Pharmacology Test 1

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Pharmacology Intro

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-studies the actions of chemicals on living cells and organisms
:pharmacy studies drug preparation and disperal
-several branches like pharmacotherapeutics (clinical vs. basic, toxicology, pharmacodynamics, and pharmacokinetics

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Pharmacotherapeutics

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-Study of chemicals which are appropriate for the treatment of disease
-clinical refers to the study restricted to humans (Hersch the mighty)
-basic refers to study of drugs on tissues or cells (lab geek)

Toxicology - Study of the harmful effects of chemicals and drugs (side effects). Is a branch of clinical pharmacology

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Pharmacodynamics

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-Studies the interaction between the drug and receptor aka what the drug does to the body
-Drugs combine with receptors which can be proteins (may or may not be enzymatic), nucleic acids, phospholipid complex, or ionic channels
-This field studies conformational changes, receptor competition (antagonist vs agonist (drug of interest)), and dose/response relationship
-DRR is the quantitative relationship btw the drug-receptor complex and the drug action

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Pharmacokinetics

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-THe sequence of events which influence a drug's ability to reach the receptor in sufficient quantity and duration aka what the body does to the drug
-To be effective drugs must reach receptors in sufficient quantity and for a duration of time.
-Factors that this branch studies are absorption, metabolism and excretion of the drug, and their distribution and binding by non-receptor molecules

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Drug Testing and Regulation 1

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-All drugs reviewed by the FDA

Preclinical - Drug company gives FDA in vitro and whole animals data to justify human research. A Investigational New Drug application is submitted to support test on humans
-Takes 2-3 years
-IND can also be submitted to refine a drug

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Drug Testing and Regulation 2

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Clinical Trials - Begin if FDA accepts IND application. A IND # is given and the 3 step processes takes 5-7 years

Phase 1 - Drug tested on small group of healthy volunteers to evaluate assess dose, pharmacokinetics, and safety

Phase 2 - Larger group (100s) with disease are studied for efficacy, dose-response, safety, and pharmacokinetics

Phase 3 - Even larger group (1000s) with disease are studied for efficacy, safety, dosing schedules

-If all this data looks good then a New Drug Application (NDA) is submitted to the FDA and phase 4 begins..

Phase 4 - Involves post-marketing surveillance for rare side effects. If side effects and benefits make it not better than already marketed drugs, it may be removed. Phase 4 also studies marketing claims like advil better than tylenol

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Phase 4 Examples of Drug Removal

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1. Bromfenac (Duract) - Analgesic removed due to liver toxicity.

2. Phenylpropylnolamine - Decongestant in OTC cough/cold removed due to cerebral vascular accidents (strokes) in young women. Worked by increasing norepinephrine

3. Cerivastatin (Baycol) - Cholesterol lowering drug removed due to high rhabdomyolysis - skeletal muscle break down leading to kidney failure

4. Rofecoxib (Vioxx) and Valdecoxib (Bextra) - COX-2 inhibitors for inflammation/pain removed due to increase strokes and heart attacks. Bextra also had skin reactions like Steven Johnson's syndrome

5. Dexfenfluramine - FenPen

6. Terfenadine (Seldane) - Non-sedating histamine causes ventricular arrhythmia (torsades de pointes)

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Drug Names

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-All drugs have 3 names

1. Chemical - acetyl-salicyclic acid. In development drug also has a manufacturer's code name

2. Generic Name - Selected by FDA council. For example, aspirin

3. Trade Name (circle with R) - Each manufacturer who uses the drug comes up with their own trade name. There are multiple trade names for the same compound. Aspirin goes by Bayer, St. Joseph's, Alka Seltzer)

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Drug Information Index

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1. Physicians Desk Reference (PDR) - FDA and manufacturer make this package insert. Updated yearly to include post-marketing surveillance. Drug indexed by trade name, generic name, product category, and manufacturer

