Basic Pharmacokinetics 1 - Student Version PDF

BASIC PHARMACOKINETICS 1: ADMINISTRATION, ABSORPTION, BIOAVAILABILITY AND DISTRIBUTION Siti Zawanah Binti Halim Master in Pharmacology and Toxicology (UPM) Faculty of Dentistry, AIMST University Learning Outcomes Explain the pharmac...

BASIC PHARMACOKINETICS 1: ADMINISTRATION, ABSORPTION, BIOAVAILABILITY AND DISTRIBUTION Siti Zawanah Binti Halim Master in Pharmacology and Toxicology (UPM) Faculty of Dentistry, AIMST University Learning Outcomes Explain the pharmacokinetics. Able to explain the various routes of drugs administration & compare their advantages & disadvantages. Explain the process of drug absorption and bioavailability. List and briefly explain the factors affecting absorption of drugs. List and briefly explain the factors affecting distribution of drugs. Main divisions of Pharmacology Pharmacokinetics Greek word: kinesis - movement Movement of the drug in the body including the alteration of the drug in the body. Basically, what the body does to the drug. Pharmacokinetics Routes of Drug Administration Advantages and disadvantages  Routes of Drug Administration Local Systemic Deeper Arterial Enteral Parenteral Topical tissue supply Cutaneous Non-injection Oral Sublingual Rectal Inhalation Injection Subcutaneous Intramuscular Intravenous Intradermal Local - topical Description Examples Advantages Disadvantage External application Lotion, ointment, cream, Bypasses Allergy to of the drug to the powder, rinse, paints, liver. patches in surface for localized drops, spray, lozenges, Produces some. action. suppositories or pessaries. prolonged Some topical drug Dosage forms - transdermal action. may act into patch, ointment. systemic action. Nitroglycerin ointment & transdermal patch in angina pectoris. Estrogen ointment for hormone replacement therapy. Local – deeper tissue Description Examples Advantage Disadvantage Approached by Intra-articular injection It has a faster It has a using a syringe and (hydrocortisone action slower needle, but the acetate in knee joint). compared to action drug should be in Infiltration around a intradermal compared to such a form that nerve or intrathecal route. intravenous systemic injection (lidocaine). route. absorption is slow. Retrobulbar injection (hydrocortisone acetate behind the eyeball). Local – arterial supply Description Examples Advantages Disadvantage Close intra- Anesthetics These routes can be used Damage to arterial injection drugs (e.g.: for drugs whose systemic peripheral is used for midazolam, absorption from these nerves that contrast media atropine, etc.). sites is minimal or can cause in angiography; absent. tingling or anticancer drugs High concentrations are prickling can be infused attained at the desired feelings. in femoral or site without exposing the brachial artery rest of the body. to localize the Systemic side effects or effect for limb toxicity are consequently malignancies. absent or minimal. Systemic – enteral (oral) The drug administered through systemic routes is intended to be absorbed into the blood stream and distributed all over, including the site of action, through circulation. Description Examples Advantages Disadvantages Drug is taken Tablets It is safer, more Action of drugs is slower through the to convenient, self and thus not suitable for mouth. swallow, administration is emergencies. chew or possible, non-invasive, May cause nausea and dissolve often painless, the vomiting. in water. medicament need not Cannot be used for OTC be sterile and cheaper. uncooperative/unconsciou drugs Does not require s/vomiting patient. etc. maximum sterility and Destroyed by digestive patients' compliance juices (penicillin G, insulin) is mostly ensured. or in liver (testosterone, High surface of lidocaine). absorption and good Food interaction might permeability of GI happen. barrier. Systemic – enteral (sublingual or buccal) Description Examples Advantages Disadvantages The tablet or Nitroglycerin Absorption is Inconvenient. pellet for chest relatively rapid— Only lipid soluble and containing the pain. action can be non-irritating drugs can drug is placed Loratadine produced in be administered. under the for fever and minutes. Only small doses can tongue or allergy. Bypassed liver be accommodated crushed in the Mirtazapine and drugs with easily. mouth and for major high first pass Irritation of the spread over the depressive metabolism can mucous membrane and buccal mucosa. disorder in be absorbed excessive salivation adults. directly into may promote Rizatriptan systemic swallowing. for migraine circulation. headaches. The drug can be spitted-off if undesired effects develop. Systemic – enteral (rectal) Description Examples Advantages Disadvantages Uses the Acetaminoph Can be used for drug Inconvenient and rectum as a en for fever. with both local and embarrassing. route of Diazepam for systemic effects. Absorption is slower, administratio seizures. Local- irregular and often n for drugs Laxatives for antihemorrhoidal unpredictable. which are constipation. agents. Rectal inflammation. absorbed by Systemic- analgesics, Presence of stool in the the rectum’s antipyretics etc. rectum reduces the blood Can be used to extent of absorption. vessels. administer irritant Only small doses can be and unpleasant accommodated easily. drugs. The surface for Suitable when absorption is very patient having limited; drug absorbed recurrent vomiting. into external Suitable route for hemorrhoidal veins children, old and (about 50%) bypasses unconscious liver, but not that patients. absorbed into internal hemorrhoidal veins. Systemic – parenteral (inhalation) Description Examples Advantages Disadvantages Drugs Beta-2 Drug is directly delivered Special apparatus is administered by agonists to the site of action. required. inhalation , e.g., Drugs are rapidly Training is required - through the salbuta absorbed and fast onset difficult in children mouth must be mol. of action; absorption and geriatric patients. atomized into takes place from the vast Prolonged inhalation smaller surface of alveoli. sometimes cause droplets, so that Bypass hepatic first pass adverse effects; the drugs can metabolism. cause inflammation pass through Avoid systemic toxicity; of respiratory tract the windpipe when the administration and increase (trachea) and is discontinued the drug secretion. into the lungs. diffuses back and is E.g.: oropharyngeal rapidly eliminated in candidiasis and expired