Alkaloids PDF

Alkaloids small-molecule N-containing, basic (name: alkaline-like), of vegetable origin, p. potent compounds ~ 27,000 known, out of 21,000 species not only plants (microorganisms, some animals also biosynthesize) N amide, quaternary N compound, etc. form is not basic not all are strong,...

Alkaloids small-molecule N-containing, basic (name: alkaline-like), of vegetable origin, p. potent compounds ~ 27,000 known, out of 21,000 species not only plants (microorganisms, some animals also biosynthesize) N amide, quaternary N compound, etc. form is not basic not all are strong, physiol is usually a condition for strong effects. Ability to protonate at pH (apolar, tertiary amine-containing compounds) grouping options: ◦ N-containing structure ("framework") - there are too many subgroups ◦ starting amino acid - this will be followed, but N (so-called pseudo-alkaloids) will be introduced into some alkaloids by transamination Alkaloids of ornithine origin ornithine ◦ participating in the urea cycle as. animals ◦ C4N component ◦ starting material for polyamines (spermidine, putrescine, spermine) Ornithine-derived alkaloids / tropane-based alkaloids intermediates of biosynthesis: N-Me-Δ1-pyrrolinium cation -> hygrine ->... alkaloids formed in this way: ◦ cocaine (methyl ecgonin ester, ecgonin backbone) - only Erythroxylum spp. ▪ a leader molecule in localanaestheticum development ◦ hyoscine, hyoscyamine, scopolamine (tropine ester, tropane backbone) - occur in many toxic Solanaceae plants: Atropa belladonna, Datura stramonium and other D. spp., Hyosciamus niger, Duboisia spp. (Australian tree, industrial herb), Scopolia carniolica, Mandragora officinarum ▪ tropane-based alkaloids usually occur enantiomerically pure in the plant, but are easily racemized (hyoscyamine -> atropine, hyoscine -> atrosine; the biological activity of the (+) enantiomer is 20-30x less than that of the (-) enantiomer) ALKALOIDS, 1 / 73 ▪ many are absorbed through the skin (can also be used in the form of patches) anatoxin-a ◦ cyanobacterial toxin (Aphanizomenon ovalisporum, Anabena flos-aquae) - toxic aquatic blooms ◦ potent neurotoxin, nACh receptor agonist epibatidin ◦ Epipedobates tricolor (Frog living in Ecuador) ◦ 200-500x more potent analgesic than morphine but nAChR agonist Belladonnae folium et radix Atropa belladonna (Solanaceae) Belladonna, deadly nightshade It is a widespread plant from Western Europe to the Himalayas. Products provided by the plant: folium radix Chemical components 0.3-0.5% tropane-based alkaloid: D-, L-hyoscyamine (mixture: atropine), scopolamine (+) - hyoscyamine (-) - hyoscyamine ALKALOIDS, 2 / 73 Clinical uses can be used / applied as an industrial herb, its phytotherapeutic use should be avoided is considered a toxic plant There is not enough evidence to judge efficacy IBS (negative results) side Effects Most likely unsafe po., Applied ◦ Toxic alkaloids can cause a number of inverse reactions ◦ 2 mg alkaloid (2-3 berries) can cause lethal poisoning in children ◦ There have been 400 reports of inverse reactions in the US related to homeopathic products !! anticholinergic side effects (hyoscyamine ~ atropine): ◦ tachycardia ◦ dry skin, decreased sweating, dry mouth ◦ constipation ◦ urinary retention ◦ central nervous system: attention deficit, memory impairment; muscle tremor, muscle stiffness, disorientation, hallucinations, psychosis, seizures, coma, cardiovascular collapse, respiratory paralysis; dilated pupil, blurred vision ◦ potentially fatal poisonings drug-drug interactions see. Atropine, not relevant contraindications is irrelevant Dosage 50-100 mg dry weight (max. 200 mg ~ 0.6 mg alkaloid) max. Per day 600 mg (leaf) (~ 1.8 mg alkaloid) or 300 mg root (~ 1.5 mg alkaloid) ALKALOIDS, 3 / 73 Hyosciami folium Hyosciamus niger (Solanaceae) Henbane It is a plant native to Eurasia and grown in many places. Products provided by the plant: folium Chemical components tropane-based alkaloids: D-, L-hyoscyamine (mixture: atropine), scopolamine Clinical uses can be used / applied as an industrial herb, its phytotherapeutic use should be avoided is considered a toxic plant GIT to relieve seizures (TU) side Effects Most likely unsafe po., Applied ◦ Toxic alkaloids can cause a number of inverse reactions ◦ Possibility of potentially fatal poisoning symptoms of poisoning: ◦ Symptoms of atropine poisoning: red skin, constipation, fever (inhibition of sweating), blurred vision, tachycardia, difficulty urinating ◦ drowsiness followed by EMS stimulation (restlessness, hallucinations, delirium, manic episodes) ◦ death due to respiratory failure is possible drug-drug interactions see. Atropine, not relevant contraindications is irrelevant ALKALOIDS, 4 / 73 Dosage max. Per day 3 g (~ 2 mg alkaloid) Stramonii folium Stramonium database (Solanaceae) Jimson weed It is also a common plant in Hungary, widespread in many parts of the world. Products provided by the plant: folium Chemical components tropane-based alkaloids: hyoscyamine, scopolamine the amount of active substance depends strongly on the plant organ and the age of the plant * atropine scopolamine Main effects anitcholinergic effect (alkaloids) anti-asthmatic effect (TU - asthma cigarette, effect also detectable in CT) antibacterial effect (IV) ALKALOIDS, 5 / 73  mitogenic effect (lectins) ◦ on lymphocytes (IV) antitumor effect - induces irreversible differentiation of glyoma cells (IV) (lectins) the effect of EMS on hyoscyamine and scopolamine is not the same, so the psychological effect depends on their ratio Clinical uses its efficacy is not supported by clinical evidence side Effects Unsafe when administered by po or inhalation ◦ all parts of the plant are toxic, especially the seeds ◦ Potentially fatal poisoning by ~ 15-100 g of leaves or 15-25 g of seeds Not safe during pregnancy and lactation symptoms of poisoning: dry mouth, dry mucous membranes, fever, hyperpyrexia, thirst side effects: “anticholinergic syndrome” ◦ urinary retention ◦ coma, seizures, hyperreflexia, blurred vision, deterioration of visual accommodation, pupil dilation ◦ altered state of consciousness, thought disorder, amnesia, confusion, euphoria, (even severe) hallucinations, psychosis, restlessness, toxic delirium, orientation disorders, etc. Poisoning already causes irreversible damage (AS) at 1.2 - 1.4 g leaves / kg drug-drug interactions its effect can be antagonized by cholinergic agents (physostigmine) and enhanced by anticholinergic agents contraindications a plant to be considered toxic, its consumption is not recommended under any circumstances Dosage is irrelevant ALKALOIDS, 6 / 73 Cocae folium Erythroxylum coca (Erythroxylaceae) Coca leaf It is a native plant in western D-America. The purified active ingredient is an illegal drug. Products provided by the plant: folium Chemical components 0.7-2.5% alkaloids: ecgonin-based alkaloids (~ 0.7% cocaine, plus cinnamyl cocaine, benzoyl ecgonin, truxillin, etc.) Main effects anesthetic (reversible inactivation of the Na + channel) antimuscarinic effect (M2, heart and brain receptors) adrenaline, noradrenaline levels szint (reuptake inhibitor) blood pressure ↑ heart rate ↑ inhibition of late-type hypersensitivity (AS) pesticidal effect weight loss (AS) Clinical uses its efficacy is not supported by clinical evidence Most likely ineffective