2. FDA Homepage, Updated bi-monthly with new drug approval and product warnings via MedWatch Program

3. American Medical Association publishes AMA Drug Evaluations every 3 years - organized by therapeutic use

4. Lippincott publishes Drug Facts and Comparisons every 2 years. Organized by therapeutic use. Compares drug by their actions, side effects, and cost

5. Medical Letter - bi-weekly publication gives up-to-date summaries of specific drugs. Also compares cost

6. Drug Information Handbook for Dentistry (Lexi-Comp) - Dental oriented CD-ROM or text

7. Monthly journals publishes by clinical researchers on recent drug findings

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Control of Drugs

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1. FDA decides which drugs are taken under guidance of health professional (prescription) and which are taken w/o control (OTC). OTC may indicate no risk or a very low dose
-Ex: is ibuprofin - at 400mg it is OTC, at 800mg it is prescription.

2. Drugs that have the potential for abuse are regulated by a branch of the FDA known as the Drug Enforcement Agency (DEA)

3.The FDA also characterizes drugs according to the hazard presented to a developing fetus

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DEA Rankings

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These are labeled as schedule I-V

I - High abuse potential and no therapeutic value like LSD and heroin

II - High abuse but approval for specific medical purposes like narcotic morphine and oxycodone (percodan). No refills for this.

III - Less potential for abuse and include mixture of hydrocodone and acetaminophen (Vicodin) or tylenol 3. Only 5 refills per 6 months (same with 4-5)

IV - Less abuse potential and represented by the benzodiazepines like diazepam (valium) and triazolam (halcion)

V - Minimal abuse potential like cough syrups containing bits of codeine

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Pregnancy Rankings

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A (0.7%)- Controlled studies in women - no risk to fetus

B (19%): lidocaine, ibuprofen
1) Animals studies showed no risk but no controlled studies in women
2) Animals studies shown adverse effect but human studies show no risk

C (66%): Aspirin in 3rd trimester (cause bleeding and premature closure of arteriosis due to lower prostaglandin synthesis), codeine, mepivacaine
1) Animals studies reveal adverse effect on fetus and no controlled studies in women
2) Neither animal nor controlled human studies available

D (7%): Definitive evidence of risk in humans but benefits outwiegh negatives like chemotherapy drugs for pregnant cancer patient or a anti-epileptic

X (7%): Drug has huge risks and the benefits do not outweigh the risks like using isotretenoin (accutane) for pregnant women which cause retardation or clefts

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Specific Drugs and Pregnancy

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A Group - prenatal vitamins and sodium fluoride

Bupivacaine (Marcaine) C - bradycardia, respiratory depression

Aspirin/Ibuprofen (advil, motrin) - B-D: fetal bleeding, delayed labor, premature ductus closing

Diazepam, Midazolam, Triazolam (D, D, X) - cleft palate and respiratory depression

Tetracycline D- Tooth discoloration and inhibtion of bone growth

Misoprostol (Cytotec) X - Abortefaceant

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Drugs Mentioned in Class 1

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Warfarin (coumadin) - blood thinner - inhibits synthesis of vit-k clotting factor. Given to people with atrial fibrillation. DOESNT GET ALONG WITH OTHER DRUGS

Propranalol (inderol) - B-blocker. B1 effect slows heart, B2 does vasoconstriction. Side effect is bradycardia, fluid build up, and heart failure

Prazosin (minipress) - Lowers bp as a alpha-1 antagonist. Since alpha-1 does vasoconstriction, the result is vasodilation. Problem is patients can pass out if they raise too quickly

Nifedipine, Verapamil (calan) - Vasodilate and block calcium channel to reduce BP. Can lead to gingiva hyperplasia

Epinephrine - Stimulate alpha 1 leading to vasoconstriction. Epi also stimulates beta 1 and beta 2 so when it goes systemic it constricts in some others but not all. If given with propranol only the alpha function of Epi works since prop blocks beta channels, and you get lots of vasoconstriction

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Drugs Mentioned in Class 1

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Diazepam (vallium) - anti-anxiety. Enhances GABA and allows Cl- to come in. Side effect is sleepiness and loss of control.

