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PHARMACOKINETIC AND

PHARMACODYNAMIC IN HERB MEDICINE


Oktavia Rahayu A, S.Farm., M.Biomed
Department of Pharmacy, Medical Faculty, Universitas Brawijaya
Capaian Pembelajaran
Mampu memahami prinsip farmakokinetik dan farmakodinamik tumbuhan obat
dengan melihat senyawa markernya

Mampu memahami proses pengembangan OT melalui penelitian ilmiah (uji pre


klinik dan klinik)
PHARMACOLOGY
Study of the interaction
of biologically active agents with
living systems

PHARMACOKINETIC
PHARMACODYNAMIC Effects the body has on the
Effects of an agent at active medicine, specifically the
sites in the body concentrations that can be achieved
at active sites
How do herbs differ from conventional drug ?

Synergy
effect Additive
effect

Synergy  effect seen by a combination of substances that is greater than


would have been expected from a consideration of individual contributions.
In other words, components of plants that are not active themselves can
act to improve the stability, solubility, bioavailability or half-life of the
active components.
SYNERGY
1 1 >2
Hypericum perforatum 
treatment of depression,
isomnia, anxiety

Cannabis sativa 
antispasmodic

Piper methysticum (kava-


kava)  anti-anxiety &
Isobole : a method for sedative effect
demonstrating synergy effect
H.Perforatum (St.john wort)

Pseudohyperisin 
antagonistic activity on
corticotropin releasing factor
(CRF)  regulation of
Hyperoside  increase
hypothalamic-pituitary adrenal
water solubility of hypericin
activity  decrease incidence
of depression
(2) Negative feedback mechanism 
Stress dan Pseudohypericin secara normal, kortisol akan
menghambat aktivasi hipotalamus untuk
memproduksi CRF  kortisol menurun
 kesetimbangan hormon

(3) Long term stress  aktivasi


hipotalamus terus menerus 
peningkatan produksi CRF 
peningkatan produksi kortisol 
efek negatif untuk tubuh
(1) Stress  menginduksi
hipotalamus untuk memproduksi CRF
 menginduksi produksi ACTH oleh
kelenjar pituitary anterior 
menginduksi pelepasan kortisol oleh
korteks adrenal  efek antidepresi,
antiinflamasi (short term exposure) a.k.a stress hormone
Cannabis sativa
Cannabinoid system in human
 plays a significant role in
memory, appetite, emesis and
lactation

Tetrahydrocannabinol (THC)

Cannabidiol (CBD)  elevate level of THC in


the brain, amplifies antispastic effect of THC
Piper methysticum

Kavalactones (kavain, dihydrokavain, methysticin, dihydromethysticin,


yangonin, and desmethoxyyangonin)  elevate kavain levels in brain (cross
BBB)  The detergent effect of saponins helps to increase the solubility of
lipophilic molecules via micelle formation
The bioavailability of lactones is up to three to five times higher for the extract than
when given as single substances  increased bioavailability of kavain was due to an
inhibition of the cytochrome P450 and P-glycoprotein.
ADDITIVE

1 1 2

Additive effects can be just as favourable to enhanced therapeutic


activity and are probably more common in phytotherapy

Passionflower extract (Passiflora incarnata, 250 mg/kg) + kava


extract (100 mg/kg)  reduction of hypermotility
The Development
Process of Herbal Pre-clinic research
Medicine Pharmacodynamics
• Mechanism
• In vivo or in vitro
Pharmacokinetics
SAMPLE

• standardized extract • ADME


• granul Toxicity
• tablet
• In pregnancy
• capsule
• Teratogenic effect
• Carsinogenic effect
Marker compound?
Pharmacokinetics issues

In what ways are plant constituents likely to interact in the


gut to affect bioavailability and activity? (A)

What is known of hepatic action on plant constituents?


(M)

what plant-derived constituents are likely to reach the


systemic circulation?