sport performance side Effects It is highly unsafe to use plant parts containing cocaine or the purified compound for medical or recreational purposes (by any route of administration: inhalation, po.) Cocaine-free leaf extracts are likely to be safe to use ALKALOIDS, 7 / 73  Not safe during pregnancy ◦ teratogenic, abortifacient, associated with increased incidence of sudden death syndrome Not safe during breast-feeding ◦ excreted in breast milk Provided a significant proportion (~ 30%) of cases requiring emergency drug care (before the advent of designer drugs) cardiovascular side effects - especially young men who are both smokers and drinkers are at risk ◦ acute tachycardia ◦ chronic arrhythmia ◦ acute coronary syndrome ◦ acute myocardial infarction ◦ heart failure ◦ sudden cardiac death ◦ vasoconstriction ◦ sympathomimetic effects ◦ prothrombotic effects: stroke ◦ Regular high blood pressure leads to kidney damage GIT side effects: nausea, vomiting, diarrhea, abdominal cramps, smooth muscle cramps EMS side effects: delirium, migraine, mood swings, convulsions, seizures ◦ addiction causes memory problems, insomnia, delusions, psychosis, sickness ◦ Acute tremor, hyperreflexia, restlessness, mental degradation, hallucinations ◦ Epidemiological study (Peruvian village): malnutrition, associated reduced ability to work and suboptimal personal hygiene among consumers due to fatigue and indifference hyperthermia tooth decay (in connection with chewing coca leaves) general deterioration of health toxicity is usually due to hypertension, arrhythmia, myocardial infarction, and cardiorespiratory collapse, but there are also brainstem depression, coma, hyperthermia, intracranial vasculitis, or stroke iv. LD50 ~ 17.5 mg / kg (AS), ~ 50 mg / kg nasal (AS) lethal human dose ~ 1200 mg drug-drug interactions alcohol enhances neurocognitive effects ALKALOIDS, 8 / 73  nifedipine increases the risk of seizures and fatal side effects contraindications no data Dosage no typical dosage 1 g of leaves are usually extracted Ornithine-derived alkaloids / pyrrolizidine alkaloids they are biosynthesized from putrescine, ie they may be partly of Arg origin occur in many Boraginaceae genera (Heliotropium, Cynoglossum, Symphytum) and Asteraceae genera (Senecio, Eupatorium) as well as in certain Fabaceae plants (Crotalaria) many herbs previously used as herbs have come out of medicine because of these compounds (Tussilago (?), Senecio, etc.) usually occur in ester form (eg senecionin) they accumulate in the plant mainly in the form of polar N-oxides, which aids their transport and are therefore non-toxic; however, they assume a base form under a slight reductive effect hepatic metabolites (pyrrole derivatives) of Δ1,2-unsaturated compounds are hepatotoxic and pulmotoxic (N-oxides are not activated by these enzymes) Lysine-derived alkaloids lysine proteinogenic amino acid C5N component Lysine-derived alkaloids / piperidine alkaloids anaferin (Withania somnifera) ALKALOIDS, 9 / 73  lobelia, lobelia (Lobelia inflata) sedamine (Sedum acre) Piper (Piper nigrum) Lobeliae herba Lobelia inflata (Lobeliaceae) Lobelia It is a plant native to North America and grown in Europe. Products provided by the plant: herba Chemical components 0.2-0.6% piperidine based alkaloid (lobeline) Main effects antidepressant effect (AS) (beta-amirin palmitate!) anti-inflammatory (IV) emeticum an alpha-glucosidase inhibitor nervous system effects ◦ Nicotinergic agonist and antagonist effects are also observed ◦ Inhibition of dopamine uptake into synaptic vesicles non-addictive (AS) Clinical uses its efficacy is not supported by clinical evidence Probably ineffective quitting smoking ALKALOIDS, 10 / 73 side Effects Most likely unsafe po. in case of use It is likely to be unsafe during pregnancy and lactation and should be avoided Potentially toxic plant Lob lobelin binds to nicotinic receptors causing tachycardia, sweating, nausea, vomiting, diarrhea, tremors, potentially death ◦ narrow therapeutic width (lobeline) 0.6-1 g can cause poisoning, 4 g can cause fatal poisoning drug-drug interactions not relevant or only speculative / theoretical, no data contraindications no data Dosage 5 mg lobeline equivalent 0.2-0.6 g of leaf is made into an infusum Lysine-derived alkaloids / quinolizidine backbone alkaloids occurs mainly in Fabaceae species, compounds suitable for repelling insects Lupinus luteus, Cytisus scoparius, Laburnum spp. toxic alkaloids, e.g. lupine, lupanine, sparteine - contain toxic amounts in humans (nAchR agonist effect - cytizine) ◦ some "sweet" (low alkaloid) variants are used as high protein feed Sarothamni scoparii herba Sarothamnus scoparius (Fabaceae) broom Scotch broom It is a perennial plant native to Europe and also found in Hungary. Products provided by the plant: ALKALOIDS, 11 / 73  herba Chemical components 0.8-1.5% alkaloids (sparteine, lupanin and their derivatives) flavonoids Main effects quinidine-like heart effects, prolongation of diastole, + no inotropic effect (sparteine) curare-like effects (sparteine) uterus stimulans (spartein) Clinical uses its efficacy is not supported by clinical evidence arrhythmia, hypotension (TU) side Effects Most likely unsafe po., Applied ◦ heart depressant Unlikely to be safe during pregnancy ◦ abortifacens Unlikely to be safe during breastfeeding ~ 30 g of drug (~ 300 mg of sparteine) can already cause toxicity symptoms of poisoning: confusion, headache, feeling of weakness in the legs, sweating, drowsiness, pupil dilation possible additional side effects: nausea, diarrhea, dizziness, tachycardia (potential collapse of the circulation), drug-drug interactions speculative / theoretical only, no data contraindications is irrelevant Dosage 1-1.5 g / day ALKALOIDS, 12 / 73 Laburni semen Laburnum anagyroides (Fabaceae) laburnum A shrub that also occurs in Hungary. Products provided by the plant: semen Chemical components alkaloids (cytizine) Main effects respiratory stimulating effect Clinical uses considered an industrial herb drug-drug interactions is irrelevant contraindications is irrelevant Dosage is irrelevant ALKALOIDS, 13 / 73 Alkaloids of nicotinic acid origin Nicotinic acid (= vitamin B3, niacin) An essential component of NAD + and NADP + coenzymes Nicotinic acid alkaloids / pyridine backbone alkaloids nicotine, anabazine (Nicotiana tabacum - tobacco) ◦ the saturated ring is of ornithine / lysine origin (intermediates similar to tropane biosynthesis) arecoline (Areca catechu - betel nut) ◦ unknown biosynthesis Tyrosine-derived alkaloids tyrosine proteinogenic amino acid precursors of many neurotransmitters and hormones ◦ L-DOPA, dopamine, catecholamines: adrenaline, noradrenaline Tyrosine-derived alkaloids / Phenylethylamines "protoalkaloids" = N is not cyclized, typically primary amines mescaline (Lophophora williamsii - mescaline cactus) Tyrosine-derived alkaloids / simple isoquinoline-based alkaloids isoquinoline backbone alkaloids ◦ papaverine Tyrosine-derived alkaloids / modified isoquinoline backbone alkaloids only 5 plant families, but ~ 2500 alkaloids! ◦ Papaveraceae, Fumariaceae, Ranunculaceae, Berberidaceae, Menispermaceae ALKALOIDS, 14 / 73  morphinan-based alkaloids (Papaver somniferum) ◦ morphine, codeine, thebaine dimers ◦ tetrandrin (Stephania tetrandra, Menispermaceae) ◦ Berbamunin (Berberis