Drugs And Their Possible Side Effects And Interactions: St John's Wort, Garlic, Kava-

Kava, Black Pepper, Ginko, Ginseng, Ephedra And Hypercium

St John's Wort St John's wort is obtained from Hypericum perforatum L. belonging to family
Clusiaceae.
Constituent: The main groups of active constituents of St John's wort are:
 Anthraquinones, including hypericin, isohypericin, pseudohypericin, proto hypericin,
protopseudohypericin and cyclopseudohypericin, and the prenylated phloroglucinols,
including hyperforin and adhyperforin.
 Flavonoids, which include kaempferol, quercetin, luteolin, hyperoside, isoquer citrin,
quercitrin and rutin; biflavonoids, which include biapigenin and amentofla vone, and
catechins are also present.
 Other polyphenolic constituents include caffeic and chlorogenic acids,
 Volatile oil containing methyl-2-octane.
Use and Indications: St John's wort is widely used to treat mild-to moderate depression,
seasonal affective disorder, low mood, anxiety and insomnia, particularly if associated with
menopause. It has also been used topically for its astringent properties.
Interactions
St lohn's wort interaction Effects
Interaction with 5- Severe phototoxic reaction attributed to a synergistic effect of
aminolevulinic acid 5-aminolevulinic acid and St John's wort
Interaction with general St John's wort may prolong the effects of anesthetics
anesthetics
Interaction with St John's wort modestly decreases the AUC of gliclazide and
antidiabetics rosiglitazone. Pioglitazone and repaglinide, but it does not affect
the metabolism of tolbutamide.
St John's wort modestly increased the clearance of single-dose
Interaction with carbamazepine, but had no effect on multiple-dose carbamazepine
antiepileptics pharmacokinetics. Carbamazepine does not appear to significantly
affect the pharmacokinetics of hypericin or pseudohypericin
 (constituents of St John's wort).
Interaction with Long-term use of St John's wort decreases the plasma levels of
benzodiazepines alprazolam, midazolam and quazepam. St John's wort preparations
taken as a single dose, or containing low-hyperforin levels, appear
to have less of an effect.
Interaction with bupropion Serotonin syndrome when bupropion was taken with long-term St
John's wort.
Interaction with buspirone Taking buspirone developed marked CNS effects after starting to
take herbal medicines including St John's wort.
Interaction with caffeine Increases the metabolism of caffeine.
Interaction with calcium- It significantly reduces the bioavailability of ifedipine and
channel blockers verapamil. Other calcium-channel blockers are expected to
interact similarly.
Interaction with Increases the clearance of chlorzoxazone.
chlorzoxazone
Interaction with ciclosporin Marked reductions in ciclosporin blood levels and transplant
rejection can occur within a few weeks of starting St John's wort.
Interaction with cimetidine Cimetidine does not significantly alter the metabolism of the
constituents of St John's wort, hypericin and pseudohypericin
Interaction with St John's wort does not affect the pharmacokinetics of
dextromethorphan dextromethorphan or debrisoquine.
Interaction with digoxin Digoxin toxicity
Interaction with eplerenone St John's wort slightly decreases the AUC of eplerenone.
Interaction with food; Hypertensive crisis may occur after consuming tyramine-rich food
Tyramine-rich and drink.
Interaction with hormonal St John's wort may affect the pharmacokinetics of desogestrel,
contraceptives ethinylestradiol and norethisterone.
Interaction with imatinib St John's wort lowers serum imatinib levels
Interaction with irinotecan St John's wort increases the metabolism of irinotecan, which may
decrease its activity.
Interaction with ivabradine The metabolism of ivabradine is increased by St John's wort.
Interaction with loperamide Delirium in a woman taking St John's wort and valerian root who
also took loperamide.
Interaction with St John's wort may decrease the efficacy of methylphenidate in the
methylphenidate treatment of attention deficit hyperactivity disorder.
Interaction with warfarin St John's wort can cause a moderate reduction in the anticoagulant
and related drugs effects of phenprocoumon and warfarin
The plasma levels of amitriptyline and its active metabolite,
Interaction with tricyclic
nortriptyline, are modestly reduced by St John's wort.
and antidepressants
Sedation, mania and serotonin syndrome
Interaction with SSRIs
St John's wort induces the metabolism of omeprazole, and this
Interaction with proton
might result in reduced efficacy.
pump inhibitors
St John's wort causes a marked reduction in the serum levels of
Interaction with protease
indinavir, which may result in HIV treatment failure. Other
inhibitors
protease inhibitors, whether used alone or boosted by ritonavir,
are predicted to interact similarly.
Interaction with opioids St John's wort reduces the plasma concentrations of methadone
and withdrawal symptoms may occur.

