Quinolone and Cinchona Alkaloids

Quinolone Alkaloids

• Alkaloids containing a quinolone nucleus are derived from cinchona bark
• Examples of quinolone alkaloids include quinine, quinidine, cinchonine, and cinchonidine

Cinchona Alkaloids

• More than 25 alkaloids are derived from Yellow Cinchona (Cinchona calisaya and Cinchona ledgeriana) or Red Cinchona (Cinchona succirubra)
• All of the above are from the Rubiaceae family
• Cinchona alkaloids typically have two rings: a quinolone ring (benzene + pyridine) and a bicyclic quinuclidine ring
• Cinchona alkaloids possess the basic skeleton of 9'-rubanol derived from ruban
• Ruban is obtained from the combination of two distinct heterocyclic nuclei

Stereoisomers

• Quinine and quinidine are stereoisomers
• Cinchonine and cinchonidine are stereoisomers
• Cinchonine and quinidine have the configuration C8= R, C9 = S
• Cinchonidine and quinine have the configuration C8 = S, C9 = R

Biosynthetic Pathway

• Studies with labeled geraniol and tryptophan indicate quinine is metabolically derived from the monoterpenoid-tryptophan pathway

Identification Tests for Quinine

• Quinine exhibits a distinct and strong blue fluorescence when treated with an oxygenated acid (acetic, sulfuric)
• The fluorescence test is pronounced even at low concentrations
• Hydrochloride and hydroiodide salts of quinine do not respond to the fluorescence test
• Thalleioquin Test: A weakly acidic solution of quinine salt with bromine-water and ammonia solution produces a characteristic emerald green color
• The colored product is termed thalleioquin, though its chemical composition is not yet established
• The Thalleioquin test can detect quinine at concentrations as low as 0.005%
• Quinidine gives a positive Thalleioquin test, while cinchonine and cinchonidine give a negative result

Uses of Cinchona Alkaloids

• Cinchona and its alkaloids have been used to treat malaria for many years
• Quinine sulfate is still used for malaria in many parts of the world and acts by poisoning protozoa and can be used as a tonic, analgesic, and to treat the common cold
• Quinidine treats cardiac arrhythmias like arterial and ventricular tachycardia and atrial fibrillation & ventricular contraction, and depresses myocardial excitability, conduction velocity, and contractility

Totaquine

• A mixture of total alkaloids should contain not less than 7% and not more than 12% of anhydrous quinine
• Should contain 70-80% total alkaloids
• It is used as an antimalarial and for colds, but cannot be used as a cardiac depressant
• The usual dose is 600mg

Cinchonism (Quinism)

• Cinchona product treatments can result in mild cinchonism symptoms even at standard doses of quinine
• Symptoms include flushed and sweaty skin, ringing in the ears (tinnitus), blurred vision, impaired hearing, confusion, reversible high-frequency hearing loss, headache, abdominal pain, rashes, dysphoria, nausea, vomiting, and diarrhea
• Ringing in the ears is a symptom of toxicity
• Cinchonism is the term for said side effects if they result from continuous use of cinchona or quinine

Isoquinoline Alkaloids

• Isoquinoline is a structural isomer of quinolone
• Isoquinoline and quinoline are benzo pyridines derivatives, consisting of a benzene ring fused to a pyridine ring

Types of Isoquinoline Alkaloids

• Benzylisoquinoline (BIQ) alkaloids are sometimes used as arrow poisons
• Tetrahydrobenzylisoquinoline (THBIQ) alkaloids: (+)-reticuline is the most important compound from a biosynthetic point of view
• Phenanthrene alkaloids are found in Papaveraceae as morphine and related alkaloids

Drugs Containing Isoquinoline Alkaloids

• Ipecac is comprised of the dried rhizomes and roots of Cephaelis ipecacuanha (Brazilian ipecac) or Cephaelis acuminate (Nicaragua or Panama ipecac)
• Ipecac yields at least 2% ether-soluble alkaloids, mainly emetine, cephailine, and psychotrine, all of which are THBIQ
• Hydrastis (golden seal) consists of the dried rhizomes and roots of Hydrastis canadensis
• Hydrastis yields at least 2.5% anhydrous ether-soluble alkaloids, including hydrastine, berberine, and canadine (THBIQ)
• Hydrastine and berberine are astringents in inflammation of the mucous membrane
• Curare (South American arrow poison) is a crude dried extract from the bark and stems of Strychnos castelnaei or S. crevauxii
• It contains (+)-tubocurarine, a quaternary compound with a bis-benzyl isoquinoline structure
• The crude extract has a paralyzing effect on voluntary muscles (curariform effect) by blocking nerve impulses to skeletal muscles

Tubocurarine

• Tubocurarine is a skeletal muscle relaxant used in surgical procedures without deep anesthesia, but is now substituted with clinical alternatives like cisatracurium and rocuronium
• Controls convulsions of strychnine poisoning and tetanus
• It is an adjunct therapy in neuropsychiatry and a diagnostic aid in myasthenia gravis