stolonifera) ◦ tubocurarine (Chondrodendron tomentosum, Menispermaceae) - non-depolarizing blockade of neuromuscular junction, traditional arrow poison aporfinok ◦ apomorphine (semi-synthetic derivative) ◦ (S) -isoboldin (Peumus boldus) ◦ izotebain ◦ aristolic acid (highly nephrotoxic, aromatic nitro compound) protoberberin backbone alkaloids ◦ Canadian, scouler ◦ berberine (Berberis, Mahonia, Berberidaceae; Hydrastis, Ranunculaceae) ▪ many biological activities ◦ protopin (Chelidonium majus) ◦ Hydrastis (Hydrastis canadensis) ◦ A number of other bioactive compounds are formed from the cleavage of the newly formed ring from protoberberine backbone alkaloids ▪ hydrastin, noscapine (= narcin) ▪ chelidonine ▪ narceine ▪ protopine Papaveris fructus sine seminibus Papaver somniferum (Papaveraceae) poppy Products provided by the plant: semen fructus opium (juice that flows out when the raw crop is cut and then dries) ALKALOIDS, 15 / 73 Chemical components alkaloids (morphine, thebaine, codeine, papaverine, noscapine), mostly in the form of a salt with meconic acid ◦ in poppy seeds ~ 0.5% total alkaloid ◦ opium: ~ 25% total alkaloid mekonsav morphine, codeine, thebaine papaverine Main effects morphine ◦ analgesic, causes euphoria, narcotic, causes tolerance and addiction, causes constipation, nausea ◦ regular users suffer from withdrawal symptoms: severe abdominal cramps, diarrhea, nausea, vomiting; symptoms persist for 10-14 days (physical dependence) ◦ in practice, it is used to relieve pain in terminally ill patients ◦ some of its metabolites are also active (morphine-6-glucuronide) codeine ◦ analgeticum (~ 10% of morphine potency), without euphoria ALKALOIDS, 16 / 73 ◦ causes constipation, therefore its long-term use is not advisable ◦ cough thebaine ◦ has no analgesic effect, rather an antagonist ◦ starting material for semi-synthesis papaverine ◦ smooth muscle relaxant noscapine ◦ Cough suppressant (~ papaverine), not analgetic or narcotic ◦ is likely to be teratogenic, so it is no longer used standardization typ. morphine (powdered opium: 10%) Clinical uses irrelevant, industrial herb (fructus), resp. food (semen) Side effects (semen) Most likely safe po., Commonly used properly in foods, GRAS status; both during pregnancy and lactation Applying very large doses, or an aqueous extract of the seed po., Is probably unsafe ◦ Very large amounts can cause intestinal obstruction ▪ case study: 900 g ◦ The morphine content of 450-900 g of aqueous extract may be sufficient to produce a toxic effect ▪ the seeds contain little alkaloids, but their surface may be contaminated with the dust of the fructus due to insect bites or processing Some people are allergic to poppy seeds Side effects (fructus) unsafe to consume, considered an industrial herb (morphine) ALKALOIDS, 17 / 73 Chelidonii herba et radix Chelidonium majus (Papaveraceae) Bloody swallow Greater Celandine It is a plant found in Asia, southern and eastern Europe, and North America. Products provided by the plant: radix herba Chemical components herb: alkaloids: chelidonine, berberine, coptizine radix: alkaloids: chelerythrine, sanguinarine chelidonine Main effects antitumor effect, cytotoxic effect (IV and AS - stomach cancer model) (alkaloids) anti-inflammatory (alkaloids) ◦ inhibition of inflammatory cytokine production ◦ Modification of T and B cell activity antimicrobial effect (IV) (alkaloids) smooth muscle antispasmodic effect ◦ Resolution of GIT convulsions, pain relief anti-ulcer effect (AS) ALKALOIDS, 18 / 73  antiviral effect (IV) choleretic (ethanolic extract) reduces the amplitude and frequency of slow waves in the small intestine, thus slowing down peristalsis Clinical uses dyspepsia ◦ in combination with many plants cholagogum (TU) There is not enough evidence to judge efficacy cancer (contradictory results) ◦ semi-synthetic iv. dosed chelidonin ("Ukrain") ◦ usually poor test design ◦ GIT symptoms (vomiting, diarrhea, constipation), fever, general burning sensation, bleeding have occurred as a side effect of Ukrain side Effects Probably unsafe po. using ◦ caused liver damage in many cases No safety data on exposed pregnancies or lactation are available No safety data related to local application Locally causes dermatitis It has been associated with idiopathic liver damage ◦ Appearance independent of dose and time of application ◦ relatively rapid recovery after cessation, but liver enzyme markers return to normal within months only ◦ Recurrence of hepatitis has also occurred ◦ The main symptom is typically jaundice drug-drug interactions not to be used with medicines with hepatotoxic side effects contraindications no data Dosage ALKALOIDS, 19 / 73  0.5 g (radix), 2.0 g (herb) / dose (TU) Fumariae herba Fumaria officinalis (Fumariaceae) Fumitory It is a plant native to temperate Europe and Asia. Other F. species are also used in medicine. Products provided by the plant: herba Chemical components 1-1.2% alkaloids (protopine, cryptophin) Malic acid hydroxycinnamate esters Main effects antitumor effect (sangvinarin and other alkaloids) ◦ induction of apoptosis anti-inflammatory effect (50% ethanol extract) (AS) antifungal effect (IV) (alkaloids) anthelminticum (IV) anti-platelet effect (IV) (sanguinarine) Relieves symptoms of cholecystopathy EMS depressant (fumariline) (ex F. vaillantii) hepatoprotective effect (AS) (other F. spp.) spasmolyticum (IV) Clinical uses its efficacy is not supported by clinical evidence biliary (TU) ALKALOIDS, 20 / 73 Probably ineffective IBS There is not enough evidence to judge efficacy bile diseases (preliminary, positive results) ◦ relief of cholestasis pain ◦ biliary dyskinesia side Effects Probably safe po., Properly used for a short time Probably unsafe in high doses and / or for long periods of time (alkaloids: protopine) No safety data on exposed pregnancies or lactation are available may increase the risk of glaucoma (poppy or smoky alkaloids) GIT complaints Convulsions and potentially fatal poisoning are possible drug-drug interactions speculative / theoretical only, no data contraindications no data Dosage 6 g / day (TU) Hydrastis rhizoma Hydrastis canadensis (Ranunculaceae) Canadian golden root Goldenseal It is a plant native to North America. ALKALOIDS, 21 / 73 Products provided by the plant: rhizoma, radix Chemical components alkaloids (hydrastine, berberine, canadine, canadine, etc.) standardization alkaloids (hydrastine: 0-3%, berberine 1-6%) hirdasztin berberine Pharmacokinetics the Berber po. absorbed very poorly, unlikely to reach pharmacologically active concentrations at normal human doses Main effects antitumor effect (IV) (pure berberine) ◦ inhibition of metastasis (AS) antihyperglycaemic effect (CT) (pure berberine) ◦ fasting Glc ↓, postprandial Glc ↓ (Glc tolerance ↑), HbA1c ↓ ◦ enhances Glc oxidation in skeletal muscle ◦ enhances fatty acid oxidation in adipocytes anti-diarrheal effect (pure berberine) ALKALOIDS, 22 / 73 ◦ delays small intestinal transit (CT) ◦ Inhibition of intestinal water secretion (AS) anti-inflammatory effect (pure berberine) ◦ prevention of swelling (AS) ◦ inhibition of the production of many inflammatory cytokines ◦ potentially useful in alcoholic liver disease antimicrobial effect (IV) ◦ broad spectrum activity: bacteria, fungi and protozoa (Plasmodium) ◦ Inhibition of protein responsible