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Pharmacokinetics (Fig. 5.5) The main constituent found to be responsible for the activity of St
John's wort is hyperforin, but other constituents are considered to contribute to its antidepressant
activity, such as hypericin and pseudohypericin, the flavo noid quercetin and its glycosides, and
rutin. Bioavailability from varying formulations and extracts appears to be low, giving variable
steady-state plasma concentrations. a. Cytochrome P450 Isoenzymes St John's wortis interacting
with wide range of drugs and known to affect several cytochrome P450 isoenzymes, P-
glycoprotein and 5 Hydro -xytryptamine. These isoenzymes exert a bi phasic effect on, with
inhibition occurring in in vitro studies with the initial exposure, and induction following long-
term use. The inter action overview of St John's wort are given in
Garlic: It is obtained by bulbs (cloves) of Allium sativum L. belonging to family Alliaceae.
Constituents: Garlic contains sulphur-containing compounds, alliin, allicin (produced by the
action of the enzyme alliinase on alliin) and/or γ-glutamyl-(S)-allyl-L-cysteine. Other sulphur
compounds such as allylmethyltrisulphid, allylpropyldisulphide, diallyldisulphide,
diallyltrisulphide, ajoene and vinyldithiines and mercaptan are also present. Garlic also contains
various glycosides, monoterpenoids enzymes, vitamins, minerals and flavonoids based on
kaempferol and quercetin
Use and Indications Garlic has been used to treat respiratory infections (such as colds, flu,
chronic bronchitis, and nasal and throat catarrh) and cardiovascular disorders. It is believed to
possess antihypertensive, antithrombotic, fibrinolytic, antimicrobial, anticancer, expectorant,
antidiabetic and lipid-lowering properties. It is also used extensively as an ingredient in foods.

Interactions Overview

Garlic interaction effects

Effects Interaction with Hypotension vasodilatation and blood pressure reduction

ACE inhibitors

Interaction with Increase the risk of bleeding with conventional antiplatelet drugs
antiplatelet drugs

Interaction with Garlic appears to inhibit the activity of the cytochrome P450
chlorzoxazone isoenzyme CYP2E1, which metabolises chlorzoxazone to 6-hydro
xychlorzoxazone.

Interaction with warfarin Increase in the anticoagulant effects of warfarin, decrease in

and related drugs anticoagulant effects of fluindione. Garlic supplements alone have
also rarely been associated with bleeding. Interaction with protease
inhibitors A garlic supplement reduced the plasma levels of
saquinavir
Interaction with herbal Garlic supplements and fish oils may have beneficial effects on
medicines; fish oil blood lipids.
Κανα-Κανα It is obtained from rhizomes of Piper methysticum belonging to family Piperaceae.
Constituents The most important constituents are alkaloids 5.5–8.3% kavalactones (kava-
pyrones). In traditional medicines, kava root is used to treat extreme states of excitation and
exhaustion.
Use and Indications: Muscle relaxation, analgesic and local anaesthetic properties, anti-anxiety
and anticonvulsant effects. The kava may directly influence the limbic system, the ancient part of
the brain associated with emotions and other brain activities. Kava is a unique anti-anxiety
alternative because it does not seem to impair reaction time or alertness when used in proper
dosage amounts.
Table 5.5: Interactions overview of kava-kava
Kava interactions Effects
Interactions with Kavalactones potentiate the effects of CNS-depressants like
CNS-depressants benzodiazepines, barbiturates or alcohol.
Interactions with Based on theoretical considerations, that there may be either
alcohol pharmacokinetic and/or pharmacodynamic interactions between alcohol
and kava, resulting perhaps in increased toxicity of either kava or
alcohol increased sleeping times in mice when alcohol and a lipid-
soluble extract of kava were administered in combination.
Interactions with Reduced the effectiveness of levodopa in Parkinson's disease.
levodopa
Interactions with Pharmacodynamic interactions between kava and caffeine are associated
caffeine with rhabdomyolysis.
Interactions with anti- Major kavalactones display anticonvulsive action against maximal
convulsants electro shock, strychnine and pentylenetetrazole induced convulsions in
mice
Interactions with Reversible inhibition of platelet MAO-B in vitro by kava kava spissum
MAO- inhibitors extract containing ~68% kavalactones avalactones may theoretically
display additive effects with MAO-B inhibitors like selegiline used in
the treatment of Parkinson disease.
Interactions with anti- Dose-dependent antithrombotic actions of (+)-kavain on human
platelet medications platelets.
or anticoagulants