How do changes in pharmaceutical formulation affect the


bioavailability and activity of plant constituents?
Study of herbal pharmacokinetics can deliver:
• Better information on which to base rational dosages
• Better interpretation of scientific information, particularly in vitro
research or in vivo studies where the active compounds are
administered by injection.
• Better appreciation of the safety and toxicity of a plant
• Anticipation of potential herb-drug interactions
• Supporting evidence for the synergistic nature of herbal medicine
• Ways to optimise the bioavailability and hence efficacy of herbal
medicines
The reason why the study of herbal pharmacokinetics is a
unique and extraordinarily complex field
• The chemical complexity of plant medicines and the potential
interactions between constituents
• The differing bioavailability of different compounds
• Often large polar molecules are involved that might be expected to
have poor and unpredictable bioavailability
• The active components are often not known, so the components in
the plant that should be studied cannot be identified
• Unlike drugs, herbal medicines are not designed for predictable
pharmacokinetic behaviour, and in particular natural compounds are
often metabolised in the digestive tract – that is, they are pro-drugs
The factors affect the bioavailability of molecule
• the pharmaceutical preparation
• the size of the molecule
• the fat (lipid) solubility of the molecule
• the water solubility of the molecule
• Specific factors related to crossing the gut wall, such as active
transport
• Factors within the gut – interaction with food, stability in the gut,
gastric emptying
• Metabolism in the gut and first-pass metabolism by the liver
• lndividual factors in the patient, including the influence of genetic
and pathological factors
Clinical study

Fase 1 Fase 2 Fase 3 Fase 4


PHARMACOLOGY OF OF THE PHYTOCHEMICAL SUBSTANCES (I)

Simple
phenols Cyanogenic
Mucilages
and glycosides
glycosides

Essential
Flavonoids Tannins
oils
Simple phenols and glycosides
Phenol structure

• compounds that have at least one hydroxyl group attached to a benzena ring

Salicyl acid

• The best known simple phenol is salicylic acid


• Its precursors are found in willow (Salix sp.) and poplar (Populus sp.) barks

Arbutin

• Arbutin is a phenolic glycoside that confers bacteriostatic properties to urine 


source bearberry (Arctostaphylos uva ursi)

Resveratrol

• Resveratrol is probably the most actively researched phytochemical worldwide.


• Resveratrol is a phytoalexin produced by several plants in response to fungal
attack.
• well-known sources are grapes (Vitis vinifera) and the Chinese herb Polygonum
cuspidatum
GLYCOSIDE = SUGAR + AGLYCONE
Mechanism Action of Resveratrol
GSH: glutation
GSH-Px/GPx: glutathione peroxidase
Antioxidant Mechanism GSH-R: glutathione reductase
SOD: superoxide dismutase
CAT: catalase

Glutathione reduces disulfide bonds formed within cytoplasmic proteins to cysteines by serving as an electron donor. In
the process, glutathione is converted to its oxidized form, glutathione disulfide (GSSG), also called L-(–)-glutathione.
Salicin and its conversion products

aglikon

Pharmacokinetic of
salicin and its derivate
Salicin
(Willow bark)

Anti pyretic
Anti inflammatory To minimalize
gastric irritant
Gastric irritant
Anti pyretic
Anti inflammatory
Antiplatelet
Salicin is a pro-drug,
that is gradually
transported to the lower
aglikon part of the intestine and
hydrolysed to saligenin
by intestinal bacteria,
producing its therapeutic
effects without gastric
injury

Relative bioavailabilities of salicin and salicylic acid


(doses are approximately equivalent).
Short term use
• Hydrocyanic acid is a violent poison  oral
intake of cyanogenic glycosides (for example via
food, especially in primitive diets) is not
Wild cherry bark (Prunus serotina)
necessarily toxic (in the short-term)
• Hydrolysis of the glycosides in the digestive tract
or by the liver leads to a slow release of
hydrocyanic acid that is readily detoxified by the
body

