ALKALOIDS

ALKALOIDS OBJECTIVESTo know what are the characteristics of alkaloidsTo know the different sources of alkaloidsTo determine the importance of alkaloids and to identify their applications in pharmacyTo know the different test in determining the presence of alkaloids

WHAT ARE ALKALOIDS? These are commonly applied to basic nitrogenous compounds of plant origin that are physiologically active. Organic nitrogenous compounds with a limited distribution in native nature.

STRUCTURE OF ALKALOIDS

4Characteristics:They are bitter in taste. Derived from amino acidsAlkaloids form double salts with compounds of mercury, gold, platinum and other heavy metals. These salts are obtained as precipitate which are microcrystallographic.

Most but not all alkaloids possess basic properties owing to the presence of amino nitrogen. Structurally complex end products of energy- requiring reaction sequences.

Alkaloids usually contain one nitrogen atom but some may contain 5 nitrogen atoms such as ergotamine. The nitrogen may exist as a primary amine (RNH2), secondary amine (R2NH), tertiary amine (RN), or as quaternary.

Properties of Alkaloids

Insoluble or sparingly soluble in water, but the salts formed on reaction with acids are usually freely soluble. Most are crystalline solids although a few are amorphous.

Free alkaloids are usually soluble in ether, chloroform, or other relatively non-polar immiscible solvents. Some alkaloids are liquid because of lacking of oxygen in their molecules. (e.g coniine, nicotine, spartenine)

The degree of basicity varies greatly, depending on the structure of the molecule and the presence and location of other functional groups. Have high melting points

Sources and Occurrence of Alkaloids

Alkaloids can occur in plant kingdoms; among the angiosperms, the Leguminosae, Papaveraceae, Ranunculaceae, Rubiaceae, Solanaceae, and Berberidaceae are outstanding alkaloid-yielding plants. The Labiatae and Rosaceae are almost free of alkaloids; the gymnosperms only rarely contain them (Taxaceae).Specific alkaloids are confined to specific plant families such as hyoscyamine in Solanaceae, colchicine in Liliaceae

Although it has been claimed that the monocotyledons do not generally produce alkaloids, investigations indicate that the Amaryllidaceae and Liliaceae are two of the most promising families (of a list 11) in which to search for alkaloid- yielding plants.

Occur in fungi (e.g ergot from Claviceps purpurea)Occur in various parts of the plant; in seeds (physostigma, areca), underground stems (sanguinaria), roots (belladonna root), rhizomes and roots (ipecac, hydrastis), barks (cinchona).

Uses of Alkaloids in Plants:

Poisonous agents which protect plants against insects and herbivoresEnd products of detoxification reactions representing a metabolic locking-up of compounds otherwise harmful to the plants.

For regulatory growth factorsReserve substance capable of supplying nitrogen or other elements necessary to the plants economy

Pharmacologic action of Alkaloids:

Analgesic (morphine, codeine)Narcotics (strychnine, brucine which are central stimulant) Mydriatics (atropine)Miotics (physostigmine, pilocarpine) Ephedrine (rises in blood pressure) Reserpine (produce fall in excessive hypertension)

Biosynthesis of Alkaloids

The biosynthesis of many alkaloidal structures can be rationalized through simple chemical reactions that involve amino acids. The amino acids that are most often serve as alkaloidal precursors are: phenylalanine, tyrosine, tryptophan, histidine, anthranilic acid, lysine and ornithine.

Some of the general reactions that are of particular importance include: decarboxylation (removal of carboxyl group or carbon dioxide) and transamination (transfer of an amino group from one molecule to another without the formation of ammonia) of the amino acids to yield a corresponding amine or aldehyde. These can react to form a Schiff base which, in turn can react with carbanion in a Mannich-type condensation.Test for Alkaloids

Wagners Test (+) Reddish brown precipitateReagent used: Wagners Reagent [Solution of iodine in potassium iodide]

Mayers Test (+) Cream color precipitatesReagent used: Mayers Reagent [Potassium mercuric iodide solution]

Dragendorffs test(+) Orange precipitateReagent used: Dragendorffs reagent [Potassium bismuth iodide solution]Hager's test(+) Yellow color precipitate Reagent used: Hager's reagent [saturated solution of Picric acid]

Tannic acid test(+)buff color precipitateReagent used: 10% Tannic acid solution

Valsers Test (+) white precipitateReagent used: Valsers reagent (Mercuric Iodide TSNaming for alkaloids