Amitriptyline (elavil) - anti-depressent blocks reuptake of norepinephrine and serotonin. Also blocks muscaric-cholinerigc receptor leading to xerostomia. Good for chronic orofacial pain like TMJ.

Atropine - Muscarin-cholinergic receptor antagonist so it dries the patient mouth during a dental procedure. Don't give to glaucoma patients

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Drugs Mentioned in Class 1

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Analesgesics - Prescribed for post-op pain. Examples are codeine, hydrocodone. Can cause nausea and constipation

Percodan - Has aspirin and oxycodon (opiod)

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Drugs Mentioned in Class 1

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Sildenalfileitrate (viafra) - side effect is priapism or long boners

Insulin - Good for type 1 diabetes. Side effects is hypoglycemia

Zolendronic Acid - For patients with osteoporosis, SE is ON of the jaw

Metronidazie - Good against strict anaerobes since it blocks conversion of alcohol at acetaldehyde steup. You can get a build up for acetaldehyde which poisons the body. It can inhibit the action of warfarin leading to bleeding. It inhibits the same enzyme which metabolizes warfarin

Fiorinal (barbituites) - Lowers amount needed of other drugs so given with warfarin the patient can stroke out

Ketordac (toradol) - great for kidney stone pain. Prolonged usage leads to GI bleed so given a phase 4 warning on the label

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Class 1 Notes...

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1) Look at percodan equation
2) Look at aspirin, acetaminophen, and ibuprofen pics
3) Look at lidocaine picture

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Routes of Adminstration

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-This affects onset time and peak blood levels
-The most common methods in order of speed are intravenous, inhalation, sublingual, and subcutaneous/intramuscular

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Intravenous Route

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-fastest mode of drug delivery
-it is the most controlled method of delivery since the doctor can titrate the drug slowly until the desired effect is reached
-It can also be the most dangerous since it is directly injected into the blood, the levels climb high, and once it's in there is no way to get it out
-A slower controlled version of IV is infusion with a pump and this can take several hours

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Inhalation Route

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-Almost as fast as IV
-Some drugs like nitrous oxide can be titrated little by little. This drug has a low blood solubility which correlates with quicker onset and offset. NO2 is also easily reverse by decreasing inhaled conc and increasing oxygen conc
-Small particles (<4u) are brought to the absorbing alveoli surface while larger particles (>10u) are not
-The aerosols are convenient for self administered like albuterol, epinephrine, or for bronchospasms (asthmatic attacks).
-The bronchodilators are beta-2 agonist

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Sublingual

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-Allows the med to enter the blood within a few minutes
-Best example is nitroglycerin (nitrostat) given during an angina episode since it dilates many veins so the heart doesn't have to work as hard

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SubQ/IM

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-require a few minutes (epi) up to 1/2 hour (insulin) to reach the blood. Depends on blood flow in the area
-Local anesthetic in dentistry are given this route, the submucosal. Just remember, the therapeutic effects are local, not systemic
-To do this we use a vasoconstrictor alpha-1 adrenergic agonist like epi
-Absorption through the blood (systemic) can be sped up by applying heat (vasodilate) or using a spreading factor like hyauronidase

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Enteric

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-This means either oral (po) or rectal routes.
-Slowest means of drug delivery and most inefficient, but also the safest. This is due to several factors
1) Rate of dissolution - Hugely seen in congestive heart failure drug digoxin. For example, aspirin quickly absorbed if dissolved in water or given in a liquid form like advil liquidgels.
-Gastric emptying (transfer from stomach to SI where most enteric absorption occurs) also plays a role. This is hindered by fatty foods except griseofulvin (fulvicin) which is speed up by fatty foods
3. First pass effect - Orally given drugs pass through the SI and liver first where enzymes can degrade them at these sites, up to 90-95%. This is why morphine is usually not given orally because its first pass effect is 90%. Due to this physicians have to give higher doses which works well with some people but can OD others

