Alkaloids

Alkaloids are alkaline nitrogen-containing heterocyclic compounds

derived from higher plants and exhibiting marked pharmacological activity. The word derives from the

term vegetable alkali, referring to the alkaline nature of these compounds.

• Alkaloids are found in 15-30% of all flowering plants, common in Fabaceae, Liliaceae, Ranunculaceae, Apocynaceae, Solanaceae, Papaveraceae.

• Most common; caffeine, berberine.

• Names of alkaloids and on -ine

• morphine, narcotine from opium; the first chemical drug derived from plants.

• Synthesized by the plant from amino acids, if they are not then they are called pseudoalkaloids, or terpenoids.

• May have defensive role in plants, or by product of primary metabolism.

• Most are susceptible to destruction by heat, some by exposure to heat and air.

• Most water insoluble, soluble in alcohol.

• Ability to cross the blood-brain barrier and exert depressant or stimulant effect on the central nervous system, and ability to interact with various neurotransmitter receptors.– morphine, codeine; CNS depressant

– caffeine, cocaine; CNS stimulants

– ephedrine; sympathetic nervous system stimulant

• Most have profound physiological actions, with nervous system effects being the most prominent.

• Analgesics/narcotics; morphine

• mydriatics; atropine

• miotics; pilocarpine

• hypertensives; ephedrine

• bronchodilator; lobeline

• antimicrobial; berberine

classification• Large and diverse chemical

group.

• Grouped together according to their ring structure.– Heterocyclic alkaloids– non-heterocyclic alkaloids; also

known as protoalkaloids, or biological amines eg ephedrine.

Piperidinine alkaloids

• Have their N atoms in typical 6 membered rings. – Nicotine; the precursor

nicotinic acid (B3) common.– Piperine (Piper nigrum);

hepatoprotective– lobeline; relaxant and

bronchodilator.

Lobelia inflata; lobeline - emetic alkaloid; works as

reflex expectorant at subemetic doses.

Lobeline similar to nicotine and used as aid to stop smoking.

Quinoline alkaloids• Cinchona alkaloids

– quinine; • antimalarial

• skeletal muscle relaxant

• febrifuge for colds, influenca

• cardiac arrythmias,

– quinidine• cardiac arrythmias, atrial flutter, fibrillation;

depresses myocardial excitability, conduction, contractibility.

– S.e. tinnitus, skin rash, vertigo, bleeding, bruising, visual distubances

Isoquinoline alkaloids

• Found in papaveraceae, berberidaceae, ranunculaceae– morphine alkaloids; morphine, codeine– protoberberines; berberine, hydrastine,

palmatine– aporphine alkaloids; boldine

Escholtzia californica

• analgesic and sedative

• rich in isoquinoline alkaloids; which establish and advantagious catecholamine status necessary for maintaining sedative and antidepressant effects.

Properties;

• Antispasmodic (papaverine)

• antimicrobial

• antifungal (jatrorhizine)

• antiinflammatory, cholagogue, hepatoprotective, antiviral, amoebicidal

• antioxidant

• enzyme inhibitor

Berberine;

• Ranunculaceae (hydrastis canadensis)

• berberis spp (berberidaceae)– amoebicidal, antibacterial, antifungal,

cholagogue, helps to repair tissues, antiinflammatory, antitumour.

– Negative inotropiceffect on heart, reduces atrial rate, also antiarrhytmic action.

Tropane alkaloids;

• Solanaceae; Atropa belladonna, Datura stramonium, Hyoscymus niger– hyoscamine, hyoscine, atropine, scopalamine.

• Hyoscamine;Anti-muscarinic and parasympathetic depressant; spasmolytic effect on bronchial and intestinal smooth muscle, the mydriatic effect (inhibits contraction of iris muscle). Reduces salivary and sweat gland secretions, controls excess motor activity in GIT, antidiarrhaeal, reduces rigidity and tremors of parkinsonism.

Atropa belladonna

Datura

Hyoscamus

Toxicity;

• Dilated pupils, impaired vision, dryness of skin and secretions, extreme thirst, hallucinations, loss of conciousness.

Pyrrolizidine alkaloids

• Few therapeutic effects, main interest has been their toxicity.

Alkaloidal amines• Ephedrine and pseudoephedrine; ephedra

sinica. The two major alkaloids, form bases of amphetamine and certain drugs. – Ephedrine; simpathomimetic or CNS stimulant,

stimulator of adrenergic receptors, effects include vasoconstriction, raised blood pressure, and pulse, bronchodilation, diuresis. Ephedrine is used as nasal decongestants, bronchodilators, anaphylactic shock.

• Excess; insomnia, tachycardia, dizziness.

