Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Discovery and development of proton pump inhibitors wikipedia , lookup
Orphan drug wikipedia , lookup
Psychopharmacology wikipedia , lookup
Drug design wikipedia , lookup
Drug discovery wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Pharmacokinetics: ◦ How drugs are handled by the body ◦ Overview followed by details!! Lets say you have a really bad headache or an infection of some kind that needs antibiotics and you have to take some meds – This illustrates the basic processes in the branch of pharmacokinetics 1. the route of administration - how a drug is taken into the body 2. absorption and distribution - factors affecting its absorption and how it gets distributed to the brain 3. metabolism (detoxification or breakdown) how a drug is broken down or made into inactive forms 4. excretion – (elimination) ◦ how the drug is eliminated Knowing about pharmacokinetics tells us critical information about insight into the actions of a drug. Ex. benzodiazepenes ultra short acting, short acting, long acting lorazepam (Ativan) and triazolam (Halcion) – pharmacokinetics lorazepam – persists for at least 24 hr triazolam – 6 – 8 hours midazolam – 1 – 2 hrs Oral Parenteral Buccal Inhalation Rectal Nasal most common, sometimes referred to as po safe, self administered, economical BUT blood levels are often irregular (most complicated route of adm) liquid more readily absorbed than solids soluble and stable in stomach (not destroyed by stomach enzymes more acidic) enter intestine; penetrate lining of intestine, pass into bloodstream and reach site of action; intestine is more basic absorption favored if the drug is nonionized and more lipophilic ◦ chemicals in stomach must deal with: ◦ stomach acids ◦ digestive enzymes ◦ first pass metabolism through liver ◦ other items in stomach ex. tetracycline ◦ Convenient - can be self- administered, pain free, easy to take ◦ Absorption - takes place along the whole length of the GI tract ◦ Inexpensive - compared to most other parenteral routes disadvantages of oral administration: ◦ ◦ ◦ ◦ ◦ ◦ vomiting/stomach distress variability in dose effect too slow for emergencies unpleasant taste of some drugs unable to use in unconscious patient first pass metabolism First pass metabolism - term used for the hepatic metabolism of a drug when it is absorbed from the gut and delivered to the liver via the portal circulation. The greater the first-pass effect, the less the agent will reach the systemic circulation when the agent is administered orally first pass metabolism disadvantages of oral administration: ◦ ◦ ◦ ◦ vomiting stomach distress variability in dose first pass metabolism ex. buspirone (BuSpar) – antianxiety drug 5% reaches central circulation and is distributed to brain disadvantages of oral administration: ex. buspirone (BuSpar) – antianxiety drug 5% reaches central circulation and is distributed to brain metabolism can be blocked by drinking grapefruit juice (suppresses CYPp450 enzyme) Hours J.Clin. Invest. 99:10, p.2545-53, 1997 Drugs that are destroyed by gastric juice or cause gastric irritation can be administered in a coating that prevents dissolution in acidic gastric contents (however may also preclude dissolving in intestines) Controlled – Release Preps - Sustained Release Controlled Release Extended Release Time or Timed Release How is this achieved? ◦ Embed in a web of substance that the body is slow to dissolve ◦ drug to swell up to form a gel with a nearly impenetrable surface, wherein the drug slowly exits the semipermeable layer ◦ may have a coating over the active ingredient, ◦ may contain tiny time release beads, individually coated DA: delayed absorption DR: delayed release EC: enteric coated ER: enteric release GC: granules within capsules SR: slow release SSR: sustained release GI motility- speed of gastric emptying affects rate of absorption ◦ ex. migraine and analgesics vs metoclopramide Malabsorptive States ◦ GI diseases, ex. Crohn’s disease can affect absorption Food ◦ iron, milk alters tetracycline ◦ fats first pass metabolism chemicals delivered with a hypodermic needle; ◦ most commonly - injected into vein, muscle or under the upper layers of skin, in rodents also