Long term use


• Consumption of cassava root (Manihot
Bitter almonds (Prunus dulcis)
esculenta) together with a diet deficient in
sulphur amino acids  an endemic upper
motor neuron disease known as konzo in
Cyanogenic glycosides Mozambique
Mucilages
Polymer structure built from many different sugar dan
uronic acid  Very hydrophilic and capable of trapping
water (Plantago psyllium)

Ex : Plantago mayor, fenugreek (Trigonella foenum) Psyllium (Flea seed)

Used as bulk laxative, topical emollient, demulcent


(anti inflammatory)
Mucilage mix with water  swells (absorb water) 
human digestive enzymes cannot break down
mucilages  decomposed by bowel flora into
benefical metabolites  short-chain fatty acids (SCFA)
 SCFA formed is a source of readily absorbed and
(Trigonella foenum-graecum)
assimilated nourishment.
Fenugreek
Preparation  water extraction
Sesquiterpenes

Essential oils
Monoterpenes Mixtures of fragrant compounds that can be isolated
from plants by the process of steam distillation

Essential oils are water-insoluble oily liquids that are


usually colourless  Not related chemically to lipid
oils (fixed oils) such as olive oil, corn oil
Phenylpropanoids Classification  the terpenoids and the
phenylpropanoids
Aromatherapy is a treatment system based on the use
of essential oils. The oils may be inhaled, applied to
the skin or orifices, added to baths or ingested
Antibacterial (Ex: TTO), antifungal, carminatives,
spamolityc activity, expectorant Aromatherapy
Flavonoids (flavus = yellow)
• They function as plant pigments and are responsible for the colours
of many flowers and fruits

• Being abundant in plants, flavonoids are commonly consumed in


the human diet, especially if it is rich in fruits and vegetables

• Flavonoid glycosides are generally water-soluble


• There are three main types, classified according to the state of
oxygenation at carbon 3  Flavones, flavonols and flavonones
• Antioxidant, enzyme inhibition (xanthine oxidase, lipoxygenase).
• Dietary flavonoid intake  decrease risk of CVD
• Antimalaria
• Toxicity : Quercetin is probably the most mutagenic (and most
widespread) flavonoid  carcinogenesis  prevented by rapid
metabolic inactivation of quercetin by catechol-O-
methyltransferase to form non-mutagenic methoxy groups on the
flavonoid
Pharmacokinetic of flavonoid
glycosides

Flavonoid-O-glycosides are converted into the aglycone


by bowel flora  the aglycones undergo further
breakdown by a process known as C-ring fission (the C-
ring is the central ring in the flavonoid structure) to give
two different phenolic products.
Pharmacokinetics of flavonoids:
 Aglycones (such as quercetin) have poor or even
zero bioavailability
 There is an active uptake and metabolism of
flavonoid glycosides by enterocytes that is
determined by the nature of their sugar (glucose)
 Before the flavonoid is taken up by the enterocyte,
it is probably hydrolysed to the aglycone by a
membrane-bound beta-glucosidase
 Quercetin-4′-O-glucoside is taken up in the small
intestine, whereas rutin (which has a glucose and
a mannose = rutinoside) is not
 Rutin travels to the large intestine (hence the lag
in QG appearance), where the terminal mannose
is removed by bacteria, exposing the glucose
which then results in uptake by enterocytes
 Measurement of the renal elimination of
flavonoids suggested that at least 6% of the
flavonoid dose was absorbed when given as
onions
Tannins
Hydrolysable tannins Condensed tannin

• Glucose linked to • Cathecin and


gallic acid epicatechin joined by
(gallotannins) or carbo-carbo bonds
ellagic acid • Oligomeric
(ellagitannins) procyanidins (OPCs)
• Readily hydrolised  consist of 2-4
• Ex: pomegranate, monomers
oak bark. • Not readily
hydrolysable
• Ex : tea

 Enter mucose membran  react with and crosslink


protein in mucos and epithelial  mucosa more
tightly and less permeable  astringency
 Antioxidant (radical scavenger), prevention of UTI
(canberry juice)
 Chelator
Astringent effect?