• CI; hypertension, angina, hyperthyroidism, pregnancy, MAOI

caffeine

Purine alkaloids

• Purine bases which includes the nucleic acids.

• Xanthine; occurs as breakdown product of nucleic acid metabolism, oxidised in the body to uric acid.

• Mobilization of intracellular calcium and inhibition of specific phosphodiesterases only occur at high physiological concentrations caffeine. The only likely mechanism of action of the methylxanthine is the antagonism at the level of adenosine receptors. Caffeine increases energy metabolism throughout the brain but decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion. Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. Many of the alerting effects of caffeine may be related to the action of the methylxanthine on serotonine neurons.

– The methylxanthine induces dose-response increases in locomotor activity in animals. Its psychostimulant action on man is, however, often subtle and not very easy to detect. The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue. Caffeine exerts obvious effects on anxiety and sleep which vary according to individual sensitivity to the methylxanthine. However, children in general do not appear more sensitive to methylxanthine effects than adults. The central nervous system does not seem to develop a great tolerance to effects of caffeine although dependence and withdrawal symptoms are reported.

• Caffeine is a central nervous system and metabolic stimulant reducing 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.

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

Caffeine is metabolized in the liver into three primary metabolites: paraxanthine (84%), theobromine (12%), and theophylline (4%)

The half-life of caffeine—the time required for the body to eliminate one-half of the total amount of caffeine consumed at a given time—varies widely among individuals according to such factors as age, liver function, pregnancy, some concurrent medications, and the level of enzymes in the liver needed for caffeine metabolism. In healthy adults, caffeine's half-life is approximately 3–4 hours. In women taking oral contraceptives this is increased to 5–10 hours, and in pregnant women the half-life is roughly 9–11 hours. Caffeine can accumulate in individuals with severe liver disease when its half-life can increase to 96 hours.

In infants and young children, the half-life may be longer than in adults; half-life in a newborn baby may be as long as 30 hours. Other factors such as smoking can shorten caffeine's half-life.Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system (specifically, the 1A2 isozyme) into three metabolic dimethylxanthines, which each have their own effects on the body:

* Paraxanthine (84%): Has the effect of increasing lipolysis, leading to elevated glycerol and free fatty acid levels in the blood plasma. * Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in cocoa, and therefore chocolate. * Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.

Caffeine's principal mode of action is as an antagonist of adenosine receptors in the brain. Caffeine acts through multiple mechanisms involving both action on receptors and channels on the cell membrane, as well as intracellular action on calcium and cAMP pathways. By virtue of its purine structure it can act on some of the same targets as adenosine related nucleosides and nucleotides.

and cAMP-phosphodiesterase (cAMP-PDE). Although the action is agonistic in some cases, it is antagonistic in others. The action is most likely through adenosine receptors.

Like alcohol, nicotine, and antidepressants, caffeine readily crosses the blood brain barrier. Once in the brain, the principal mode of action of caffeine is as an antagonist of adenosine receptors found in the brain. The caffeine molecule is structurally similar to adenosine, and binds to adenosine receptors on the surface of cells without activating them (an "antagonist" mechanism of action). Therefore, caffeine acts as a competitive inhibitor. The reduction in adenosine activity results in increased activity of the neurotransmitter dopamine, largely accounting for the stimulatory effects of caffeine. Caffeine can also increase levels of epinephrine/adrenaline possibly via a different mechanism. Acute usage of caffeine also increases levels of serotonin, causing positive changes in mood.

Caffeine is also a known competitive inhibitor of the enzyme cAMP-phosphodiesterase (cAMP-PDE), which converts cyclic AMP (cAMP) in cells to its noncyclic form, allowing cAMP to build up in cells. Cyclic AMP participates in activation of Protein Kinase A (PKA) to begin the phosphorylation of specific enzymes used in glucose synthesis. By blocking its removal caffeine intensifies and prolongs the effects of epinephrine and epinephrine-like drugs such as amphetamine, methamphetamine, or methylphenidate. Increased concentrations of cAMP in parietal cells causes an increased activation of protein kinase A (PKA) which in turn increases activation of H+/K+ ATPase, resulting finally in increased gastric acid secretion by the cell.

Caffeine (and theophylline) can freely diffuse into cells and causes intracellular calcium release (independent of extracellular calcium) from the calcium stores in the endoplasmic reticulum(ER).

The metabolites of caffeine– Theobromine is a vasodilator that increases the

amount of oxygen and nutrient flow to the brain and muscles.

– Theophylline, the second of the three primary metabolites, acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases heart rate and efficiency. The third metabolic derivative.

– Paraxanthine, is responsible for an increase in the lipolysis process, which releases glycerol and fatty acids into the blood to be used as a source of fuel by the muscles.