for anchoring Gram- + bacteria (IV) platelet inhibitory effect (AS, IV) reduces PTH-induced bone resorption (pure berberine) cardiovascular effects (pure berberine) ◦ antihypertensive, inotropic, antiarrhythmic effect ◦ alpha-adrenergic inhibitor (partial alpha-2-adrenoceptor agonism) ◦ TAG ↓, Chl ↓, LDL ↓, HDL ↑ reduction of gastric acid secretion (pure berberine) hepatoprotective effect (pure berberine) ◦ can protect the liver from hepatotoxins (AS) ◦ increases hepatic bilirubin secretion (potential treatment for fibrosis) (AS) muscle relaxants (pure berberine) (IV) ◦ beta-adrenoceptor mediated phenomenon Clinical uses its efficacy is not supported by clinical evidence Probably ineffective as a masking agent in urine-drug tests (such use is advertised by many but does not work) side Effects Probably safe po., Properly used in the short term ◦ Berberine can be given to adults at a dose of 2 g / day for 8 weeks without a severe adverse reaction There are no test results for its long-term use ALKALOIDS, 23 / 73 ◦ increases the risk of hepatocellular adenoma and carcinoma after 2 years after taking (AS) based on animal experiments Unlikely to be safe in children Unlikely to be safe during pregnancy and lactation (berberine) ◦ berberine crosses the placenta, is excreted in breast milk, may cause kernicterus and fatal adverse reactions side effects: rash, diarrhea, constipation, bloating, vomiting, abdominal pain, bitter taste, headache (berberine) po. LD50 ~ 330 mg / kg (berberine) (AS) drug-drug interactions significant inhibition of CYP2D6 - blood levels of the following medicines may increase: ◦ amitriptyline, clozapine, codeine, fentanyl (!), Methadone (!), Metoprolol, olanzapine, ondansetron, tramadol, etc. significant inhibition of CYP3A4 - blood levels of the following medicines may increase: ◦ lovastatin, sildenafil, ketoconazole, fexofenadine, midazolam, etc. ◦ There are also conflicting results Dosage no typical dosage Berberidis radicis cortex Berberis vulgaris (Berberidaceae) Barberry root bark European barberry It also occurs in Hungary. Products provided by the plant: radicis cortex radix Chemical components alkaloids: berberine, oxiacanthin, berbamine, berberrubin, jatorrhizine, bervulcin, columbamine, etc. Main effects analgesic (AS) ALKALOIDS, 24 / 73  anticholinergic antidiabetic effect (berberine) (AS) ◦ improves insulin resistance antihistamine anti-inflammatory (berberine) ◦ selective inhibition of COX-2 expression antimicrobial effect (IV) (berberine) cytotoxic (IV) (berberine and alkaloids) antioxidant (berberine) cardiovascular effects ◦ hypotensive (AS) ◦ vasodilator ◦ antiarrhythmic effect (AS) ◦ alpha-adrenergic inhibition ◦ reduces ventricular tachycardia and early ventricular contractions (AS) ◦ increases blood flow to the heart, decreases total peripheral resistance (AS) local treatment of skin burns (berberine) reduction of gastric acid secretion, delay of small intestinal transit time hepatoprotective effect ◦ protection against toxins ◦ inhibits the production of proinflammatory cytokines (IL-1 and TNFalpha) prevents a decrease in bone density (berberine) ◦ osteoclast apoptosis induction ◦ Inhibition of parathyroid hormone-induced bone resorption Inhibition of Ca-oxalate kidney stone formation (AS) Clinical uses its efficacy is not supported by clinical evidence bile and liver diseases (TU) There is not enough evidence to judge efficacy acne (preliminary, positive results) ALKALOIDS, 25 / 73  bacterial vaginosis (to supplement standard treatment; mild, positive result, further tests required) dental plaque, gingivitis (preliminary, positive results) diabetes (to supplement standard treatment; preliminary, positive result) side Effects Most likely safe when consumed in the usual amounts in food Probably safe applied locally in the short term (7 days) There are no safety data on the use of po., Medical amounts Unlikely to be safe during pregnancy and lactation ◦ kernicterus develops in newborns, berberine is harmful to the fetus ◦ berberine is excreted in breast milk can cause potentially fatal poisoning in young children nausea, vomiting, hypotension, hypertension, bradycardia, leukopenia, respiratory failure, paresthesia in children: vomiting drug-drug interactions possible increase in effectiveness with antidiabetics contraindications childhood, pregnancy, breastfeeding Dosage Topical preparations containing 1% berberine 1.5-3 g / day (TU) Tyrosine-derived alkaloids / phenethylisoquinoline backbone alkaloids ◦ Liliaceae ◦ the condensing unit from Tyr is phenylpropanoid, instead of phenylethanoid (+1 C) -> homomorphinan skeleton ◦ autumnalin ◦ colchicine (Colchicum autumnale and other Liliaceae, eg Bulbocodium, Gloriosa suberba (also purified from it), Merendera, Sandersonia) ▪ it is in the N amide group, so it does not behave chemically as a typical alkaloid ▪ binds to tubulin such as podophyllotoxin or vincristine (the angle of the two aromatic rings is important for binding) ALKALOIDS, 26 / 73 Colchic tuber Colchicum autumnale (Liliaceae) Autumn Crocus It is a plant native to Europe. Products provided by the plant: tuber all parts of the plant are toxic Chemical components alkaloids (colchicine) colchicine Clinical uses its efficacy is not supported by clinical evidence is considered a toxic industrial herb side Effects Unsafe po., Applied, all parts of the plant are highly toxic ◦ the risks significantly outweigh the expected benefits Do not use during pregnancy and lactation symptoms of acute poisoning: burning sensation in the mouth, pharynx, nausea, vomiting, thrombocytopenia, diarrhea, dehydration, thirst, elevated urea levels, creatinine levels and liver function tests, pancytopenia, leukopenia, coagulopathy, etc. severe intoxication with hypotension, hypovolaemia, respiratory failure followed by multiple organ failure, cerebral edema, encephalopathy, arrhythmia, cardiovascular collapse, shock and death Prolonged use causes agranulocytosis, aplastic anemia, peripheral neuritis drug-drug interactions is irrelevant contraindications ALKALOIDS, 27 / 73  is irrelevant Dosage is irrelevant Ipecacuanhae radix Cephaelis ipecacuanha (Rubiaceae) Ipecacuanha ipecac It is a native plant in the rainforests of Brazil and D and Central America. It is grown elsewhere. Products provided by the plant: radix Chemical components 2-3.5% alkaloids (cephalin, emetine) Main effects emeticum (central and peripheral mechanisms) ◦ stimulation of peripheral receptors first, later central (chemosensitive trigger zone) receptors Clinical uses its efficacy is not supported by clinical evidence expectorans, emeticum amoebic dysentery Probably ineffective reducing the risk of poisonings - as an emetic (does not improve the outcome of poisonings) side Effects Probably safe po., Properly used for a short time; Also in children over 1 year It may not be safe to apply to the skin or inhaling plant dust ALKALOIDS, 28 / 73  Unlikely to be unsafe in high doses and / or for long periods of time ◦ high doses lead to cardiomyopathy, toxicity, potentially fatal poisoning may result from overdose Contraindicated in pregnancy (uterus stimulans) There are no safety studies during breast-feeding and its use should be avoided more serious side effects are associated with abuse ◦ myopathy (gait disturbance, difficulty