1. 1 LECTURE OUTLINE 10/7/2011 Chemicals Interaction –An additive effect –Potentiation effect –Synergistic effect –Antagonistic effect (desirable effect) Safety evaluation and toxicometrics –Acute and Chronic studies Types of Undesired Effects –Allergic reaction –Immediate vs delayed reaction –Local vs systemic reaction –Reversible vs irreversible reaction –Idiosyncratic reaction

2. 2 Chemicals Interaction 1)An additive effect * If the effect of agent A=2 & effect of agent B=3 * So, the effect of these 2 chemicals together (A+B), at the same dose & volume = sum of each alone example: 2 organic phosphate insecticides(“A” 2+ “B” 3 =5) (cholinesterase inhibitors) 2)Potentiation effect * If the effect of agent A=0 & effect of agent B=2 * So, the effect of these 2 chemicals together (A+B), at the same dose & volume =   toxicity of B example: chemical A (isoproprnol, rubbing alcohol) = 0 effect on the liver & chemical B (Carbon Tetrachloride CTC, -used as a solvent and in refrigeration- (hepatotoxic = 2 ) *** A+B= sever hepato toxicity of B (0+2+=10)

3. 3 Chemicals Interaction –Synergistic effect : * The effect of agent A=2 & effect of agent B=2 * So, the effect of these 2 chemicals together (A+B), at the same dose & volume = (2+2=20) example: chemical A (ethanol), (hepatotoxicity = 2 ) chemical B (Carbon Tetrachloride CTC, (hepatotoxicity = 2 ) *** A+B= sever hepato toxicity =20

4. 4 Chemicals Interaction 4) Antagonistic effect (desirable effect ); 2 chemicals interfere with each other   toxic effect a. Functional antagonism: 2 chemicals producing opposite effect Example: Barbiturate   BP & NE  BP b. Chemical antagonism = inactivation: use of chemicals to treat heavy metal (HM) toxicity Example: dimercaprol chelates heavy metal (Pb, As, Hg) c. Dispositional antagonism: a chemical alter the kinetic of other before reaching target tissue Example: ammonium chloride OR ascorbic acid  Amphet Toxicity d. Receptor antagonism = Receptor blockers: 2 chemicals compete for the same receptor   toxic effect [4+ (-4)=0 OR 4+0=1] Example:   morphine (4)  respiratory depression + naloxone OR naltrexone (-4)  0

5. 5 Toxicometrics = Safety evaluation The practice of measurement of toxic or poisonous properties of chemicals Toxicity is measured quantitatively (TD 50 and LD 50 ) & detected by log dose (acute & chronic studies) There is a need to quantify the toxicity of a compound which is governed by FDA (Drugs, food additives, cosmetics) & EPA (any thing in the environments that human can expose to) Physicians and Pharmacists are interest to maximizing the effect of a drug and minimizing the side (toxic) effects Pesticides scientists are interest in examining the interactions between chemicals to  the toxicity to target pests, not to beneficial insects

6. 6 Acute Toxicity Study 1)Performed in animals (rats, mice,..) 2)One single dose/exposure/24 hrs period 3)Very essential, it will tell scientists if this substance will produce a reaction or death upon one exposure 4)Valuable information are obtained: TD50: (Toxic dose 50)= the dose that produce toxicity in 50% of the population LD50: (Lethal dose 50) = the dose that produce death in 50% of the population The smaller LD 50 value   toxicity and the higher LD50 value   the toxicity (safer compound)

7. 7 Acute Toxicity Study Substances are grouped depending on their toxicity (LD 50 value: 1)Supertoxic: LD50 < 5 mg/kg (< than 7drops) example: Botulinum toxin, Aconite-plant extract (used in political assassinations) 2)Extremely toxic : 5-50mg/kg (7 drops-tea spoon) 3)Very toxic: 50-500 mg/kg (tea spoon-1 ounce) 4)Moderately toxic: 500-5000 mg/kg (1 ounce-pint) 5)Slightly toxic: 5-15 gm/kg (pint-quarter) 6)Practically none toxic: >15gm/kg (> quarter)

