S1 L1 Introduction to Pharmacognosy

Anna Drew

with slide contribution from Bob Hoffman

& grateful acknowledgement for inspirational teaching received at the School of Pharmacy, University of London

• ‘Pharmacognosy’ – pharmakon ‘a drug’ (Greek)– gignosco ‘ to acquire knowledge of’ (Greek)– OR cognosco ‘to know about’ (Latin)

• Johann Adam Schmidt (1759-1809)– Lehrbuch der Materia Medica– Published Vienna 1811– Beethoven’s physician

Naturally occurring substances having a medicinal action:

• Surgical dressings prepared from natural fibres• Flavourings and suspending agents• Disintegrants• Filtering and support media

• Other associated fields:– Poisonous and hallucinogenic plants– Raw materials for production of oral contraceptives– Allergens– Herbicides and insecticides

Pharmacognosy is related to:

– Botany– Ethnobotany– Marine biology– Microbiology– Herbal medicine– Chemistry (phytochemistry)– Pharmacology– Pharmaceutics

Skills & techniques valuable elsewhere:

Analysis of other commodoties• Foods, spices, gums, perfumes, fabrics, cosmetics

Used by• Public analysts, forensic sciences, quality-control scientists

Role in pure sciences• Botany, plant taxonomy, phytochemistry

Botanists and chemists looking at:• Chemical plant taxonomy, genetic/enzymatic studies involving 2y

metabolites• Artificial and tissue culture • Effects of chemicals on plant metabolites • Induction of abnormal syntheses • Bioassay-guided isolation techniques

Vegetable drugs can be arranged for study:

– Alphabetical– Taxonomic**

• botanical classification

– Morphological• Organised drugs: leaves, flowers, fruit, seeds etc• Unorganised drugs: extracts, gums, resins, oils etc

– Pharmacological/therapeutic*• Increasingly used with screening• Constituents of one drug may fall into several groups

– Chemical/biogenetic• Constituents or biosynthetic pathways

CLASS Angiospermae (Angiosperms) Plants which produce flowers

Gymnospermae (Gymnosperms) Plants which don't produce flowers

SUBCLASS Dicotyledonae (Dicotyledons, Dicots) Plants with two seed leaves

Monocotyledonae (Monocotyledons, Monocots) Plants with one seed leaf

SUPERORDER A group of related Plant Families, classified in the order in which they are thought to have developed their differences from a common ancestor.

There are six Superorders in the Dicotyledonae (Magnoliidae, Hamamelidae, Caryophyllidae, Dilleniidae, Rosidae, Asteridae), and four Superorders in the Monocotyledonae (Alismatidae, Commelinidae, Arecidae, Liliidae)

The names of the Superorders end in -idae

ORDER Each Superorder is further divided into several Orders. The names of the Orders end in -ales

FAMILY Each Order is divided into Families. These are plants with many botanical features in common, and is the highest classification normally used. At this level, the similarity between plants is often easily recognisable by the layman.

Modern botanical classification assigns a type plant to each Family, which has the particular characteristics which separate this group of plants from others, and names the Family after this plant.

The number of Plant Families varies according to the botanist whose classification you follow. Some botanists recognise only 150 or so families, preferring to classify other similar plants as sub-families, while others recognise nearly 500 plant families. A widely-accepted system is that devised by Cronquist in 1968, which is only slightly revised today.

The names of the Families end in -aceae

SUBFAMILY The Family may be further divided into a number of sub-families, which group together plants within the Family that have some significant botanical differences.

The names of the Subfamilies end in -oideae

TRIBE A further division of plants within a Family, based on smaller botanical differences, but still usually comprising many different plants.

The names of the Tribes end in -eae

SUBTRIBE A further division, based on even smaller botanical differences, often only recognisable to botanists. The names of the Subtribes end in -inae

GENUS This is the part of the plant name that is most familiar, the normal name that you give a plant - Papaver (Poppy), Aquilegia (Columbine), and so on. The plants in a Genus are often easily recognisable as belonging to the same group.

The name of the Genus should be written with a capital letter.

SPECIES This is the level that defines an individual plant. Often, the name will describe some aspect of the plant - the colour of the flowers, size or shape of the leaves, or it may be named after the place where it was found. Together, the Genus and species name refer to only one plant, and they are used to identify that particular plant. Sometimes, the species is further divided into sub-species that contain plants not quite so distinct that they are classified as Varieties.

The name of the species should be written after the Genus name, in small letters, with no capital letter.

VARIETY A Variety is a plant that is only slightly different from the species plant, but the differences are not so insignificant as the differences in a form. The Latin is varietas, which is usually abbreviated to var.

The name follows the Genus and species name, with var. before the individual variety name.

FORM A form is a plant within a species that has minor botanical differences, such as the colour of flower or shape of the leaves.

The name follows the Genus and species name, with form (or f.) before the individual variety name.

CULTIVAR A Cultivar is a cultivated variety, a particular plant that has arisen either naturally or through deliberate hybridisation, and can be reproduced (vegetatively or by seed) to produce more of the same plant.

The name follows the Genus and species name. It is written in the language of the person who described it, and should not be translated. It is either written in single quotation marks or has cv. written in front of the name.

Example

• Linnaeus (1707-1778), Swedish biologist

• Division Angiospermae• Class Dicotyledoneae• Subclass Sympetalae• Order Tubiflorae• Suborder Verbenineae• Family Labiatae (Lamiaceae)• Subfamily Stachydoideae• Tribe Satureieae• Genus Mentha• Species Mentha piperita Linnaeus (peppermint)• Varieties Mentha piperita var. officinalis Sole

(White Peppermint); Mentha piperita var. vulgaris Sole (Black Peppermint)

Contribution of plants to medicine and pharmacy

• 18th century drugs plant based

• 19th century a range of drugs was isolated:

• 1805 morphine• 1817 emetine• 1819 strychnine• 1820 quinine

• Famous plants/plant drugs?