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Enteric 2

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-enteric route is least predictable due to different rates of dissolution, gastric emptying, and first pass effect
-Drugs taken orally need to have liquid solubility so they can pass membranes. Otherwise they have to come in through pores and channels which is very slowly
-Rectal is a good route for anti-nausea drugs because it avoids the problem of them being thrown up

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Transmucosal/Topical

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Transmucosal - Driven through mucus membranes. An example is nicotine gum which is taken in the buccal mucosa

Topical - Drugs don't usually penetrate skin unless it is damaged. Sunburn lotion works because the skin is already damaged
1. Eutetic Mixture of Local Anesthetic (EMLA) - Combo of lidocaine and prilocaine. When on skin for 30-60min you get some anesthesia. Used for kids. Dental version is oraqix, squirted in gingival crevice for scaling and root planning
2. Scopalamine - A anti-cholinergic drug that is produced in a patch to promote motion sickness. Drug triggers vomiting center muscarinic receptor

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Pharmacokinetics Factors

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-This includes all factors which govern the rate a drug reaches its receptor in sufficient quantity/time to be effective. Knowing this information helps people determine the concentration and duration of the drug for adequate drug/receptor interaction
-includes route of administration, lipid solubility,

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Lipid Solubility

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-Solubility is important because at some point, where in the gut, BV, or final organ, drugs must pass through a cellular lipid membrane
-Therefore, lipid solubility favors passage across biological membranes
-Non-polar, lipophilic pass easily, polar, lipophobic, pass more slowly through hydrophilic channels
-Lipophilicity is measured by comparing the solubility of a drug in octanol/oil vs. water. A oil:water coefficient is given, and the higher this number the more lipophilic
-A o:w of 3-100 is needed in the stomach and a o:w of 25-300 is needed for the blood brain barrier

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Drugs as Acid/Base

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Most drugs are either weak acids (aspirin) or wear bases (lidocaine and the opioids) so their environment pH affects the penetration
-Uncharged forms of drugs pass better than charged forms
-Presence of excess proton in stomach converts a weak acid RCOO- to RCOOH making it more lipid soluble. On the flip side, this proton will convert a weak base RNH2 to RNH3+ making it less lipid soluble
-Some drugs like curare are permanently charged so it's not given orally. Same with antibiotic streptomyocin for gram- infection like TB
-Environment can be a problem for a drug like lidocaine. When given orally more than 99% changed to charged RNH3+ and not absorbed. Also, if it's given in a area of infection with lots of protons then the same thing will happen
-Foods can also effect the charge of the drug and affect solubility. Tetracycline given for periodontal infections will chelate with divalent ions, typical found in products like milk. So if you drink milk and then take this drug you can lose 70% of it
-Finally, to help someone with a potential overdose of a weak acid they give a alkaline solution like sodium bicarbonate to help with the rate of elimination. This changes the RCOOH to RCOO- and keeping it trapped in the kidney where it is excreted

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Dilution

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-When a drug enters the body it is diluted in water. This water comes from plasma and extracellular and intracellular fluid
-For a normal child the total body water is 40L of fluid
-4L from plasma
-8L from extracellular
-28L from intracellular
-The amount of fluid that a drug appears to be dissolved in is the (Vd) apparent volume of distribution. It can be more (if it vigorously binds to tissue like CNS, heart) or less than 40L
Ex: 400mg of a drug taken IV and after 30 seconds the blood sample says we have 0.01mg/mL of the drug in our body. Volume of Distribution = Q (initial conc)/Co (conc upon withdrawl). So 400mg/0.01mg/mL = 40000mL = 40L Vd. 40 means it is stored all over the body
-Alcohol has a Vd of 40 (all over body)
For drug B the 400mg given and only 0.1mg/mL recovered. The Vd = 4L meaning it was retained in the blood bound to albumin
-If Vd is 4L than it is plasma retained, usually to albumin