Black Pepper
Black pepper is obtained from unripe fruit of Piper nigrum L. belonging to family Piperaceae,
when immersed in hot water and dried in the sun, during which the outer pericarp shrinks and
darkens into a thin, wrinkled black layer.
White pepper consists of the seed only, prepared by soaking the fully ripe berries, removing the
pericarp and drying the naked seed.
Long pepper, Piper longum I related species where the fruits are so occur embedded in flower
'spikes' which form the seed heads.
Constituents: The major constituents are alkaloids and alkylamides, piperine, with piperanine,
piperettine, piperlongumine, pipernonaline, lignans and minor constituents are piperoleins. It also
contains a volatile oil composed of bisabolene, sabinene. The pungent taste of pepper is
principally due to piperine, which acts at the vanilloid receptor.
Use and Indications It is used as a stimulant and carminative and is reputed to have anti-
asthmatic, antioxidant, antimicrobial, hepatoprotective and hypocholesterolaemic effects. Most
of the pharmacological effects reported to date are attributed to piperine. A black pepper extract
containing 95% piperine is used in a number of herbal Supplements. Both long pepper and black
pepper are important ingredients of many Ayurvedic herbal medicines which they are intended to
enhance absorption of other medicines.

Table 5.6: Interaction overview of pepper

Pepper interaction Effects
Interaction with Coenzyme Piperine modestly increased the AUC of one dose of coenzyme
Q10 Q10
Interaction with herbal Piperine might reduce the anti-depressant activity of rhodiola
medicines: Rhodiola
Interaction with turmeric Piperine increased the bio-availability of curcumin
Interaction with nevirapine Piperine markedly increases the AUC of a single dose of
nevirapine
Interaction with phenytoin Piperine appears to increase the maximum levels and AUC of
 phenytoin, although the effect may be less in patients receiving
long-term phenytoin.
Interaction with propranolol Piperine pretreatment increased the AUC of a single dose of
propranolol by twofold in a study in healthy subjects.
Interaction with rifampicin Piperine increased the AUC of rifampicin, but a small dose of
(rifampin) Trikatu had no effect.
Interaction with theophylline Piperine almost doubled the AUC of a single dose of
theophylline.

Ginkgo It is obtained from leaves of Ginkgo biloba L. belonging to family Ginkgoaceae.

Synonym(s) and related species: Fossil tree, Kew tree, Maidenhair tree. Salisburia adiantifolia
Sm., Salisburia biloba Hoffmanns.
Constituents
Ginkgo leaves contain numerous flavonoids including the biflavone glycosides such ginkgetin,
isoginkgetin, bilobetin, sciadopitysin, and also some quercetin and kaempferol derivatives.
Terpene lactones are the other major component, and these include ginkgolides A, B and C, and
bilobalide, ginkgo extracts may be standardised to contain between 22 and 27% flavonoids
(flavone glycosides) and between 5 and 12% terpene lactones, both on the dried basis. The
leaves contain only minor amounts of ginkgolic acids, and some pharmacopoeias specify a limit
for these. The seeds contain ginkgotoxin (4-O-methylpyridoxine) and ginkgolic acids.
Use and Indications: Ginkgo is often used to improve cognitive func tion in cases of dementia
and memory loss, and it has been investigated for use in the treatment of Alzheimer's disease.
The ginkgolides are thought to possess antiplatelet and anti-inflammatory properties and it has
been used for cerebrovascular and peripheral vascular disorders, tinnitus, asthma and to relieve
the symptoms of altitude sickness. Ginkgo seeds contain some toxic constituents; nevertheless,
they are used in china and japan, including as a food
Table 5.7: Interaction overview of ginkgo
Interaction with ginkgo Effects
Interaction with It may cause seizures taking valproate, or valproate and phenytoin
antiepileptics
Interaction with Ginkgo biloba has been associated with platelet, bleeding and clotting
antiplatelet drugs disorders, and there are isolated reports of serious adverse reaction
after its concurrent use with antiplatelet drugs such as aspirin,
clopidogrelan and ticlopidine
Interaction with Ginkgo does not significantly affect the pharmacokinetics of
benzodiazepines alprazolam
Interaction with Ginkgo may increase the levels and some of the effects of nifedipine.
calcium- channel
blockers; Nifedipine
Interaction with Ginkgo may increase extrapyramidal effects in response to
haloperidol haloperidol.
Interaction with Fatal intracerebral bleeding in a patient taking ginkgo with ibuprofen,
NSAIDs and another case describes prolonged bleeding and subdural
haematomas in another patient taking gingko and rofecoxib.
Interaction with An isolated case describes priapism in a patient taking risperidone and
risperidone ginkgo.
Interaction with proton Ginkgo induces the metabolism of omeprazole. Most other proton
pump inhibitors pump inhibitors are likely to be similarly affected.
Interaction with Intracerebral haemorrhage associated with the use of ginkgo and
warfarin and related warfarin, and there are a few reports of bleeding associated with the
drugs use of ginkgo alone.
Interaction with Coma developed in an elderly patient with Alzheimer's disease after
trazodone she took trazodone and ginkgo.