From the generic name or the genus of the plant yielding them (e.g hydrastine, atropine) The specific name or species of the plant yielding alkaloids ( e.g cocaine, belladonnine)Common name of the drug yielding them (e.g ergotamine)

From their physiologic activity (e.g emetine, morphine)From the discoverer (e.g pelletierine)

~ All names of alkaloids should end in -ine.~ A prefix or suffix is added to the name of a principal alkaloid from the same source. (quinine, quinidine, hydroquinine)

Classification of Alkaloids

Pyridine- Piperidine CombinedTropaneQuinolineIsoquinolineIndoleImidazoleSteroidAlkaloidal amine Purine

Pyridine- Piperidine Combined

Also referred to as Pyrrolizidine alkaloidsUpon reduction, the tertiary base, pyridine, is converted into the secondary base, piperidine.

3 SubgroupsDerivatives of piperidineDerivatives of nicotinic acidDerivatives of both pyridine and pyrrolidine

Important alkaloidal drugs and alkaloids that are classified in this group are:

ArecaArecolineHydrobromideLobeliaLobeline Nicotine

Nicotine A primarily product of root metabolism, but the formation of small amounts, as well as subsequent reactions such as demethylation of nicotine, can occur in leaves of plants.

It is a pyridine alkaloid obtained from the dried leaves of the tobacco plant Nicotiana tabacum Linn (Fam. Solanaceae)Nicotiana was named after Jean Nicot who introduced tobacco in Europe

Tabacum refers to the Indian name for the pipe or tube used in smoking itIt is colorless to pale yellow, very hygroscopic, oily, volatile liquid with unpleasant, pungent odor and a sharp, burning, persistent taste.

USES: It is bound to an ion exchange resin in a chewing gum base as a temporary aid to the cigarette smoker seeking to give up smoking. Chronic use of nicotine may result in psychological and physical dependence.

Areca Areca nut or Betel Nut A dried, ripe seed of Areca catechu (Fam. Palmae) Areca- a Spanish and Portuguese term for betel nut

Catechu- East Indian name for an astringent extract or juiceAreca mixed with lime, the leaves of Piper bette Linn and occasionally gambir is known as PUNSUPARI. This mixture is used as a stimulant masticatory. Consists of 0.45% alkaloids, 15% tannins, lipids, volatile oils and gum.

Uses:Pharmaceutic purposesAnthelmintic or vermicide in veterinary practiceTaenifuge

Constituents: These are reduced pyridine derivatives. Arecoline (arecaidine methyl ester) Arecaidine (N-methyl guvacine)Guvacine (Tetrahydronicotinic acid) Guvacoline (Guvacine methyl ester)

LOBELIA

Indian tobacco Consists of dried leaves and tops of Lobelia inflata Linn (Fam. Lobeliaceae)Lobelia named in honour of a Flemish botanist Matthias de L Obel

Inflata refers to a hollow and distended fruit Substitute for tobacco Uses:Similar but weaker pharmacological effects in nicotine on the peripheral circulation, neuromuscular junctions, and CNS.Anti-smoking preparations

Lobeline sulfate incorporated in tablets or lozenges are smoking deterrents. Lobeline had placebo effect on decreasing the physical craving for cigarettes.Traditionally used by the Native Americans for asthmaChronic bronchitisInjection of lobeline hydrochloride is used in the resuscitation of newborn infants

Constituents: Contains 14 alkaloids which LOBELINE is the major and most important. It has a pungent, volatile oil, resin, lipids, and gum. Lobeline, (-) lobeline or alpha lobelineThis occurs as colorless crystals which are slightly soluble in water but readily soluble in hot alcohol.

Tropane Alkaloids

A dicyclic compound formed by the condensation of a pyrrolidine precursor (ornithine) with three acetate-derived carbon atoms. Both pyrrolidine and piperidine ring system can be discerned in the molecule. The 3-hydroxy derivative of tropane is known as tropine. Its esterification with (-)- tropic acid yields hyoscamine (tropine, tropate), which may be racemized to form atropine.