Quinine

• Cinchona bark, South American tree• Used by Incas; dried bark ground and mixed

with wine• First used in Rome in 1631• Extracted 1820• Large scale use 1850• Chemical synthesis 1944• Actual tree remains the most economic source

Belladonna -> atropine

Anticholinergic

syndrome:

• Hot as hell• Blind as a bat• Red as a beet• Dry as a bone• Mad as a hatter

Physostigma venosumCalabar bean

Efik People

Efik Law• Trial by ordeal

“A suspected person is given 8 beans ground and added to water as a drink. If he is guilty, his mouth shakes and mucus comes from his nose. His innocence is proved if he lifts his right hand and then regurgitates” (Simmons 1952)

• Deadly esere• Administration of the Calabar bean

• First observed by WF Daniell in 1840• Later described by Freeman 1846 in a

Communication to the Ethnological Society of Edinburgh

Physostigmine or Eserine

First isolated in 1864 by Jobst & Hesse

‘Taxol’

• Pacific Yew tree, Taxus brevifolia, bark

• 1964 activity discovered at NCI

• 1966 paclitaxel isolated

• Mitotic inhibitor– interferes with normal microtubule growth during cell div

• Used for cancer chemotherapy– lung, ovarian, breast, head & neck, Kaposi’s sarcoma

• 1969 • 1200kg bark -> 28kg crude extract -> 10g pure

• 1975 active in another in vitro assay• 1977 7000 pounds bark requested to make 600g

• 1978 Mildly active in leukaemic mice• 1979 Horowitz; unknown mechanism

• involved stabilising of microtubules• 1980 20,000 pounds of bark needed

• 1982 Animal studies completed

• 1984 Phase I trials• 12,000 pounds for Phase II to go ahead

• 1986 Phase II trials began• Recognised 60,000 pounds miniumum needed• Environmental concerns voiced

• 1988 • An effect in melanoma• RR of 30% refractory ovarian cases• Annual destruction of 360,000 trees to treat all US cases

• 1989 NCI handed over to BMS• Agreed to find alternative production pathway• 1992 BMS given FDA approval & 5yrs marketing rights• Trademark ‘Taxol’ Generic paclitaxel

• 2000 sales peaked US$1.6 billion• Now available as generic

Alternative production

– 1967-1993 all sourced from Pacific Yew– Late 1970s synthetic production from petrochemical-

derived starting materials– 1981 Potier isolated 10-deacetylbaccitin from Taxus

baccata needles– 1988 published semi-synthetic route– 1992 Holton patented improved process improving

yield to 80%– 1995 use of Pacific Yew stopped– Now plant cell fermentation (PCF) technology used– Also found in fungi– Race for synthetic production -> docetaxel

Why do we need plants?

1. Source of drug molecules

• Most drugs can be synthesised• Still more economical to use the plant

Papaver opium -> morphine, codeine (strong medicinal pain)

Ergot fungus –> ergotamine (headache), ergometrine (direct action on uterine muscle)

Digitalis foxglove -> digoxin (acts on cardiac muscle)

2. Source of complex molecules that can be modified to medicinal compounds

• Examples:

Droscera yam: molecule -> steroids

Soya: saponins -> steroids

3. Source of toxic molecules

• To study the way the body responds to their pharmacological use

• Investigating pharmacological mechanisms

picrotoxin – nerve conduction

Morphine:

No better painkiller. Once structure worked out wanted to improve it. What is required?

Diacetylmorphine (heroin):

OH group -> O-O-diacetyl. Still addictive?

Codeine:

Methylate hydroxyl phenolic; O-Me. 1/5 analgesic capacity of morphine, useful to suppress cough reflex

Dihydromorphinone:

Reduced =, oxidised 2y alc. Potential analgesic.

4. Source of compounds to use as templates for designing new drugs

Dihydrocodeine:

Me-ether of previous. More powerful than codeine, less than morphine.

Dextromethorphan:

Good against cough reflex

Is lower ring necessary?

Pentazocin

Phenazocine

Is middle ring needed?

Pethidine

Methadone

• 5. Source of novel structures

• these might never be thought of

Catharanthus periwinkle -> vincristine (alkaloid dimer)

• 6. Source of plant drugs

• As a powder or extract

• The pure compound is often not isolated because:

» Active ingredient is unknown» Active ingredient is unstable» Isolation process is too costly

• 250,-500,000 species of higher plants on earth

• <10% investigated and only for one activity

• Huge potential in plant kingdom

Future: intense screening

» Anticancer - NCI» Antimicrobial» Antiviral» Antimalarial» Insecticidal» Hypoglycaemic» Cardiotonic» Antiprotozoal» Antifertility - WHO

• Screening– Pharmacological – in vitro testing– Chemical – certain constituents Eg alkaloids

• Failed screening work– Incorrect identification of plant material– Plants exist in chemical races – different

constituents– Low yield of active compound– Solubility – have to find correct solvent

Future

80% world population rely on natural remedies

• Westernization of societies (‘traditional’ knowledge)

• Extermination of species» conservation, retain gene pools

• Natural resources exhausted» cultivation, artificial propogation

Conclusion

• Natural products very important to medicine

• Exist in range of structures that one wouldn’t think of synthesizing

• Can act as templates for new drug development

• Untapped reservoir of new compounds