intraperitoneal cavity requirements for parenteral: must be soluble in solution (so it can be injected) ◦ ◦ ◦ ◦ ◦ ◦ Intravenous Intramuscular Subcutaneous Intracranial Epidural Intraperitoneal absorption more rapid than SC ◦ less chance of irritation; ways to speed up or slow down absorption depot injections - extremely rapid rate of absorption adv: useful when you need rapid response or for irritating substances Disadv: rapid rate of absorption contingent on blood flow SO ◦ IV, intraperitoneal, IM, SC increasing or decreasing blood flow affects drug absorption Drugs leave bloodstream and are exchanged between blood capillaries and body tissues bolus or depot shots related - drugs that accumulate in fat ◦ ex. THC nasal, oral, buccal medications include: nitroglycerine, fentanyl –(1998) , nicotine gum, lozenges, buprenorphine cocaine – snuff, cigars ◦ Advantages: rapid absorption avoid first-pass effect ◦ Disadvantages: inconvenient small doses unpleasant taste of some drugs 1990’s – several medications incorporated into transdermal patches: ◦ estrogen, nicotine, fentanyl, nitroglycerin, scopolamine controlled slow release for extended periods of time Novel approaches…..Audra Stinchcomb usually suppository form for unconscious, vomiting or unable to swallow disadv: not very well regulated dose; absorbed plus irritation (yikes) not really used for psychotropics Route for administration -Time until effect intravenous 30-60 seconds inhalation 2-3 minutes sublingual 3-5 minutes intramuscular 10-20 minutes subcutaneous 15-30 minutes rectal 5-30 minutes ingestion 30-90 minutes transdermal (topical) variable (minutes to hours) The rate at which a drug reaches it site of action depends on: ◦ Absorption - involves the passage of the drug from its site of administration into the blood ◦ Distribution - involves the delivery of the drug to the tissues Factors which influence the rate of absorption ◦ ◦ ◦ ◦ routes of administration dosage forms the physicochemical properties of the drug protein binding Factors which influence the rate of absorption ◦ ◦ ◦ ◦ ◦ ◦ routes of administration dosage forms the physicochemical properties of the drug protein binding circulation at the site of absorption concentration of the drug Mostly a passive process ◦ from higher conc to lower (in blood) Concentration Gradient Drug goes from higher concentration to lower concentration [DRUG] receptors ≈ [DRUG] circulation Pharmacokinetics Distribution Drug molecules may be found in different places in the blood. 1. Plasma–more likely with water soluble drugs 2. Platelets–more likely with lipid soluble drugs 3. Attached to proteins (e.g., albumin)–bound vs. free Mostly a passive process ◦ from higher conc to lower (in blood) Binding to plasma proteins ◦ results in a store of bound drug in plasma examples 95-99% - chlorpromazine, diazepam, imipramine 90 - 95% - valproate, propanolol, phenytoin Renal insufficiency last trimester of pregnancy drug interactions (other drugs that bind to proteins) diseases Blood brain barrier◦ layer of thickly packed epithelial cells and astrocytes that restrict access of many toxins/drugs to the brain Lipid solubility – how soluble the drug is in fats ◦ cell membranes are lipid bilayers ◦ similar characteristics allow drugs to cross brain as to cross into cells Lipid solubility Size of molecule Ionization – whether the degree has a charge (+ or -) pKa – the pH at which ½ of the molecules are ionized most drugs are either weakly basic or weakly acidic Basic drugs are highly ionized in acidic environment Acidic drugs are highly ionized in basic environment pKa – the pH at which ½ of the molecules are ionized the closer the pKa of the drug is to the local tissue pH, the more unionized the drug is. ex. morphine – pKa of 8 stomach ~ pH ~ 3 caffeine – pH .5 ◦ Distribution half-life: the amount of time it takes for half of the drug to be distributed throughout the body ◦ Therapeutic level: the minimum amount of the distributed drug necessary for the main effect. Until this time, drug movement has been mostly passive from regions of higher concentration to lower concentration. Elimination of drugs usually requires more of an active process (except gaseous drugs). 