Important alkaloidal drugs and alkaloids that are classified in this group are:

Belladonna leafHyoscyamusStramoniumAtropineHyoscyamineScopolamineCocaCocaineBELLADONNA

Belladonna leaf, Belladonna herb or deadly nightshade leafConsists of dried leaf and flowering or fruiting top of Atropa belladonna Linn or of its variety acuminata Royle ex Lindley (Fam. Solanaceae)

Atropa is from Atropos meaning inflexibleBelladonna from Italian word bella meaning beautiful and donna meaning ladyUses:It acts as an antimuscarinic agent which accounts for its use as a spasmolytic drug.Treating diarrhea, diverticulitis , pancreatitis

Used as a adjunctive therapy in the treatment of peptic ulcer; functional digestive disordersIt possesses anticholinergic properties and is used to control excess motor activity of the GI tract and spasm of the urinary tract. It is commonly administered in the tincture (3mg alkaloids/ 100ml) or the extract (1.25 g alkaloids/100g)

Constituents:

(-)- hyoscyamine remainder atropine ApoatropineBelladonnineCuscohygrineScopolamineSolanaceous Alkaloids

The principal alkaloids of this group are: (-) hyoscyamineatropine [() hyoscyamine]scopolamine (also known as hyoscine)

These are tropine derivatives and esters and may be prepared synthetically but are usually obtained by extraction from plants of the Solanaceae such as:Atropa belladonnaDatura stramonium Hyoscyamus niger Hyoscyamus muticus (also known as Henbane) Dubosia plants

Atropine An antidote in case of poisoning caused by cholinesterase inhibitors. It is a CNS stimulant.

Scopolamine It has a depressant activity on the CNS.It is used to treat motion sickness. It is employed for preanesthetic sedation and for obstetric amnesia in conjunction with analgesics and to calm delirium.

Toxicity symptoms occur in using atropine, scopolamine and belladonna tincture include:Skin rashSkin flushingMouth dryness Difficulty in urination Eye pain Blurred visionLight sensitivity

Hyoscyamine a tropine ester of (-)-tropic acid

Hyoscyamine sulfate extremely poisonous It occurs as white, odourless crystals or as crystalline powder. It is a deliquescent and is affected of light.

It is an anticholinergic and used as an aid in the control of gastric secretion, visual spasm, hypermotility in spastic colitis, pylorospasm and abdominal cramps. In Parkinsonism, it is used to reduce rigidity and tremors and to control associated sialorrhea and hyperhidrosis. Atropine sulfate It occurs as colorless crystals or as a white, crystalline powder. It is extremely poisonous. It effloresces in dry air and is slowly affected by light. It is an anticholinergic, used in surgery as an antisialogogue.

Scopolamine or hyoscine An alkaloid abundant in Datura fastuosa var. alba and in D. Metel. It is an ester that, upon hydrolysis, yields tropic acid and scopoline. It occurs as an almost colorless, syrupy liquid from its chloroformic solution and colorless crystals from its ether solution. LEVOROTATORY

Scopolamine hydrobromide or hyoscine hydrobromide It occurs as colorless or white crystals or as a white, granular powder that is odourless and slightly efflorescent in dry air. It is extremely poisonous. It is classified as anticholinergic. It is employed for preanesthetic sedation and for obstetric amnesia in conjunction with analgesics and to calm delirium. It is administered SC or IM in a single dose.

Hyoscyamus Also known as Henbanedried leaf with or without the stem and flowering or fruiting crop of Hyoscyamus niger Linn (Fam. Solanaceae) It contains not less than 0.04% alkaloids of hyoscyamus.

Hyoscyamus (a Greek and Latin name formed from two Greek words, meaning hog and bean. The plant is poisonous to swine. The alkaloids, hyoscyamine and scopolamine, 0.05% to 0.15% of which three fourths is hyoscyamine are the active ingredients.

Hyoscyamus

Stramonium

Also known as Jimson weed, Jamestown weeddried leaf with or without the stem and flowering or fruiting crop of Datura stramonium Linn (Fam. Solanaceae)

It yields not less than 0.25% of alkaloids. Datura (from Sanskrit dhatura, and from Arabic tatura or tatula, the native name)Stramonium (from the French word stramoine meaning stinkweed) It was used as a pot herb It can serves as atropine

Stramonium seed

from D. stramonium The seed contains 0.4% of alkaloids, principally hyoscyamine with a small portion of scopolamine and traces of atropine.

It is generally regarded as a noxious weed and has frequently caused poisoning in children when seeds were ingested. The chief toxic symptoms are those of atropine: Dilated pupilsImpaired visionsDryness of the skin Secretions Extreme thirst Hallucination Loss of consciousness

Cocaine Coca leaves or Coca Dried leaves of Erythroxylum coca Lamarck which is commercially known as Huanuco coca or of E. truxillense Rusby Truxillo coca (Fam. Erythroxylaceae)

Erythroxylum (is from the two Greek words meaning red and wood)Coca ( is the Spanish name for the tree) Truxillense (from Truxillo a coastal city in Peru) Contains three basic types of alkaloids:Derivatives of ecgonine Derivatives of tropine Derivatives of hygrine

Huanuco cocaContains 0.5 to 1% of ester alkaloids, derivatives of tropine and ecgonineCuscohygrine is the principal nonester alkaloid in the leaf.