Ginseng
Panax ginseng (Araliaceae)
Synonym(s) and related species: Panax ginseng is also known as Asian ginseng, Chinese
ginseng, Korean ginseng, Oriental ginseng, Renshen. Panax quinquefolius L. is also known as
American ginseng. Other species used include: Panax notoginseng known as Sanchi ginseng, -
Tienchi ginseng and Panax pseudo-ginseng - Wall. also known as Himalayan ginseng.
Constituents: ?.
Use and Indications: Ginseng is used to enhance the body's resistance to stress and to improve
mental and physical performance. It has also been used for diabetes, insomnia, sexual
inadequacy, for degenerative conditions associated with ageing, to improve healing and as a
stimulant.
Table 5.8: Interactions overview of ginseng
Interaction with ginseng Effects
Interaction with alcohol Panax ginseng (Asian ginseng) increases the clearance of alcohol and
lowers blood-alcohol levels
Interaction with anti- Taking various oral anti-diabetics, Panax quinquefolius and Panax
diabetics ginseng have both shown modest reductions in postprandial glucose
levels after a glucose tolerance test, but Panax ginseng did not result
in any improvement in diabetes control when given for 12 weeks
Interaction with caffeine Ginseng and caffeine have stimulant effects.
Interaction with herbal The stimulant effects of guarana, a caffeine-containing herb, appear
medicines Guarana to be additive to those of Panax ginseng (Asian ginseng).
Ginseng + Laboratory Panax ginseng (Asian ginseng), Panax quinquefolius (American
tests ginseng) and Eleutherococcus senticosus (Siberian ginseng) may
interfere with the results of digoxin assays.
Interaction with MAOls Case reports describe headache, insomnia and tremulousness, which
was attributed to the concurrent use of ginseng and phenelzine.
interaction with Ginseng may contain oestrogenic compounds that might directly
tamoxifen and other stimulate breast cancer growth and oppose the actions of competitive
oestrogen antagonists oestrogen receptor antagonists such as tamoxifen. However, there is
some evidence that ginseng use before diagnosis might not adversely
affect breast cancer survival.
Interaction with It might increase or decrease the rate of absorption of tolbutamide in
tolbutamide animal studies
Interaction with warfarin Panax quinquefolius (American ginseng) modestly decreased the
and related drugs effect of warfarin, whereas another study found that Panax ginseng
(Asian ginseng) did not alter the effect of warfarin.
Ephedra Ephedra sinica Stapf, Ephedra gerardiana Wall, Ephedra equisetina Bunge
(Ephedraceae)
Synonym(s) and related species: Mahuang.
Constituents: The main active components of ephedra are the amines (sometimes referred to as
alkaloids, or more properly pseudoalkaloids) ephedrine, pseudoephedrine, norephedrine,
norpseudo ephedrine, N-methylephedrine, ephedroxane, maokonine, a series of ephedradines and
others. Other constituents include the diterpenes ephedrannin A and mahuannin, catechins, and a
trace of volatile oil containing terpinen-4-ol, a-terpineol, linalool and other monoterpenes.
Use and Indications: Ephedra is used traditionally for asthma, bronchitis, hayfever and colds,
but recently the herb has become liable to abuse as a stimulant and slimming aid. Its main active
constituents are ephedrine and pseudoephedrine; however ephedra herb is claimed to have many
more effects than those ascribed to ephedrine and its derivatives. It is these compounds that also
give rise to the toxic effects of ephedra.
Interactions Overview (Table 5.8) Ephedra herb contains ephedrine and pseudo ephedrine, and
therefore has the potential to interact in the same manner as conventional medicines containing
these substances. The most notable of these interactions is the potential for hypertensive crises
with MAOIs; it would therefore seem unwise to take ephedra during, or for 2 weeks after, the
use of an MAOI
Ephedra + Caffeine Ephedrine can raise blood pressure and in some cases this may be further
increased by caffeine. Combined use has resulted in hypertensive in few individuals. Isolated
reports describe the development of acute psychosis when caffeine was given with ephedra.