swallowing, faecal incontinence, diffuse pain), cardiomyopathy (-> potentially fatal heart failure), anorexia, bulimia, Münchausen syndrome (intentional development of diseases with appropriate substances, agents, = / = hypochondria) ◦ cardiomyopathy is reversible - a healthy condition is restored after stopping the drug side effects in acute use: ◦ nausea, nausea, vomiting, esophageal and gastric rupture also occurred in case studies due to prolonged (> 24h!) Vomiting; vomiting due to aspiration pneumonitis drug-drug interactions speculative / theoretical only, no data contraindications no data Dosage emeticum: 30-50 ml (120-160 mg alkaloid / 100 ml) expectorans: 0.05 g / dose (adult), much less in childhood Tyrosine-derived alkaloids / Amaryllidaceae alkaloids ◦ Partially analogous biosynthesis with morphinan-based alkaloids ◦ galantamine (Galanthus spp., Narcissus spp., Leucojum spp.) ▪ a reversible, much less toxic acetylcholinesterase inhibitor than others ◦ liqueur, krin ALKALOIDS, 29 / 73 Tryptophan-derived alkaloids tryptophan succinic acid pathway-derived amino acid with indole side chain rearrangement to a quinoline ring system is also possible, so it may be a precursor where other amino acids are likely Tryptophan-derived alkaloids / simple indole alkaloids "biogenic amines" ◦ tryptamine, N-Me-tryptamine, N, N-dimethyltryptamine, serotonin (5-HT, 5-OH-tryptamine) ◦ Also a 5-HT mammalian neurotransmitter ◦ melatonin (regulation of circadian rhythms in mammals) ◦ gramin (Hordeum vulgare, Poaceae) ◦ psilocybin (Psilocybe mexicana, P. semilanceata and other Psilocybe spp.; Conocybe spp., Panaeolus, Stropharia) Tryptophan-derived alkaloids / beta-carboline alkaloids harman, harmin (Peganum harmala, Zygophyllaceae); eleagnin (Eleagnus angustifolia, Eleagnaceae) condensation of keto acids + tryptamine Tryptophan-derived alkaloids / terpenoid indole alkaloids ~ 3000 known mainly Apocynaceae, Loganiaceae, Rubiaceae extreme structural diversity tyramine is recognizable in the vast majority of cases, to which a C9 or C10 unit of secoiridoid (secologanine) origin is attached ◦ For iridoid C9, the circle marked C is missing can be classified into Corynanthe, Aspidosperma and Iboga types based on the arrangement of iridoid atoms ◦ Corynanthe type: ▪ Rauwolfia serpentina (Apocynaceae) alkaloids (yohimbine, ajmalicin, serpentine, reserpine) reserpine: causes the neurotransmitter depletion, so it is antihypertensive and mild tranquillans, but its long-term use leads to severe depression, no longer used ▪ Strychnos alkaloids (strychnine, brucine, toxiferin-1 (curare-like effect)) they are among the most complex compounds possible in relation to their molecular size ALKALOIDS, 30 / 73  Trp + C2 (AcCoA origin) + C9 (Iridoid origin) ◦ Aspidosperma type: ▪ Vinca minor alkaloids: vincamine ▪ Catharanthus roseus alkaloids: vindoline (building block of vincristine, vinblastine) ◦ Iboga type: ▪ Catharanthus roseus alkaloids: catharanthine (building block of vincristine, vinblastine) ▪ Taberanthe iboga (traditional African stimulants, psychoactive, toxic) alkaloids (ibogaine) ◦ ellipticine and its derivatives, e.g. 9-MeO-ellipticin (Ochrosia elliptica, Apocynaceae) Uncariae tomentosae radix Uncaria tomentosa (Rubiaceae) Cat's claw root Cat's claw It is a plant native to Central and South America. Products provided by the plant: cortex radix Chemical components 0.15-0.5% alkaloid: oxindole alkaloids: ◦ tetracyclic alkaloids: richnofillin, isorichnofillin ◦ pentacyclic alkaloids: pteropodine, isopteropodine, mitrafillin, isomitrafillin ◦ There are several chemotypes, some POA, others TOA manufacturers triterpenes (Hungarian acid C, D), sterols pteropodin ALKALOIDS, 31 / 73 standardization pentacyclic oxindole alkaloids Main effects antibacterial effect (IV) anti-platelet effect (AS) ◦ isorichnofillin (IV) anti-inflammatory (AS) ◦ TNF-alpha and PGE2 production ↓ ◦ some authors say that alkaloids are not relevant to this effect, some say that sterols and triterpenes are active antinociceptive effect (AS) antioxidant effect (IV, on cell cultures) antitumor effect (AS) ◦ longer lymphocyte t1 / 2 Neutrophil granulocyte count ◦ tumor cell apoptosis a ◦ direct antiproliferative effect on several tumor lines (IV) antiviral effect (IV) cardiovascular effect (AS) ◦ Ca2 + channel modulation ◦ hypertension, bradycardia, arrhythmia occur (cf. richnofillin) cholinergic effects (AS) effect against memory impairment caused by cholinergic dysfunction (pteropodine, isopteropodine) chondroprotective effect (IV) EMS effects (tetracyclic oxindole alkaloids) ◦ inhibition of amnesia-inducing effect of scopolamine (unkarin C, E; mitrafillin, richnofillin, isorichnofillin) ◦ anticonvulsans (AS) (hirsutin, hirsutin) ◦ effects of the extract in vivo in KIR diseases (sedation, vascular dementia, epileptic seizures, drug addiction, cerebral ischemia) (vsz Ca2 + channel modulation) (isorichnofillin, richnofillin) ◦ neuroprotective effect (AS) ◦ Therapeutic effects against Parkinson's disease (AS) Inhibition of CYP3A4 (IV) ALKALOIDS, 32 / 73  endocrine effects ◦ dose-dependent progesterone inhibition (IV) ◦ estrogen receptor binding inhibition (IV) immunomodulation ◦ pentacyclic oxindole alkaloids enhance immune function, tetracyclic oxindole alkaloids inhibit the development of the same effect (IV) ◦ myeloid progenitor number ↑ (AS) ◦ white blood cell count enters ↑, without changing the proportions (AS) - long-term treatment does not create structural change ◦ formation of dendritic cells ↑, promotion of T cell immunity (Hungarian acid C + IFN-gamma) ◦ Promoting recovery from doxorubicin-induced leukopenia (AS) steroid metabolism ◦ anti-inflammatory (beta-sitosterol, stigmasterol, campesterol) (AS) Prevention of UV damage (IV, on skin cultures) Clinical uses osteoarthritis ◦ positive effect within one week of treatment (lyophilized aqueous extract of U. guianensis) ▪ the pain experienced during movement improves ▪ no change in resting pain or swelling ◦ other effects have been described for combination products (decreased joint stiffness) rheumatoid arthritis ◦ extract containing tentacyclic alkaloids and containing pentacyclic alkaloids ◦ Reduces swelling and pain ◦ Can be used for 24 weeks in combination (sulfasalazine) There is not enough evidence to judge efficacy tumors (preliminary, positive results) ◦ 5% extract standardized to mitrafillin Fatigue ↓, QoL ↑, social functions ↑ side Effects Probably safe po., Properly used for a short time ◦ A certain lyophilized aqueous extract is safe for 4 weeks ◦ Tetracyclic oxindole alkaloid-free extract can be used safely for 24 weeks Probably unsafe during pregnancy ALKALOIDS, 33 / 73 ◦ traditional contraceptivum Generally well tolerated side effects in patients with solid tumors (incidence between 2 and 10%): ◦ nausea, nausea, abdominal pain, abdominal tension, tightness, epigastric pain, diarrhea ◦ anemia, leukopenia, thrombocytopenia ◦ headache, fatigue, insomnia, neuropathy Toxicology ◦ free from toxic effects in volunteers at normal dosing drug-drug interactions speculative / theoretical only, no data may interfere with immunosuppressants (cyclosporine, tacrolimus, sirolimus, prednisolone and corticosteroids) Based on preliminary results, it may be an inhibitor of CYP3A4 - caution potentiation is possible with anticoagulants (richnofillin, isorichnofillin) (AS) possible enhancement with antihypertensive drugs (AS) contraindications no data autoimmune diseases (lupus erythematosus, multiple sclerosis, etc.) Dosage 60-100 mg extract / day (~ 1.5% POA) Vincae minoris herba Vinca minor (Apocynaceae) Little evergreen Perinwinkle Products provided by the plant: herba Chemical components 0.25-1% alkaloids: vincamine ALKALOIDS, 34 / 73 Main effects cerebral vasodilator (vincamine) Clinical uses used as an industrial herb, used as a raw material for semi-synthesis (vincamine → apovincaminic acid ethyl ester) acute post-stroke phasis (preliminary, positive results) side Effects skin rash, GIT complaints reduction in blood pressure drug-drug interactions is irrelevant contraindications is irrelevant Dosage 2-3 g / day (TU) Catharanthi herba Catharanthus roseus (Apocynaceae) Madgascar perinwinkle Products provided by the plant: herba Chemical components 0.7% alkaloid mixture (total 0.0005% vincristine and vinblastine) Main effects ALKALOIDS, 35 / 73  cytotoxic effect Clinical uses considered an industrial herb vincristine side Effects Unsafe po., When used, is considered an industrial herb ◦ causes nervous, liver and kidney damage, but bone marrow depression and neuropathy (acute neurotoxic syndrome) may also occur drug-drug interactions is irrelevant contraindications is irrelevant Dosage is irrelevant ALKALOIDS, 36 / 73 Strychni semen Strychnos nux-vomica (Loganiaceae) Nux vomica It is a plant native to Southeast Asia. Products provided by the plant: semen Chemical components 2-5% alkaloid (1-1.4% strychnine, 1-1.4% brucine) iridoid glycosides Main effects analgesic effect (AS, morphine-like mechanism of action, central target) anti-inflammatory effect (non-NSAID-like mechanism of action) (brucine, brucine N- oxide) selective, competitive antagonist - inhibition of postsynaptic binding of glycine (a major inhibitory transmitter of spinal cord interneurons and motor neurons) Clinical uses its efficacy is not supported by clinical evidence is considered a toxic plant side Effects Unsafe po., Applied ◦ 30-50 mg of the drug can already cause severe inverse reactions ◦ 1-2 g of drug already causes fatal poisoning ◦ Regular consumption can cause fatal poisoning within a few weeks Not safe during pregnancy Not safe during breast-feeding ALKALOIDS, 37 / 73  Symptoms of overdose: difficulty swallowing, climbing sensation in the cervix, irritability, restlessness, anxiety, increased perception, hyperreflexia, dizziness, sore and / or stiff neck, seizures (→ hyperthermia, metabolic and respiratory acidosis, rhabdomyolysis) Symptoms of poisoning: painful seizures, convulsions, difficulty breathing, confusion, muscle pain, muscle stiffness; rhabdomyolysis may also occur in association with muscle damage; based on case studies, self-awareness does not change during seizures Most deaths occur within 6 hours of consumption due to cardiac arrest, anoxic brain damage, or multiple organ failure due to hyperthermia drug-drug interactions speculative / theoretical only, no data contraindications no data Dosage Max. 300 mg / day (historical significance) Tryptophan-derived alkaloids / quinoline alkaloids They are formed from Corynanthe C9 type terpenoid indole alkaloids (biosynthesis starts from strichtosidine) rearrangement, but only at the end of biosynthesis (indole -> quinoline) Cinchona alkaloids (Rubiaceae) ◦ quinine, quinidine, cinchonidine, cinchonidine ◦ anti-malarial effect (Plasmodium spp.) (Mainly quinine) ◦ quinidine: a previously used antiarrhythmic agent Tryptophan-derived alkaloids / pyroquinoline alkaloids ◦ camptothecin (Camptotheca acuminata, Nyssaceae; Nothapodytes foetida, Icaniaceae; Merilliodendron megacarpum, Icariaceae; etc.) ▪ practically intact secoiridoid part! ▪ starting material for the semi-synthesis of antitumor drugs (topotecan, irinotecan - much more water soluble) ◦ pumiloside, deoxypumiloside (Ophiorrhiza pumila, Rubiaceae) ◦ practically intact secoiridoid part! ALKALOIDS, 38 / 73 Cinchonae cortex Cinchona pubescens (Rubiaceae) China Tree bark cinchona A tree native to Peru, Ecuador and Colombia. Products provided by the plant: cortex Chemical components 6.5% alkaloid mixture: quinine, cinchonidine, cinchonine, quinidine tanning triterpenoids Main effects anti-malarial effect (quinine) ◦ primarily effective against asexual forms (in erythrocytes) anti-platelet effect (cinchonine) ◦ vsz Inhibition of Ca2 + influx cardiovascular effects (quinidine) ◦ Inhibition of Na +, K + channels ◦ Elongation of QRS complex ◦ block of adrenoceptors Clinical uses its efficacy is not supported by clinical evidence considered an industrial herb ◦ quinine: antimalarial agent, antipyretic ◦ Quinidine: antiarrhythmic agent side Effects ALKALOIDS, 39 / 73  Most likely safe when used in food in the usual amounts of po ◦ Used for flavoring ~ 80 ppm final concentration is allowed in beverages Probably unsafe po., Used in medical amounts ◦ OTC products should state that they should be discontinued if certain side effects occur (ringing in the ears, deafness, skin rash or blurred vision) ◦ Quinine - a narrow therapeutic index, no longer OTC in the US, although previously it was ◦ in large quantities is unlikely to be safe ▪ Doses equivalent to 2 g of alkaloids already cause serious side effects Unlikely to be safe during pregnancy and lactation ◦ uterus stimulans effect, teratogenic (causes visual and auditory defects) ◦ Alkaloids are excreted in breast milk and can cause poisoning Prolonged use of high doses or an alkaloid above 3 g leads to a syndrome of toxicity known as cinchonism ◦ headache, confusion, nausea, vomiting, haemolysis, hypotension, arrhythmia, tinnitus, deafness, blurred vision, blindness, abdominal pain, paralysis, collapsus ◦ 10-15 g of quinine causes fatal poisoning contact dermatitis or urticaria may occur with topical application quinine side effects: nausea, nausea, diarrhea, tinnitus, blurred vision, even deafness, blindness quinine, quinidine: QT prolongation, arrhythmia (torsade de pointes), sometimes thrombocytopenia, bone marrow depression, thrombotic thrombocytopenias purpura and haemolytic uremic syndrome drug-drug interactions increases the blood levels of carbamazepine (quinine) Anticoagulants are expected to increase efficacy contraindications pregnancy, breast-feeding Dosage 1.5 g / day (TU) Tryptophan-derived alkaloids / pyrroloindole alkaloids very rare, occurring in some plants, amphibians and marine algae physostigmine (= eserine) (Physostigma venenosum, Fabaceae) ◦ interestingly, biological activity does not require the heterocyclic system, but the carbamate side chain does ◦ reversible AChE inhibitor, now rarely used ◦ antidote to anticholinergic poisoning (eg atropine) ALKALOIDS, 40 / 73  chimonant (Chimonanthus fragrans, Calycanthaceae) Physostigmae semen Physostigma venenosum (Fabaceae) Although kala-beans Calabar bean It is a plant native to Africa. Products provided by the plant: semen Chemical components alkaloids (physostigmine) Clinical uses its efficacy is not supported by clinical evidence considered a toxic industrial herb (manufacture of physostigmine) side Effects Unsafe po., Applied, all parts of the plant are extremely toxic Do not use during pregnancy and lactation symptoms of acute poisoning: cholinergic