Lifecycle of
tannin

Caution with the long-


term oral and topical
use (on damaged skin)
of tannin-containing
herbs  carcinogenic
(oesophageal cancers)
PHARMACOLOGY OF OF THE PHYTOCHEMICAL SUBSTANCES (I)

Cardiac
Alkaloids Saponins
glycosides

Phyto-
Antraquinones
estrogen
Alkaloids (alkaline = basic)
Ex: hygrine
Ex: strychnine

Ex: seneciphylline Ex: pilocarpine

Ex: lobeline
Ex: quinine

Ex: hyoscyamine
Ex: sparteine
Ex: nicotine Ex: morphine

Ex: caffeine
an ability to cross the blood-brain barrier and exert depressant or stimulant
Two key properties to effects on the central nervous system (CNS)
determine the
pharmacology of alkaloid
an ability to interact with various neurotransmitter receptors

Lobelia (Lobelia inflata)


Ex CNS depressants  • Contain emetic alkaloids (lobeline and emetine) that act as reflex
morphine and codeine expectorants at sub-emetic doses (similar to the expectorant
saponins)
• Oral preparations are also used as an aid to stop smoking, since
Ex CNS stimulants  lobeline is very similar to nicotine in its pharmacodynamic actions
caffeine and cocaine
Ephedra sp.
Ex Sympathetic nervous • Contain the protoalkaloids ephedrine and pseudoephedrine
system stimulants  • Used for diaphoretic, antipyretic, antiallergic and antiasthmatic
ephedrine properties
Saponin (sapo=soap)
Detergent like effect (reducing the surface tension
of the water  foam)

Steroid and triterpenoid glycosides

Haemolysis  RF
Gastrointestinal irritants

Enhance cholesterol secretion into bile

Influence steroid hormon metabolism 


inhibit 11-beta-hydroxysteroid dehydrogenase
(11-beta-HSD)  ↑ cortisol

Ex: licorice, gotu kola


Pharmacokinetic of saponin

• If a saponin exhibits good fat solubility  absorbed in the small


IF … intestine

• If saponins are not absorbed  will pass to the large intestine 


IF … the gut flora will convert them to the sapogenin (aglycone)  the
sapogenin has better lipid solubility

• Glycyrrhizin (GL) is converted to glycyrrhetinic acid (GA) by human


Example: intestinal flora  Some GL may be absorbed, although this could
also be recycled GA-glucuronide being misread as GL on
Licorice chromatograms  GA has been shown to be more
hepatoprotective than GL
Cardiac glycosides
Similar to steroidal saponin

Aglicon: 23 carbons (the cardenolide


glycosides)

24 carbons (the bufadienolide


glycosides)
Inhibit Na-Ca cellular pump
increase intracelluler Ca level 
increase contactile force and heart
muscle.

Ex : digitalis
Antraquinones

• Anthracene structure

• Ex : rhubarb (Rheum
palmatum), senna

• Laxative effect
Pharmacokinetics
of anthraquinone
Phyto-estrogen
phytochemicals that have oestrogenic activity
because they bear some structural similarity
to 17-beta-oestradiol

Intestinal microbial metabolism is crucial for


ensuring bioavailability of aglikon

Binding to estrogen reseptor alpha (ER alpha)


and ER beta
OPTIMISING EFFICACY
Relationship to meals
• Polyphenolics should be taken away from meals
because of their interaction with protein
• Components relying on gastric acid hydrolysis should
be taken with meals
• Components damaged by gastric acid should be taken
away from meals
• Lipophilic components will probably be better
absorbed with a high fat meal and polar (hydrophilic)
Saponins can be used to improve absorption
compounds will probably be better absorbed with a
low-fat
Some foodsmeal
can be used to inhibit gut
biotransformation, for example grapefruit juice
The frequency of dosage should be based on
bioavailability and metabolism
Reference
Thank You