1. Biotransformation (metabolism) chemical transformation of a drug into a different compound in the body (metabolite) Most biotransformation takes place in the liver 2. Excretion - removal of drug to outside world ***Drug elimination may be by both or either of these mechanisms role of liver ◦ most significant organ in biotransformation role of liver ◦ most significant organ in biotransformation ◦ largest organ in body ◦ serves many functions transforms molecules via enzymes 1. deactivating the molecule 2. ionize the molecule 3. make it less lipid soluble ** product of biotransformation is called a metabolite Cytochrome p450 enzyme family located primarily in hepatocytes important for metabolism of alcohol, tranquilizers, barbiturates, antianxiety drugs, estrogens, androgens, PCBs and other agents oxidative metabolism – makes drugs more water soluble (so more easily excreted) There are about 12 CYP families. ◦ CYP1, 2, and 3 = most common for drug metabolism. ◦ CYP2D6 and CYP3A (especially 3A4) metabolize over 50 percent of drugs. CYP enzymes ◦ enzyme induction liver produces extra enzyme to break down drug with continued exposure Pharmacokinetics Examples and Consequences: St. John's Wort: (with active ingredient hyperforin) stimulates a receptor (SXR in humans, PXR in nonhumans) in the liver to induce CYP3A, CYP3A breaks down many other drugs: theophylline (asthma), warfarin (anticlotting), birth control pills, and immunosuppressant cyclosporin. CYP enzymes ◦ enzyme induction liver produces extra enzyme to break down drug with continued exposure Genetics Pharmacokinetics Estimates that there is a 10-year gap between medically relevant bio-technological advances and appropriate application, or translation into routine medical practice Pharmacokinetics Enzyme Inhibition ◦ ◦ Some drugs inhibit CYP enzymes and increase their own levels, as well as levels of any other drug metabolized by that enzyme. Can produce toxicities. Example: Inhibition of antipsychotic medication by SSRIs. CYP enzymes - ◦ enzyme induction liver produces extra enzyme to break down drug with continued exposure Genetics Liver disease cirrhotic liver In some cases, biotransformation can be to another psychoactive compound ex. benzodiazepenes diazepam nordiazepam oxazepam Pharmacokinetics Excretion ◦ Primarily accomplished by kidneys. 2 organs (about the size of a fist) located on either side of the spine in the back. Keep the right balance of water and salt in the body Filter everything out of blood and then selectively reabsorb what is required. Can be useful for eliminating certain drugs in overdose. all drugs not in gaseous state need to use fluid routes of excretion ◦ fluid routes include -sweat, tears, saliva, mucous, urine, bile, human milk ◦ amount of drug excreted in each of these fluids is in direct proportion to amount of fluid excreted SO……. Pharmacokinetics Sometimes drugs are not metabolized and are excreted intact. ◦ Lithium ◦ Mushroom amanita muscaria In large doses it is toxic and lethal; small amounts are hallucinogenic. Hallucinogenic ingredients are not greatly metabolized and are passed to the urine. Siberian tribespeople discovered this and recycled the drug by drinking their urine. Pharmacokinetics Sometimes drugs are not metabolized and are excreted intact. ◦ Lithium ◦ Mushroom amanita muscaria In large doses it is toxic and lethal; small amounts are hallucinogenic. Hallucinogenic ingredients are not greatly metabolized and are passed to the urine. Siberian tribespeople discovered this and recycled the drug by drinking their urine. absorption, distribution and excretion do not occur independently 1. Body weight - smaller size • concentration of drug based on body fluid 2. Sex differences 3. Age 4. Interspecies differences rabbits – belladonna (deadly nightshade) 5. Intraspieces differences 6. Disease states 7. Nutrition 8. Biorhythm half-life - time takes for the blood concentration to fall to half its initial value after a single dose ½ life tells us critical information about how long the action of a drug will last How long would it take for a drug to reach 12.5% remaining in blood if its ½ life is 2 hours? How long would it take for a drug to reach 12.5% remaining in blood if its ½ life is 100 hours? first pass metabolism blood brain