Alkaloids Physiological effects

Introduction
Low molecular weight Nitrogen-containing compounds mostly derived from amino acids Defensive role Pharmaceuticals, stimulants, narcotics, potions / poisons. Broad range pharmaceutical effects

Benzylisoquinoline alkaloids Tropane alkaloids Nicotine Terpenoid indole alkaloids Purine alkaloids Pyrrolizidine alkaloids 122 Other alkaloids

Benzylisoquinoline alkaloids

Morphine

Morphine is the most effective method of pain relief in modern medicine - most extensively used analgesic for the management of acute pain associated with injury, neuropathic conditions and cancer.

Morphine acts on the central nervous system by activating membrane opioid receptors.

The pharmacological effects of morphine vary enormously with dosage.

- Small doses induce euphoria and sedation - High doses cause pupil dilation, irregular respiration, pale skin, a deep sleep and eventual death within 68 h due to respiratory paralysis. - Even at moderate doses, morphine causes constipation, loss of appetite, hypothermia, a slow heart rate and urine retention.

Codeine
- Pharmacologically, codeine displays similar but less potent properties compared with morphine. - Codeine is often combined with other analgesics, such as acetaminophen or acetylsalicylic acid - Codeine is also commonly used as a cough-suppressant and can be found in most prescription cough syrups. In this regard, codeine reduces bronchial secretion and suppresses the cough centre of the medulla oblongata

Sanguinarine
Sanguinarine, has been used in oral hygiene products to treat gingivitis and plaque formation due to its anti-microbial and antiinflammatory properties. Bloodroot accumulates sanguinarine and was used by Native Americans to purify the blood, relieve pain, heal wounds and reduce fevers. Sanguinarine has been shown to control inflammation by regulating a relevant transcription factor, to modulate apoptosis as a potential chemotherapy drug, and to inhibit angiogenesis.

Sanguinaria canadensis

Berberine
Berberine is the major protoberberine alkaloid in goldenseal (Hydrastis canadensis), Native Americans used the plant to dye cloth, reduce inflammation, stimulate digestion, treat infections, regulate menstrual abnormalities, and induce abortions. Possible pharmacological effects of ingesting goldenseal extracts include an inhibition of phosphodiesterase activity, modulation of potassium and calcium channels, and a release of nitric oxide. Goldenseal is often combined with dried roots of Echinacea spp. to prevent colds and flu.

Tubocurarine
Muscle relaxant during surgery, and to control muscle spasms and convulsions. (+)-Tubocurarine acts as a competitive antagonist of nicotinic acetycholine receptors at neuromuscular junctions, effectively blocking nerve impulses to muscle fibers

Tropane alkaloids

Atropine, the racemic form of hyoscyamine, is a muscarinic acetylcholine receptor antagonist used to dilate the pupil during opthalmological examinations and to treat cases of poisoning, particularly by organophosphorous insecticides, nerve gas and the toxic principles of the red fly agaric mushroom (Amanita muscaria).
Atropa belladonna- Deadly Nightshade

The physiological effects of atropine poisoning: tachycardia, mydriasis, inhibited glandular secretions and smooth muscle relaxation. Excitatory effects of atropine on the central nervous system cause irritability and hyperactivity, accompanied by a considerable rise in body temperature potentiated by the inability to sweat. Anti-cholinergic poisoning of adolescents following deliberate ingestion of the common Angels trumpet (Datura suaveolens) to induce hallucinations Scopolamine causes sedation and possesses an antiemetic effect, which makes it useful in the treatment of motion sickness. Autumn mandrake (Mandragora autumnalis) is often mistaken for the edible borage (Borago officinalis)or intentionally used as a hallucinogen.

Nicotine

Nicotiana tabacum

- Nicotine is one of the most biologically active chemicals in nature, binding to several different receptors and activating a number of key signal transduction pathways. - Many of the physiological effects of nicotine, including addiction, are exerted by its action on nicotinic acetylcholine receptors. -Nicotine modulates the phosphatidylinositol pathway and increases intracellular calcium levels. - Although the cancer-causing properties of tobacco smoke were once solely associated with carcinogenic tars, nicotine exhibits genotoxic effects by inhibiting programmed cell death (apoptosis) and promoting oxidative damage by reactive oxygen species

Terpenoid indole alkaloids Reserpine

Hindus have used the Indian snakeroot (Rauwolfia serpentaria) as a febrifuge, an antidote to poisonous snakebites, and a treatment for dysentery and other intestinal afflictions. Reserpine, the major indole alkaloid present in roots, stems and leaves, is an effective hypotensive Reserpine is reported to influence the concentration of glycogen, acetylcholine,-amino butyric acid, nucleic acids and anti-diuretic hormones. The effects of reserpine include respiratory inhibition, stimulation of peristalsis, myosis, relaxation of nictitating membranes and influence on the temperature-regulating centre. The drug is primarily used to treat young patients suffering from mild hypertension but is also marketed as an aphrodisiac, an energy booster and a treatment for male impotence

