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ENVIRONMENTAL PHARMACOLOGY

R a v I G h a n g h a s

Definition

• Environmental pharmacology: It is a branch of pharmacology that deals entry of chemicals or drugs into the environment after elimination from humans andanimals as post-therapy.

• Environmental problems we face today – 1. Climate change2. Biodiversity loss3. Water scarcity and4. The health impacts of pollution

Pharmacology

• Clinical

- For benefit of recipient

- Benefit outweigh risk

• Environmental

- Only side-effect

- Uses are unproven

WHY IT IS NECESSARY TO STUDY E.P.?

• Low levels of medicines have been detected in environment.

• The effects of some drugs on environment• Boomerang effect on human beings• Methods to control them

• Several beta-blockers were identified in wastewater

. • Propranolol, bisoprolol and

metoprolol were found at highest levels (0.59, 2.9 and 2.2 g/L, respectively, in surface water), with lower levels of nadolol.

• Clofibric acid, the active metabolite from a series of widely used blood lipid regulator

• Many chemicals including steroids, insect repellents and so on found in the American water supply.

ENTRY

INTO ENVIRONMENT

P P C P

Pharmaceuticals and Personal Care Products (PPCPs)?

• Diverse group of chemicals including, but not limited to, prescription and over-the-counter human drugs, veterinary drugs, diagnostic agents, nutritional supplements, and other consumer products

• Human and veterinary drugs (available by prescription or OTC; including the new genre of “biologics”),

• Diagnostic agents (e.g., X-ray contrast media)

• Consumer chemicals• Fragrances (e.g.,

Musks) and sun-screen agents (e.G., Camphor; octocrylene);

• “Excipients” e.g., Parabens).

• Nutraceuticals

Origins of PPCPs in the Environment

• Portions of most ingested drugs are excreted in varying unmetabolized amounts (and in undissolved states because of protection by excipients) primarily via the urine and feces.

• Bio-active metabolites • Conjugates• Free excreted drugs and derivatives can escape degradation

in municipal sewage treatment facilities; the conjugates can be hydrolyzed back to the free parent drug.

• Un-degraded molecules are then discharged to receiving surface waters or find their way to ground waters, e.g., leaching, recharge

Drugs Having Double Uses:Medicinals and Pest-Control Agents(alternative sources for introduction to the environment)

Examples include: 4-aminopyridine: experimental multiple sclerosis drug and an

avicide warfarin: anticoagulant and a rat poison triclosan: general biocide and gingivitis agent used in

toothpaste azacholesterols: antilipidemic drugs and avian/rodent

reproductive inhibitors [e.g., Ornitrol] acetaminophen: an analgesic and useful for control of Brown

Tree snake caffeine: stimulant and approved for control of coqui frog in

Hawaii; also repels and kills snails pentobarbital: used in animal euthanasia; raptors poisoned by

disposed carcasses

Fate: Depletion Mechanisms

• Photolysis - Quinolones

• Hydrolysis –β lactum

• Biodegradation

Ramifications

• On Environment• Human-beings

Toxicity of Complex Environmental

Mixtures: Poses Major Unanswered

Questions

Impact of drugs on environment• Sharp decline in vultures after

consuming carcasses of animals treated with diclofenac sodium .

• Diclofenac is banned only for use in cattle (vet use). Meloxicam, which has found to be safe in vultures.

Impacts:

• Harmful effect on aquatic organism• Antidepressants like fluoxetine could trigger spawning in

some shellfish• Ppm and sub-ppm levels of various drugs (NSAIDS,

glucocorticoids, anti-fibrotics) affect collagen metabolism in teleost fish, leading to defective/blocked fin regeneration

Potential Subtle, Difficult-to-Detect Effects:• Profound effects on development, spawning, and wide array of

other behaviors in shellfish, ciliates, and other aquatic organisms by SSRI and tricyclic antidepressants (ppb levels).

• Dramatic inhibition of sperm activity in certain aquatic organisms by calcium-channel blockers.

• Multi-drug transporters (efflux pumps) are common defensive strategies for aquatic biota — possible significance of efflux pump inhibitors in compromising aquatic health?

Regional concerns:

May be more critical in arid environments

– Ground water recharge of treated sewage

– Reuse of treated waste for irrigation

– Natural streams contain greater percentage of effluent.

Humans - Organ effect

• Dermatological – Most common• Cardiovascular effects- not explained• Emergency medicine- Asphyxiants, ARDS,• Endocrinal – Diabetes by a biocide (Vacor)• Antiepileptic drugs (e.g., phenytoin, valproate,

carbamazepine) have potential as human neuroteratogens, triggering extensive apoptosis in the developing brain neurodegeneration.

• Ammonium perchlorate cause of hypothyroidism

• Concern about chronic exposure

- Hormone disruption - Antibiotic resistance

Most evidence from fish and wildlife studiesLinks to human impacts not yet definitive

Possible problems include:

• lower sperm counts,• increased rate of breast, testicular, prostate cancer,• increased incidence of hyperactivity and learning• Developing embryos probably most at risk

General Findings:

Pharmaceuticals have now been found in treated sewage effluents, surface waters, soils and tap water.

Up to 90% of oral drugs can pass through humans unchanged.

Many do not biodegrade

Some persist in groundwater for years.

General approach

Pharmacological approach

Control what gets into environment:

Add advance waste and water treatment technologies and source control at point of entry into environment.

Litigation

Minimize over use or misuse of drugs/chemicals

Future roles of PPCPs

• Water recycling: With water reuse, especially "toilet-to-tap" programs, the occurrence of even ultra-trace levels of human-use drugs in water serves to highlight to the public what the origin of the water was. This risk-communication/perception problem will have major problems with regard to public acceptance.

• Biopharming: Environmental ramifications of molecular farming or "biopharming" (plant-made pharmaceuticals) are unknown.

• Homeland Security: Certain PPCPs hold the potential for being used in water sabotage (e.g., psychoactive agents; teratogens).

Environmental risk assessment• Predicted Environmental Concentration PEC={A X (100-R) } (365 X PXV X D X 100) A (Kg)-predicted amount used /yr in test area. R(%)-Removal rate, V- vol. of wastewater/day D- is factor of dilution of wastewater in surface water• Predicted No-effect Concentration For estimating con. drug in environment at which no adverse

effect expected PNEC= EC/ AF EC – Effect con., AF-assessment factor• PEC/PNEC if ratio>1 indicates further information to refine risk

assessment.

Pharmacologist perspective• New drug design• Increasing the specificity of drug action at the target receptor• Non-degradable techniques to be avoided• Nanomaterials: The environmental fate and ramifications of

nanomaterials (which will play ever-growing roles in nanomedicine) might be useful.

• Education of health care practitioner

REGULATION

• FDA and the European Union have set some cut-off limit for environmental concentration of drugs

• No actual testing is conducted after a drug is marketed to see if the environmental concentration was estimated correctly.

• FDA assessment for new drug - If the risk assessment concludes that the concentration will be less than one part per billion, the drug is assumed to pose acceptable risks.

Conclusion• Strict rules and regulation should be applied for

disposing pharmaceuticals waste product.• Special attention should be given to sewage treatment• Awareness should be created in people and doctor about

impact of drugs on environment.• Environmental pharmacology should be component of

pharmacovigilance.

References

• www.ijp-online.com/article.asp?issn=0253-7613• Beta-blockers in sewage waters

(Ternes, 1998; Sedlak and Pinkston, 2001)• www.fda.org• Journal List > Biol Lett > v.2(2); Jun 22, 2006.

Toxicity of diclofenac to Gyps vultures. Gerry E Swan

T H A N K Y O U