike many other psychoactive substances it is legal and unregulated iearly all jurisdictions. In North America, 90% of adults consume caffeine daily. The U.S. Food and Drug Administration lists caffeine as a “Multiple Purpose Generally Recognized as Safe Food Substance”.

Pharmacology

Global consumption of caffeine has been estimated at 120,000 tonnes per annum, making it one of the world’s most popular psychoactive substances. This number equates to one serving of a caffeine beverage for every person, per day. Caffeine is a central nervous system and metabolic stimulant and is used both recreationally and medically to reduce physical fatigue and restore mental alertness when unusual weakness or drowsiness occurs. Caffeine stimulates the central nervous system first at the higher levels, resulting in increased alertness and wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination, and later at the spinal cord level at higher doses. Once inside the body, it has a complex chemistry, and acts through several mechanisms as described below.

Metabolism and half-life

Caffeine is metabolized in the liver into three primary metabolites: paraxanthine (80%), theobromine (10%), and theophylline (4%)

Each of these metabolites is further metabolized and then excreted in the urine.

Mechanism of action

Caffeine’s principal mode of action is as an antagonist of adenosine receptors in the brain.

Overview of the more common side effects of caffeine, possibly appearing even at levels below overdos

 

         Theobromine, also known as xantheose, is a bitter alkaloid of the cacao plant, found in chocolate, as well as in a number of chocolate-free foods made from theobromine sources including the leaves of the tea plant, the kola or cola nut, and acai berries. It is in the methylxanthine class of chemical compounds, which also includes the similar compounds theophylline and caffeine. Despite its name, the compound contains no bromine — theobromine is derived from Theobroma, the name of the genus of the cacao tree, (which itself is made up of the Greek roots theo (“God”) and brosi (“food”), meaning “food of the gods”) with the suffix -ine given to alkaloids and other basic nitrogen-containing compounds.

Theobromine is a water insoluble, crystalline, bitter powder; the colour has been listed as either white or colourless. It has a similar, but lesser, effect to caffeine, making it a lesser homologue. Theobromine is an isomer of theophylline as well as paraxanthine. Theobromine is categorized as a dimethyl xanthine, which means it is a xanthine with two methyl groups.

Theobromine was first discovered in 1841 in cacao beans by Russian chemist Alexander Woskresensky. Theobromine was first isolated from the seeds of the cacao tree in 1878  and then shortly afterwards was synthesized from xanthine by Hermann Emil Fischer.

Sources

 

A chocolate bar and melted chocolate. Chocolate is made from the cacao bean, which is a natural source of theobromine.

The mean theobromine concentrations in cocoa and carob products are:

Item	Mean theobromine content (mg/g)
Cocoa	20.3
Cocoa cereals	0.695
Chocolate bakery products	1.47
Chocolate toppings	1.95
Cocoa beverages	2.66
Chocolate ice creams	0.621
Chocolate milks	0.226
Carob products	0-0.504

Pharmacology

Even without dietary intake, theobromine may occur in the body as it is a product of the human metabolism of caffeine which is metabolised in the liver into 10% theobromine, 4% theophylline, and 80% paraxanthine.

In the liver, theobromine is metabolized into methylxanthine and subsequently into methyluric acid. Important enzymes include CYP1A2 and CYP2E1.

As a methylated xanthine, theobromine is a potent Cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor; this means that it helps prevent the enzyme phosphodiesterase from converting the active cAMP to an inactive form. cAMP works as a second messenger in many hormone- and neurotransmitter-controlled metabolic systems, such as the breakdown of glycogen. When the inactivation of cAMP is inhibited by a compound such as theobromine, the effects of the neurotransmitter or hormone which stimulated the production of cAMP are much longer lived. The net result is generally a stimulatory effect.

Theobromine

Uncontrolled substance

Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD or asthma under a variety of brand names. Due to its numerous side-effects, these drugs are now rarely administered for clinical use. As a member of the xanthine family, it bears structural and pharmacological similarity to caffeine. It is naturally found in tea, although in trace quantities (~1 mg/L), significantly less than therapeutic doses.

The main actions of theophylline involve:

• relaxing bronchial smooth muscle

• increasing heart muscle contractility and efficiency: positive inotropic

• increasing heart rate: positive chronotropic

• increasing blood pressure

• increasing renal blood flow

• some anti-inflammatory effects

• central nervous system stimulatory effect mainly on the medullary respiratory center.

Synthesis

 

Theophylline can be prepared synthetically starting from dimethylurea and ethyl 2-cyanoacetate.

Theophylline

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