Strychnine
Nux-vomica is described as a lethal poison. In Europe,S. nux vomica was mainly used as a poison to kill dogs, cats and rodents. Members of the Strychnos genus were also used by Amazonian Indians as arrowhead poisons, or curares, which are highly toxic in the bloodstream Strychnine is a competitive antagonist that blocks postsynaptic receptors of glycine in the spinal cord and motor neurons, resulting in hyperexcitability, convulsions and spinal paralysis. Aqueous extracts of Strychnos bark also cause convulsive and contradictory relaxation of the neuromuscular junction and cardiac muscle due to the presence of bisnordihydrotoxiferine, a sedative that affects the central nervous system (Neuwinger 1998). S. nux-vomica seeds with reduced strychnine levels are used to treat rheumatism, musculoskeletal injuries and limb paralysis

Vinblastine and vincristine

Vinblastine and vincristine are commonly used in cancer therapy Bind to microtubules and inhibit hydrolysis of GTP, thus arresting cell division at metaphase. The binding of vinblastine and vincristine to tubulin occurs at protein domains different from other drugs, such as colchicines, that disrupt microtubules. Other biological effects associated with vinblastine and vincristine treatment include inhibition of protein, nucleic acid, and lipid biosynthesis, and reduced protein kinase C, which modulates cell growth and differentiation Vinblastine is a component of chemotherapy for metastatic testicular cancer, Hodgkins disease and other lymphomas, and a variety of solid neoplasms. Vincristine is the preferred treatment for acute lymphocytic leukaemia in children, management of Hodgkins disease and other lymphomas, and pediatric tumours. Vinblastine has also been used in patients with autoimmune blood disorders due to its immunosuppressant properties However, vinblastine is toxic to bone marrow and white blood cells, causes nausea and sometimes results in neuropathic effects.

Camptothecin
Camptothecin is currently one of the most important compounds in cancer research due to its activity against leukaemias and other cancers resistant to vincristine. Camptothecin inhibits nucleic acid biosynthesis and topo isomerase I, which is necessary for the relaxation of DNA during vital cellular processes. Camptothecin also inhibits the replication of DNA viruses by disrupting the normal function of DNA in cellular ontogenesis. Side effects of camptothecin include haematopoietic depression, diarrhoea, alopecia, haematuria, and other urinary tract irritations.

Quinine
Quinine is used as an antipyretic to combat malaria, to induce uterine contractions during labour, and to treat infectious diseases. Synthetic substitutes have also been developed, but quinine has regained popularity due to the increased resistance of malaria against synthetic drugs. Quinine antagonizes muscarinic acetylcholine receptors and -adrenoceptors, and inhibits nucleic acid synthesis through DNA intercalation and reduced carbohydrate metabolism, in the malarial parasites Plasmodium falciparum, P. ovale, P. vivax and P. malariae. Quinine also binds to sarcoplasmic reticulum vesicles, diminishes binding and uptake of calcium, and inhibits Na+/K + ATPases.

Purine alkaloids

Coffea arabica

Caffeine

As an antagonist of endogenous adenosine receptors, caffeine causes vasoconstriction and increases blood pressure. Other short-term, unpleasant side effects include palpitations, gastrointestinal disturbances, anxiety, tremors and insomnia. In rare cases, caffeine ingestion can lead to cardiac arrhythmias. Possible mechanisms controlling the cardiac effects of caffeine include antagonism of adenosine receptors, inhibition of phosphodiesterases, activation of the sympathetic nervous system, stimulation of the adrenal cortex and renal effects.

Caffeine
Caffeine might also be potentially beneficial to human health since it increases extracellular levels of acetylcholine and serotonin by binding to adenosine receptors in the human brain suggesting that caffeine usage can reduce agerelated cognitive decline. Caffeine also improves performance of tasks requiring verbal memory and information processing speed and has a positive effect on mood at low doses. The drug is added to many over-the-counter and prescription medicines including anti-inflammatory drugs (included in analgesic formulations), ephedrine (to promote weight loss) and ergotamine (to treat migraines). Caffeine might have analgesic properties of its own for specific types of pain, such as headaches . Caffeine also induces apoptosis by activating p53-mediated Bax and caspase-3 pathways suggesting possible chemo-protective properties

Pyrrolizidine alkaloids
The most noxious pyrrolizidine alkaloids display acute and chronic toxicity, and genotoxicity, and are produced by species of the genera Senecio, Crotalaria and Heliotropium. The most potent genotoxic and tumorigenic pyrrolizidine alkaloids are the retronecine-and otonecine-type macrocyclic diesters. Pyrrolizidine alkaloids exhibit differential potency, the functional groups at C-7 and C-9 of pyrrolic ester derivatives generally bind to and cross-link DNA and protein. Acute exposure causes considerable hepato toxicity with hemorrhagic necrosis, whereas chronic poisoning primarily affects the liver, lungs and blood vessels

Symphytum officinale Comfrey extract is as a skin treatment

Other alkaloids Quinolizidine alkaloids

Lupinus angustifolius

Other alkaloids Quinolizidine alkaloids

Leguminoseae.
Biosynthesis of quinolizidine alkaloids. Enzyme abbreviations: ECT,pcoumaroyl-CoA: (+)-epilupinine O-p-coumaryltransferase; HMT/HLT, Tigloyl-CoA:()-13a-hydroxymultiflorine/(+)-13-hydroxylupanine-Otigloyltransferase; LDC, lysine decarboxylase

Alkaloid biosynthesis
Plants biosynthesize alkaloids from simple precursors, using many unique enzymes.

Berberine synthesis pathway