Berberis (Barberry)

• Berberis vulgaris contains quaternary protoberberines and bisbenzyl isoquinolines, along with (-)-tejedine (a new seco-bisbenzyl isoquinoline)
• Berberine is an antibiotic and is also anti-inflammatory, hypertensive, haemostatic, diuretic and vasodilator

Opium

• Opium or gum opium is the air-dried milky exudate obtained by incising the unripe capsules of Papaver somniferum
• The term "opium" comes from the Greek word "opion," meaning poppy juice
• "Papaver" is the Latin name for the poppy
• "Somniferum" is Latin for "to produce sleep"

Opium Cultivation

• Opium poppy cultivation is internationally controlled by the International Narcotic Control Board of the United Nations

Opium Alkaloids

• Opium contains 30 different alkaloids
• The most important are: morphine (4-21%), codeine (0.8-2.5%), noscapine (4-8%), papaverine (0.5-2.5%), and thebaine (0.5-2%)
• Opium also contains 3-5% of meconic acid, which exists freely or in combination with morphine, codeine, and other alkaloids

Classification of Opium Alkaloids

• Phenanthrene alkaloids primarily act on the CNS, producing a depressant effect and stimulating smooth muscle contraction (e.g., morphine, codeine, thebaine)
• Benzylisoquinoline alkaloids have little action on the CNS but mainly act as antispasmodics (smooth muscle relaxants) (e.g., papaverine and noscapine)
• Phenylethylamine alkaloids such as narceine

Phanathrene Derivatives and Opiates

• Phanathrene derivatives contains a benzene ring, phenolic OH, N-CH3 (tertiary amine), and an ether linkage
• Phenolic OH at position-3 changed to OCH3 yields codeine
• If the other OH is changed to OCH3 with changing double bonds, thebaine is produced

Morphine

• Morphine is the most important alkaloids of opium
• Morphine and related alkaloids are phenanthrene derivatives
• Morphine derivatives contain a phenolic and an alcoholic hydroxyl group
• Morphine and its salts are classified as narcotic analgesics
• They are strong hypnotics and narcotics
• Morphine use induces nausea, vomiting, constipation, and habit formation

Codeine

• Codeine and its salts are narcotic analgesics and antitussives
• Codeine's action is similar to morphine, but less toxic and less habit-forming

Thebaine

• Thebaine is a phenanthrene derivative used as a CNS stimulant

Ethylmorphine (Dionine)

• Used less extensively than codeine
• Formed by the ethylation of phenolic OH of morphine
• Used in ophthalmology as an analgesic

Hydrocodone

• Known as dihydrocodeinone
• Bears the same relation to codeine as hydromorphone dose to morphine
• Used mainly as a cough suppressant agent

Diacetylmorphine (Heroine)

• Formed by acetylation of morphine
• Toxic and expensive, 100 times stronger than morphine
• Highly addictive
• Heroin is sometimes available in free base form and due to its lower boiling point, can be smoked

Hydromorphone

• Hydromorphone (dihydromorphinone) is prepared by reducing morphine in HCl solution (one OH group is replaced by a ketone group, and an adjacent double bond is removed)
• It is a powerful narcotic analgesic with potent respiratory depression

Apomorphine

• Prepared by heating morphine in a sealed tube with HCl
• Used as an emetic, particularly in cases of poisoning

Papaverine

• Papaverine is a derivative of benzylisoquinoline and it is a smooth muscle relaxant

Noscapine

• Commonly called narcotine
• It is also a derivative of benzyl isoquinoline
• Has no narcotic properties, and is used as an anti-tussive

Pantopon

• Preparation of the total alkaloids of opium deprived or excluded from any other non-alkaloidal material
• The alkaloids are found in the same proportion as in the opium drug.
• Pantopon contains about 50% morphine
• More preferable to be prescribed than morphine alone because of the synergistic effect

Opioids

• Refers to synthetic morphine-like compounds
• Many offer the same narcotic and pain-relieving properties as morphine, but are not as habit-forming
• Others possess cough-relieving activity like codeine but are not addictive, e.g., morphinan opioids, methadone, and meperidine

Opioid Classification

• Natural opiates: morphine, codeine, thebaine
• Semi-synthetic opioids: created from natural opiates or morphine esters, such as hydromorphone
• Fully synthetic opioids: pethidine, tramadol

Opiates vs Opioids

• While often used synonymously, "opiate" should be limited to alkaloids found in the resin of the opium poppy (Papaver somniferum)
• "Opioid" refers to both opiates and synthetic substances, as well as opioid peptides

Sanguinaria (Blood Root)

• Sanguinaria consists of dried rhizomes & roots of Sanguinaria canadensis
• Sanguinaria contains the benzyl phenanthridine alkaloids sanguinarine, chelerythrine, and protopine
• It's mainly used as an ingredient of compound white pine syrup