crisis (prolongs acetylcholine activity); increased secretion (GIT, saliva, etc.), increased peristalsis, pupillary contraction, decreased heart contractility, respiratory paralysis, death drug-drug interactions is irrelevant contraindications is irrelevant Dosage is irrelevant ALKALOIDS, 41 / 73 Tryptophan-derived alkaloids / ergot alkaloids Claviceps species (plant pathogenic fungi), as well as Aspergillus, Rhizopus, Penicillium species are also capable of production; in plants: Ipomea, Rivea (Convulvulaceae) also occur (mainly ergin = lysergic acid amide, ~ 0.05%), but it may also be of fungal origin here basically plant-fungal metabolic co-products in situ, but the fungus itself can produce them other compounds are formed from lysergic acid by amide formation -> ergometrine (2-aminopropanol), ergotamine (peptide) Claviceps alkaloids can be divided into ergotamine, ergoxin and ergotoxin subgroups, depending on the first linking amino acid side chain (-Me, -Et, -iPr)) ◦ R = Me: ergotamine ◦ R = Et: ergostine ◦ R = iPR: ergocristine within this, different variants are created by the addition of additional amino acids (Ala, Val, Leu, Ile, Phe, Pro, alpha-aminobutyrate can join in different combinations; Pro is always present) Usage: ◦ have alpha-adrenergic, dopaminergic and serotonergic effects ◦ ergometrine - induction of uterus contractio (vasoconstrictor) ◦ LSD - hallucinogenic drug, the most active known psychotomimetic (dose 30-50 µg), mixed 5-HT agonist / antagonist ◦ ergin - hallucinogenic, 1/10 efficacy compared to LSD, although the sedative effect is stronger ◦ long-term exposure is undesirable (vasoconstrictor, peripheral tissue hypoxia, necrosis) Secale cornutum Claviceps purpurea (Clavicipitaceae) Ergot ergot Mushrooms living on the ears of cereals (mainly rye). Products provided by the mushroom: whole fruiting body Chemical components ergot alkaloids (lysergic acid, ergocristine, ergotamine, ergometrine) ALKALOIDS, 42 / 73 Main effects serotonin and dopamine agonism, some alpha-adrenergic agonists (ergot alkaloids) arterial vasoconstriction enhancement of smooth muscle contraction in the uterus (ergometry) Clinical uses its effectiveness is not supported by clinical evidence, its consumption is too risky industrial pharmaceutical raw material side Effects Unsafe po., Used due to the risk of poisoning and its interaction with many diseases Not safe during pregnancy and lactation drug-drug interactions only speculative / theoretical, no data, but risks are serious ◦ Serotonin-related side effects may be increased when co-administered with serotonergic antidepressants (SSRIs) or MAOIs (serotonergic syndrome, vasoconstrictive diseases) contraindications no data Dosage is irrelevant Anthranilic acid alkaloids anthranilic A key intermediate in Trp biosynthesis Quinazoline backbone alkaloids peganin = vasicin (Peganum harmala, Zygophyllaceae; Justicia adhatoda, Acanthaceae) - bronchodilator ALKALOIDS, 43 / 73  febrifugin (Dichroa febrifuga, Saxifragaceae; Hydrangea umbellata, Hydrangeaceae) - a very strong antimalarial drug (~ 100-200x more potent than quinine), with very serious side effects Quinoline and acridine backbone alkaloids occurs mainly in Rutaceae species anthranilic acid + malonyl-CoA quinoline skeleton: dictamnin, skimmianin (Dictamnus albus, Skimmia japonica, Rutaceae) acridine backbone: ◦ is formed in a similar way to chalcone biosynthesis (N-Me-anthranoyl-CoA + acetate polymer) ◦ rutacridone (Ruta graveolens, Rutaceae), acronicin (Acronychia baueri), melicopicin (Melicope fareana) Histidine-derived alkaloids relatively little is known histidine imidazole is a cyclic proteinogenic amino acid histamine a molecule involved in allergic reactions in mammals (mast cells) Histidine alkaloids / imidazole backbone alkaloids dolichothin (Dolichothele sphaerica, Cactaceae) pilocarpine, pilosin (Pilocarpus microphyllus, P. jaborandi, Rutaceae) ◦ previously commonly used glaucoma medication; ophthalmic medicine ◦ cholinergic substance ALKALOIDS, 44 / 73 Jaborandi folium Pilocarpus jaborandi, P. microphyllus, P.spp. (Rutaceae) It is a plant native to D-America (Brazil). Products provided by the plant: folium Chemical components 0.5 - 7% alkaloids: pilocarpine, pilocarpidine, pilosin. Clinical uses not relevant (see purified pilocarpine) Side effects pilocarpine The use of the plant is not safe, it is only of historical significance used as an industrial herb Lethal dose of 5-10 g leaves (~ 60 mg pilocarpine) Unsafe for use in pregnancy: teratogenic, uterine stimulants Symptoms of poisoning (pilocarpine - parasympatomymeticum): bradycardia, bronchospasm, colica, cardiovascular collapse, cardiac arrest, hypotension, respiratory failure, nausea, intense salivation and sweating, vomiting, ocular myosis drug-drug interactions not relevant (see purified pilocarpine) contraindications not relevant (see purified pilocarpine) Dosage not relevant (see purified pilocarpine) ALKALOIDS, 45 / 73 Alkaloids biosynthesized by amination reaction are primarily biosynthesized from non-amino acid precursors, so-called "Pseudo-alkaloids" terpenoid or other backbone, N is given by amino acid transamination Conine (Conium maculatum, Apiaceae) - of fatty acid origin pinidine (Pinus spp.) - of polyacetate origin ephedrine and its derivatives (Ephedra spp.) - of Phe origin, but only C atoms, N is transaminated ◦ ephedrine - bronchodilator, anti-nasal congestion (sympathomimetic, KIR stimulans, weak alpha-, beta-adrenergic agonist, but accumulates in storage vesicles instead of noradrenaline) ◦ (-) - cathinone (Catha edulis, Celastraceae) - indigenous to Ethiopia, D- and K-Africa, Yemen, stimulant, general feeling of well- being; psychiatric addictive drug ◦ MMDA (methoxymethylenedioxyamphetamine) - putative human metabolite of myristicin (Myristica fragans Myristicaceae, (nutmeg)) Ephedrae herba Ephedra distachya, E. spp. (Ephedraceae) ephedra Ephedra Ma Huang Illegal, doping. Products provided by the plant: herba Chemical components (proto) alkaloids: ephedrine, pseudoephedrine, phenylpropanolamine Main effects inflammatory antitussive, bronchodilator ALKALOIDS, 46 / 73  cardiovascular effects: Systolic, diastolic blood pressure Heart rate Heart contractility ◦ peripheral vasoconstriction ◦ coronary vasoconstriction -> AMI ◦ refractoricus section ↓ -> arrhythmia KIR stimulation ◦ prob. catecholamine release ↑ metabolic effects: Energy consumption Thermogenesis ◦ gastric emptying ↓ Clinical uses obesity ◦ 0.9 kg / month for up to 6 months ◦ also in combination (in combination with caffeine according to even more effective clinical trials) Probably ineffective training performance side Effects the expected benefits do not outweigh the risks Most likely unsafe, po., Applied ◦ Life-threatening or permanently damaging side effects occur during use ◦ Prolonged use or high doses increase the risk of serious side effects ▪ Dose above 32 mg alkaloids / day: risk of 3x haemorrhagic stroke (both intracerebral and subarachnoid haemorrhage) ◦ Some sensitive individuals may experience severe side effects with short-term use of small doses (case studies) long-term use develops dependence, tolerance, psychosis (the latter sometimes persists for months after cessation) the frequency of adverse reactions has not been systematically analyzed (case studies in