8. 8 Acute Toxicity Study *Physicians & Pharmacists are interest to know: Therapeutic Index (TI): The ratio between LD50/ED50 (the greater the ration, the safer the compound) Lithium (Li) and Digoxin have very narrow TI Margin of Safety (MS): The ratio between TD1/ED99 OR LD1/ED99 (the greater the MS, the safer the drug), where: –TD1=maximum tolerated dose in 1% of the population, –LD1= maximum lethal dose that kill 1% of the population –ED99=maximum effective dose in 99% of the population Identify target tissue (organ) & clinical manifestation

9. 9 Chronic Toxicity Study Performed in animal (rats, mice, dogs,..) Daily exposure for Min 90 day to <1 year Very important study, provides information on organs & type of injury, clinical chemistry, long term effect. Determine: –NEL = No effect level –LOEL =lowest observed effect level –LOAEL= lowest observed adverse effect level –NOAEL= No observed adverse effect level ADI = acceptable daily intake (set by FDA for food additives or contamination (pesticides), calculated from NOAEL

10. 10 Types of Undesired Effects 1)Allergic reaction 2)Immediate vs delayed reaction 3)Local vs systemic reaction 4)Reversible vs irreversible 5)Idiosyncrasy

11. 11 Types of Undesired Effects 1)Allergic reaction = hypersensitivity An adverse reaction to a chemical resulted from previous sensitization to the same chemical or one related or its metabolites (e.g., poison Ivey) This chemical (antigen, AG)  Antibodies (AB) (10-20 day) More AB produced upon subsequent exposure to that chemical, AG-AB interaction  allergic reaction In human: Skin: dermatitis, itching, rash, urticaria, sweating Eye: swelling, irritable, redness, lacrimation In Guinea pig: bronchiolar constriction, asphyxia, death

12. 12 Types of Undesired Effects 2) Immediate vs delayed reaction: –Immediate reaction: adverse effects after short time effect (seconds-minutes) from single exposure Example : inhaling toxic fume, acid-induced skin injury –Delayed reaction: adverse reaction after days, months or years Example: diethylstilbestrol (DES) exposure in utero causing vaginal/uterine cancer in ♀ offspring 18-22 years later

13. 13 Types of Undesired Effects 3) Local vs systemic reaction: –Local reaction (=immediate): occurs at the site of exposure (1 st contact) (skin, eye, lung) –Systemic reaction: require absorption, distribution from site of exposure to the target tissues/organs Some chemical can induce both reactions (tetraethyl lead, cause skin irritation & CNS effect) –Most common (frequent) target organs for systemic toxicity are: –CNS > Circulation > Visceral organs (liver, kidney, lung), > skin > muscle > bone

14. 14 Types of Undesired Effects 4) Reversible vs irreversible reaction: –Reversible where the harmful effects of chemicals on tissues or organs is restored in time (if exposure to this chemical is discontinued) Example: liver cell can regenerate after large damage to almost normal size and function –Irreversible reaction: the harmful effect of chemical on tissue/organs will be never restored and will remain for life, even if exposure is discontinued Example: CNS neurons (cells) will not regenerate, divide or multiply, so once CNS neurons are dead, the damage is permanent =irreversible

15. 15 Types of Undesired Effects 5) Idiosyncratic reaction: –Is a genetically determined abnormal reactivity to a chemical either: sever sensitivities to very low dose OR sever insensitivity to very high dose) –Some individual in the same family are deficient in enzymes systems Or having inactive (atypical) enzymes systems Example: Succinylcholine (a short lasting muscle relaxant, metabolized rapidly by pseudo choline esterase), in some patients who have atypical (none-typical, none-functional) enzyme the effect may last for hours