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Drug Binding

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-Drugs are bound by plasma proteins albumin (bulk) and alpha acid glycoprotein (AAG - basic drugs)
-This prevents infiltration of the drug
-Drugs which are highly protein bound have low Vd because only a small portion of the drug is free to leave the plasma

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Things that affect drug binding

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1) Competition - Drugs can compete for the same plasma proteins and bump each other off increasing their Vd
Ex: Warfarin is usually 99% bound but only 1% free is needed. If given with ibuprofen (98% bound), warfarin becomes 4% free, its dose increase 4X and patient can bleed to death
Ex: Glyburide (Micronase) is 98% protein bound and given for type 2 diabetes (releases insulin). If given with ibuprofen it will becomes 10% free, lots of K+ channels are blocked, neurons become polarized, and insulin is released. The result is hypoglycemia

2) Conditions which lower plasma proteins - Diseases like kidney disease, liver disease, and severe burns lower the amount of circulating plasma proteins. Therefore, drugs which used to be 99% bound would be 95% bound and be a lot more potent

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Dilution Continued

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-A bumping agent is propofol
-If the Vd is ridiculously high like 4000mL that means the drug is completely out of the blood system and usualy hiding in adipose tissue of neurons. Very lipophilic drugs like MJ Drug behave like this

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Therapeutic Level of a Drug

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-described in terms of plasma level which is a balance between the dose (amount/time) and the factors which reduce the level of the drug like dilution, metabolism, and excretion
-The amount of time it takes for the drugs plasma levels to fall by 1/2 are called the half life
-If identical doses of a drug are given every 1/2 life for 4 consecutive half lives then you get a constant level of the drug in the plasma. This is called plateau state or steady state. Too low a dose is a sub-therapeutic range and too high is a toxic range

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T1/2 and Renal Function

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-Half life combines Vd and total body clearence which includes renal and hepatic function. All together this equals dilution, metabolism, and excretion
-Renal clearence is measured by looking at creatinine clearence because it is (normal person) freely filtered and stays constant, although it gradually declines with age. Renal clearence dips in later years so the half life of drugs in the elderly is longer and they accumulate in the elderly body
-Drugs eliminated by tubular secretion (active) are eliminated 4-5 times more rapidly than creatinine. As renal function dips with age this rate begins to resemble glomerular filtration and this causes a increase in the 1/2 life of drugs

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T1/2 and Liver Perfusion

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Liver Perfusion: Alters T1/2 of drugs. As the elderly cardiac output dips with age their liver perfusion also decreases.
-Additionally, drugs can alter liver perfusion and therefore their metabolism. The nonselecter beta BLOCKERS like propranolol reduces liver perfusion by reducing cardiac output (beta-1 block) and constricting the vessel supply to the liver (beta-2 block). The T1/2 of lidocaine increases when propranolol is given. On the flip side, the drug isoproterenol increases perfusion because it stimulates the beta receptors

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T1/2 and Vd

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-Usually drugs confined to the plasma are more rapidly eliminated
-When a drug is in fluid/cells not in equilibrium with the plasma then their availability of the drug to the kidney is reduced. This increases the T1/2
-However, if the drug IS in the plasma BUT it is protein bound, it cannot undergo glomerular filtration and the T1/2 will increase

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Biotransformation - Conjugation

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-Conjugation is when a drug combines with a substrate to add on a R group that usually inactivates the drug - sulfate, amino acid, acetyl-CoA
-Acetaminophen undergoes conjugation in the liver, and 95% of the product is inactive. The other 5% is conjugated by CYP2E1 (cytochrome p450) creating a toxic molecule NAPQI
-CYP2E1 induces small changes like oxidation, demethylation, and bromidation
-In normal circumstances our body protects the liver from CYP2E1 induced conjugation. We use free radical scavenger glutathione to convert the NAPQI to a inactive non-toxic form
-If we overdose on acetaminophen then normal glucuronidation pathway becomes saturated and instead of 5% going down CYP2E1, 25% go down this pathway. This overload our glutathione pathway and hepatocytes die, coagulation factors are hindered, and you bleed

