1. Double-blind Clinical Trials A double-blind or double-masked study is one in which neither the participants nor the study staff know which participants are receiving the experimental treatment and which ones are receiving either a standard treatment or a placebo. These studies are performed so that neither the patients’ nor the doctors’ expectations about the experimental drug can influence the outcome.

2. Is a Drug Polar or Non-polar (and why does this matter?)

3. To reach its target, the drug must pass through several membranes If orally administered, this begins with the stomach and continues to the small and large intestine.

4. http://health.howstuffworks.com/adam- 200142.htmhttp://health.howstuffworks.com/adam- 200142.htm

5. “Like Dissolves Like” To get across most membranes, the drug must be relatively non polar To be soluble in water, a drug must be polar If a drug is too nonpolar, it may be not be water soluble, or may bind too tightly to components in food, or to proteins in the blood.

6. The polarity of a substance is measured by its partition coefficient in a two phase system consisting of 1- octanol and water P = [amount of drug dissolved in octanol] [amount of drug dissolved in water] Usually the logarithm logP, is used to describe this ratio. Christopher Lipinski noticed that most of the orally bioavailable drugs on the market seemed to have logP values less than 5. There are now computer programs that will attempt to calculate this number from the structure. This calculated version is usually referred to as clogP, meaning calculated logP

7. But some drugs change their ionic form, depending on the pH of the surrounding medium. Ionized (I.e. charged) states of molecules are always more polar than the uncharged forms. Two such classes of drugs are amines, R-NH 2, and Carboxylic acids, RCOOH.

8. At approximately pH = 12, the equilibrium below is evenly distributed between ammonium salt and amine. At the pH of blood, pH = 7.4, the equilibrium below is strongly shifted toward the ammonium salt.

9. This is NOT true for amides RCONH 2, Which are significantly different electronically from amines. Amides are Much harder to protonate. At pH = 7.4, amides exist in the unprotonated state, as shown.

10. Carboxylic acids are evenly distributed between charged, and uncharged form at pH = 4 At pH = 7.4, the equilibrium lies in favor of the charged form.

11. Lots of drugs have amines (primary, secondary, and tertiary) as a part of their structure. This allows the drug to exist in two forms, a charged version, which dissolves readily in water… As well as an uncharged form, which can easily cross membranes.

13. pH stomach = 1 to 3 (the stomach itself is protected by the mucous that coats it. pH intestine = 6.4 pH blood = 7.4 Thus each drug will exist in different ionic states in different regions of the body.

14. http://soolin.sunderland.ac.uk/fdcps/pharmacokinetics.ht ml

15. Ways to administer a drug Enteral = Through or within the intestines or gastrointestinal tract. Parenteral = Not in or through the digestive system.

16. Oral Administration Easiest Disadvantages –Some drugs (eg proteins) are not stable to the acidic environment and digestive enzymes of the stomach –May cause emesis –Drug may not be absorbed properly

17. Sublingual: Under the tongue. Example: Nitroglycerin (brand name: nitrostat) This medication is a nitrate used to relieve and prevent chest pain (angina). Nitroglycerin relaxes blood vessels allowing more blood to flow through. This reduces the workload on the heart and improves blood flow to the heart.

18. Suppositories Rectal: the substance crosses the rectal mucosa into the bloodstream Vaginal: commonly used to treat gynaecological ailments, including vaginal infections such as candidiasis.

19. Transdermal

20. Parenteral Routes Intravascular (IV, IA)- placing a drug directly into the blood stream Intramuscular (IM) - drug injected into skeletal muscle Subcutaneous - Absorption of drugs from the subcutaneous tissues Inhalation - Absorption through the lungs

23. Intraosseous infusion is the process of injection directly into the marrow of the bone. The needle is injected through the bone's hard cortex and into the soft marrow interior. This route of fluid and medication administration is an alternate one to the preferred IV route when the latter can't be established in a timely manner especially during pediatric emergencies. When IV access cannot be obtained in pediatric emergencies, intraosseous access is usually the next approach. It can be maintained for 24-48 hours, after which another route of access should be obtained. Intraosseous access is used less frequently in adult cases due to greater difficulty penetrating denser adult bone.

24. Intrathecal Injection An intrathecal injection (often simply called "intrathecal") is an injection into the spinal canal (intrathecal space surrounding the spinal cord), as in a spinal anaesthesia or in chemotherapy or pain management applications. This route is also used for some infections, particularly post-neurosurgical. The drug needs to be given this way to avoid the blood brain barrier. If the drug were given via other routes of administration where it would enter the blood stream it would be unable to reach the brain. Drugs given intrathecally often have to be made up specially by a pharmacist or technician because they cannot contain any preservative or other potentially harmful inactive ingredients that are sometimes found in standard injectable drug preparations.

25. Metabolism of drugs 101 Overall your body is trying to make drug more water-soluble Phase 1 metabolism may involve oxidation, hydrolysis, or reduction, all catalyzed by enzymes in the liver Phase 2 metabolism involves direct conjugation with