Truxillo cocaHas lower content of ester alkaloids but higher percentage of cocaine (75%)The shrub was known as The Divine Plant of the Incas

Cocaine hydrochlorideColorless crystals or as a white, crystalline powder. Ingredient in Bromptons cocktailUse to control severe pain CNS stimulant Administered IV or SC while cocaine free-based is smoked

Crackextremely addictive smokable forms of cocaine processed from cocaine hydrochlorideIts name refers to the sound made when rocks of cocaine are smoked.

Quinoline Alkaloids

These are alkaloids which contain quinoline as their nucleus including those obtained from cinchona (quinine, quinidine, cinchonine, and cinchonidine) Cinchona and its alkaloids are the only members of this group that are therapeutically important at present. Cinchonine, is isomeric with cinchonidine which is the parent alkaloid of the quinine series. Quinine and its isomer, quinidine, represent 6-methoxycinchonine.

CINCHONA BARK Cinchona bark or Peruvian barkdried bark of the stem or of the root of Cinchona succirubra Pavon et Klotzch or its hybrids, known in commerce as red cinchona or of C. ledgeriana (Howard) Moens et Trimen, C. calisaya Weddell, or hybrids of these with other species of Cinchona, known in commerce as calisaya bark or yellow cinchona (Fam. Rubiaceae)

Cinchona (named in honor of the Countess of Chinchon, wife of viceroy of Peru)Succirubra (Latin word meaning red juice) Calisaya (a tree)Ledgeriana ( named in honor of Charles Ledger)

Cinchona toxicity results in temporary loss of hearing and in impaired sight. Ringing in the ears is one of the symptoms of toxicity. When these symptoms are produced as the result of continuous use of cinchona or of quinine. The condition has been called cinchoism. Cinchona was formerly given in doses of 1g.

Cuprea bark obtained from Remijia purdieana Triana and R. Pedunculata Fluckiger (Fam.Rubiaceae)it has a copper red color hard , compact, and heavy it contains numerous transversely elongated stone cells and 2-6 % of alkaloids of which 1/3 maybe quinine its a commercial source of quinidine.

Cinchona alkaloids

Quinidine Its a stereoisomer of quinine and is present in cinchona barks to the extent of 0.25-1.25%.It depresses myocardial excitability, conduction velocity and to a lesser extent, contractility.

Use to treat various cardiac arrhythmias such as mature atrial , AV junctional, and ventricular contractions : atrial flutter and atrial fibrilations.When administered orally, the peak serum levels are slightly lower with the gluconate and poylgalacturonate salt than with sulfate salt .

The usual real dose available is 10 to 20 mg/kg/day in 4 to 6 divided doses in order to obtain the average therapeutic serum levels of 3 to 6mcg/ml.A toxic reaction occurs at levels above 8mcg/ml.The patient should be instructed to notify the physician if skin rash,fever,unusual bleeding/bruising,ringing in the ears,or visual disturbance occurs.

Quinidine sulfatesulfate of an alkaloid obtain from cinchona from Remijia pedunculata or prepared from quinine.It occurs as fine needle like white crystals that frequently cohere in masses.It is odorless , has a bitter taste and darkens when exposed to light.It is readily soluble in water, alcohol, methanol and chloroform.

Quinidine gluconateIt occurs as a white powder odorless and has a bitter taste available in sustained release tablet.

Quinidine polygalacturonateIt affords control and more uniforms absorptions through the intestinal mucosa than does quinidine sulfate.In addition it produces a lower incidence of GI irritation

QuinineDiastereoisomer of quinidineIt occurs as white, odourless, bulky crystals or as a crystalline powder. It darkens when exposed to light and effloresces in dry air. It is freely soluble in alcohol, ether and chloroform but slightly soluble in water.

Quinine Sulfate a sulfate of an alkaloid obtained from the bark of Cinchona species. A white, odourless, bitter, fine, needlelike crystals that are usually lusterless. It becomes brownish when exposed to light. It is not readily soluble in water, alcohol, chloroform or ether.

UsesAntimalarialFor treating of chloroquinine resistant falciparum malaria combination with pyrimethamine and sulfadoxine or tetracycline or clindamycin. It has a skeletal muscle relaxant effect.It is widely used for the prevention and treatment of nocturnal recumbency leg cramps.