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Aspirin Conjugation

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-Aspirin is acetylsalicylic acid with a half life of 1 hour. It has pain management and anti-platelet activity
-Aspirin's metabolite is salicyclic acid. Its half life is 3 hours. It is good in pain management but not anti-platelet activity
-Aspirin's 3rd metabolite is inactive
-We give aspirin every 4 hours before acetylsalicyclic acid and salicyclic acid have a combined half life of 4 hours
-Although acetylsalicyclic T1/2 is 1 hour, only 1 given to people at risk of a stroke. This is because while the T1/2 is 1 hour, we cannot measure how much is still bound to platelet or how long COX is irreversibly inhibited

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Diazepam Conjugation

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-Anti-anxiety drug diazepam has a long half life and its metabolites are active with their own half life
-The half life even increases more in the elderly
-Diazepam (valium) T24hr is converted to desmethyldiazepam T12hr is converted to oxazepam (serax) T6hr is converted to a inactive form
-If you don't want such a long acting drug you can give a short-acting benzodiazepine which doesn't have active metabolites

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Analgesic ProDrugs

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-Prodrugs enter your body inactive and they are metabolized to their active form
Ex: Codeine (Tylenol 3) is inactive and is processed by cytochrome p450 in the SI to active morphine
Ex: Tramadol (ultram) is a cross of a anti-depressent and a opioid. It starts off as a anti-depressent which stimulates seratonin in the brain. Once de-methylated by CYP2D6 it stimulates Mu Opioid receptors

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Cytochrome P450

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-Large family is drug enzymes with many isoforms
-Seems like many isoforms can work on same drugs and inhibitors/inducers can target one or many isoforms
-There are 3 categories of drugs that effect this enzyme: substrates, inhibitors, and inducers. Depending on the category you must be careful when mixing drugs
-Isoform 3A4 is the most important, 50% of drugs metabolized by this enzyme
-Enzyme inhibitor increase drug blood levels, enzyme inducer does the opposite
Ex: Cholesterol drugs lovastatin and simvastatin have grapefruit warnings because grapefruit is a 3A4 inhibitor and these drug levels can get too high
-When people take statins and grapefruit juice their blood levels skyrocket. High levels of statins leads to rhabdomyolysis and kidney failure
Ex: Midazolam is a sedative given to kids before surgery. Having grapefruit juice or erythromycin beforehand causes the levels to get too high leading to lose of breathing
Ex: Don't mix cipro (inhibitor for montezuma revenge) with theophylline (substrate - caffeine) or else blood levels get too high

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Seldane Case Report

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-Seldane was a anti-histamine that had potential because it didn't cause drowsiness (R- group prevented BBB cross)
-Seldane was converted to Allegra by 3A4
-However, many people taking the drug ended up with arrhythmia
-What happened is that mixing seldane (pro-drug) with 3A4 inhibitors lead to high levels of seldane in blood and the heart problems

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P450 Interference Cases Continued

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1. Codeine and Tramadol pro-drugs converted to active state by 2D6. When 2D6 inhibitors given (quinidine, paroxitene, fluoxitene, sertraline) these pro-drugs remain in their inactive state

2. Contraceptives - Women given contraceptives became pregnant when also given rifampin for TB. Problem was that rifampin is a 2C9 inducer causes 2C9 to rapidly conjugate oral contraceptive main ingredient ethanol-estradiol. The levels dropped so low that they were ineffective

3. Women given oral contraceptive and St. John's Wort become pregnant. As a 3A4 inducer St John's cuts the half life of the oral contraceptive down in half