the literature) -> incidence is difficult to assess ◦ DE: 3% of known adverse reactions associated with Ephedra were severe or fatal ALKALOIDS, 47 / 73 ◦ Cardiovascular patients are likely to be at higher risk, but symptoms also occur in healthy subjects ◦ Life-threatening conditions may occur with the use of the indicated doses cardiovascular side effects: cardiomyopathy, myocarditis, chest pain, AMI, sudden death due to cardiac arrest, hypertension, tachycardia, arrhythmia, QT prolongation (also in healthy subjects), early atrial contraction ◦ Life-threatening side effects: hypertension, myocardial infarction, seizures, stroke, sudden death GIT side effects: dry mouth, nausea, nausea, heartburn, abdominal discomfort EMS side effects (common!): Restlessness, irritability, confusion, personality changes, difficulty concentrating, insomnia, headache, dry mouth; less commonly, provocation of seizures, transient ischemic attack (TIA), loss of consciousness, loss / impairment of brain function (eg transient blindness in a case study) other common side effects: hyperthermia, urinary incontinence other side effects: heptotoxicity (some affected people needed a transplant) drug-drug interactions Increased efficacy (increased hypertension and / or cardiovascular side effects) may occur: ◦ caffeine (insomnia, confusion, tremor, increased cvas risk) ◦ MAOI ◦ ergot derivatives ◦ KIR stimulants ◦ QT prolonging agents contraindications consumption of the plant should be avoided, it is more risky than usual in cardiovascular diseases or hyperthyroidism Dosage 15-40 mg / day ephedra alkaloid (ephedrine) equivalent non-phytotherapeutic use also occurs: ephedrine capsaicinoids ◦ Capsicum annuum, Solanaceae ◦ phenylalanine -> vanillin -> vanillamine + polyketide-derived, branched side chain ◦ C8-C13 long branched side chains ALKALOIDS, 48 / 73 ◦ TRPV1 agonist (transient receptor potential vanilloid type 1) - although other agonists do not really contain a vanilloid group - pain desensitization ◦ the ω-OH derivative is not pungent Capsici fructus Capsicum annuum, C. fructescens, C. spp. (Solanaceae) Pepper crop Capsicum It is a native, widely cultivated plant in America. Products provided by the plant: fructus Chemical components 0.01-0.5% capsaicinoid (capsaicin, dihydro-capsaicin, homocapsaicin, homo-dihydro-capsaicin, nor-dihydro-capsaicin) capsinoids carotenoids steroid saponins standardization capsaicin "Scoville scale" ◦ is the highest dilution that can still sting ◦ Capsaicin: 16,000,000 ◦ peppers: 0-3,200,000 (Carolina Reaper, Dragon's Breath, Pepper X) ◦ is now more of an HPLC test Main effects painkiller ◦ selective stimulation of afferent C fibers = thermo- and nociceptors ALKALOIDS, 49 / 73 ◦ first neuronal excitatio and hypersensitivity develop (burning sensation, itching, vasodilatation) ◦ refractory period, temporary loss of membrane potential, insensitivity ◦ Persistent desensitization occurs after repeated application (substance P depletion) antibacterial effect (IV) antitumor effect (cytostatic effect, IV) antidiabetic effect ◦ Consumption of 5 g powder: Glc tolerance ↑, insulin level ↓, postprandial Glc ↓ ◦ Inhibition of Glc absorption (IV) ◦ There are conflicting experimental results as well anti-inflammatory effect with prolonged use ◦ Suppression of histamine and bradykinin-induced watering and inflammation ◦ there are also conflicting experimental results (in pro-inflammatory psoriasis) antioxidant effect (also CT) ◦ improvement of oxidative markers cardiovascular effects ◦ vasodilatation -> may be useful in cluster headaches and coronary artery disease GIT effects ◦ gastroprotective effect according to some studies (prevention of alcohol or NSAID-induced gastric mucosa damage) ▪ a thin protective layer forms on the stomach wall (AS) ◦ Consumption of large amounts causes necrosis, ulcers, increased risk of stomach cancer effects on the respiratory system ◦ C-fiber stimulation Weight loss ◦ increases metabolic rate, energy expenditure, fat oxidation and body temperature ◦ has an appetite suppressant effect - due to increased GIT stress? Clinical uses diabetic peripheral neuropathy ◦ externally, 8% capsaicin patch after localanaesthetic pre-treatment (for 12 weeks) ◦ decreasing pain ◦ A single application also causes a 30-50% reduction in pain ALKALOIDS, 50 / 73 ◦ cream: 0.075% capsaicin, 4x daily pain Relief ◦ cream: 0.05-0.075% ◦ 3 times a day for 21 days ◦ rheumatoid arthritis, osteoarthritis, back pain, jaw pain, psoriasis, neuropathy post-herpes neuralgia ◦ externally, a patch containing 8% capsaicin ◦ in the 12-week protocol the effect starts to develop after a few days and approx. It lasts for 5 months ◦ Better in treating mild pain Back pain cluster headache (intranasal application, 0.025%, acute) Alkalmazás Application for 7 days reduces the severity of the following week's symptoms perennial rhinitis ◦ Reduces symptoms of non-allergic, non-infectious perennial rhinitis ◦ A reduction in symptoms was observed for 6-9 months after treatment PONV (postoperative nausea and vomiting) ◦ Patches applied to certain points of the hand before anesthesia postoperative pain relief ◦ Patches applied to certain points of the hand before anesthesia ◦ Decreased analgesic demand There is not enough evidence to judge the effect allergic rhinitis (intranasal treatment, conflicting results) burning mouth syndrome (rinsing, control group-free examinations) diabetes (preliminary results, 5 mg capsaicin / day) ◦ Chl ↓, postprandial Glc ↓ dyspepsia (preliminary results, improving symptoms, although a temporary worsening may be observed in some patients) increase of athletic performance (negative result, in combination) fibromyalgia ◦ improves the pain threshold, reduces the sensitivity of sensitive points ◦ physical function does not improve ◦ overall pain does not decrease (the disease is associated with chronic pain) ALKALOIDS, 51 / 73 ◦ long-term effect is unknown HIV-associated peripheral neuropathy (conflicting results) ◦ 8% capsaicin patch, 30-90 minutes application ◦ It starts to work after a few days, the effect lasts for 5 months IBS (negative result) joint pain (in combination only, efficacy cannot be judged) migraine headache (preliminary, positive result) Morton's neuroma (injection, preliminary results: decreased walking pain, many other QoL parameters unchanged) myofascial pain (the combination is not better than conventional treatment) peptic ulcers ◦ Epidemiol. study: consumption at least 24 times a month carries a lower risk of ulcers (vs. 8 times a month eaters) ◦ CT: does not help heal existing duodenal ulcers peripheral neuropathy (preliminary, positive result) prurigo nodularis (preliminary, positive result, symptoms may return after stopping therapy) sinonasal polyposis (preliminary, positive result: some parameters improve, others do not) swallowing dysfunction (prevention of aspiration in elderly patients, preliminary results, rinsing) weight loss (preliminary results) ◦ Capsaicin 2x3 mg daily for 12 weeks ▪ -1% body fat, weight unchanged ◦ there is a more effective combination preparation, but there the effectiveness of the peppers is not clear side Effects Highly likely to be safe in dosages typically found in foods, GRAS status Probably safe for po or intranasal use for a sufficiently short period of time (