air. Thus, dysphonia with controlled administration prolong steroid is possible with moment- inhalation. to-moment adjustment. Systemic – parenteral (cutaneous) Description Examples Advantages Disadvantages The Ointment, Highly lipid soluble Possibility of local skin application of cream, drugs can be applied irritation at the site of suitable drug lotion, over the skin for slow application. dosage forms etc. and prolonged Contact dermatitis due to the skin for absorption. to some drug and/or systemic Bypassed liver. excipients may occur. effects. The drug can be incorporated in an ointment and applied over specified area of skin. Absorption of the drug can be enhanced by rubbing the preparation, by using an oily base and by an occlusive dressing. Systemic – parenteral (injection) Description Examples Advantages Disadvantages Direct Intravenous Drugs are directly introduced Invasive and injection of (injection into a into the systemic circulation painful. administrati vein and directly without having to cross the Administratio on to the into the enteral mucosa. n is systemic bloodstream) – Used for drugs which are irreversible circulation. chemotherapy unstable in acid in stomach or and cannot be drugs such as not absorbed from GIT as self cisplatin. gastric irritation and vomiting administered. Intradermal are not provoked. Chances of (injection into the Suitable for emergency as drug local tissue dermis) – action is faster and surer. injury. tuberculosis and Unconscious, uncooperative or Preparation allergy testing. vomiting patients. must be Intramuscular High bioavailability (IV route sterilized and (injection into a 100% bioavailability) and costly. muscle) – predictable action. More risky vaccines. There are no chances of than oral. Subcutaneous interference by food or (injection under digestive juices; liver is the skin) – insulin. bypassed. Absorption Movement of the drug from its site of administration into the circulation. E.g.: ❑ If oral, the drug move from stomach & intestine to circulation. ❑ If through rectal, the drug move from rectum to circulation. ❑ If intramuscular, the drug move from muscles to circulation. Meanwhile, drug given through intravenous must cross biological membranes without going through absorption. Processes of drugs absorption Processes of drugs absorption Passive Transport: Passive or simple diffusion The drug diffuses across the membrane in the direction of its concentration gradient, the membrane playing no active role in the process. Factor affecting simple diffusion: Higher concentration of lipid-soluble drug attains in the membrane, the rate of diffusion increased. The greater the difference in the concentration of the drug on the two sides of the membrane, the rate of diffusion increased. Processes of drugs absorption Passive Transport: Facilitated diffusion Carrier transport is specific for the substrate (or the type of substrate, e.g., an organic anion), saturable, competitively inhibited by analogues which utilize the same transporter, and is much slower than the flux through channels. Operates passively without needing energy and translocates the substrate in the direction of its electrochemical gradient, i.e., from higher to lower concentration. E.g.: Uptake of glucose by cell Processes of drugs absorption Active Transport Drugs molecule pass across biological membrane against their concentration gradient. It requires energy, transports the solute against its electrochemical gradient (low to high), resulting in selective accumulation of the substance on one side of the membrane. Site of active transport: neuronal membrane, BBB, renal tubular cell, biliary tract and GIT. E.g.: levodopa and methyl dopa are actively absorbed from the gut by the aromatic amino acid transporter. Processes of drugs absorption Endocytosis Endocytosis is the process of capturing a substance or particle from outside the cell by engulfing it with the cell membrane. The membrane folds over the substance and it becomes completely enclosed by the membrane. At this point a membrane-bound sac, or vesicle pinches off and moves the substance into the cytosol. Specific receptors for the transport proteins must be present for this process to work. E.g.: The transport of vitamin B12 across the wall of the gut into the blood. Processes of drugs absorption Exocytosis Involve the process of vesicles fusing with the plasma membrane and releasing their contents to the outside of the cell. Exocytosis occurs when a cell produces substances for export, such as a protein, or when the cell is getting rid of a waste product or a toxin. Newly made membrane proteins and membrane lipids are moved to the plasma membrane by exocytosis. E.g.: Hormones – insulin; neurotransmitter – noradrenaline.  1 MINUTE BREAK First-pass metabolism Metabolism of a drug during its passage from the site of absorption into the systemic circulation is called first-pass metabolism or pre-systemic elimination. By oral route – drug may undergo metabolism in intestine, portal circulation & liver (predominantly) before entering systemic circulation. Example of drugs with high first pass metabolism are propranolol, lidocaine, nitroglycerine and salbutamol. Bioavailability Bioavailability refers to the rate and extent of absorption of a drug from a dosage form as determined by its concentration-time curve in blood or by its excretion in urine. Bioavailability is expressed as a fraction of administered drug that reaches the systemic circulation in the unchanged form. Bioavailability of drug injected IV is 100%, but is frequently lower after oral ingestion because: ❑ The drug may be incompletely absorbed. ❑ The absorbed drug may undergo first pass metabolism in the intestinal wall/liver or be excreted in bile. E.g.: if 100 mg of a drug administered orally, and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or 70%. Bioavailability Factors affecting drug absorption and bioavailability Drug related factors by 1 oral route Patients related factors 2 by oral route 3 Parental site (except IV) Drug related factors by oral route Physical state Lipid and water solubility Particle size Disintegration time and dissolution rate: Higher disintegration time and low dissolution rate, lower rate of absorption. Formulation: Tetracycline with calcium or magnesium retard the absorption and bioavailability. Drug related factors by oral route Ionization constant and effect of pKa: Non-ionized forms are lipid soluble & diffuse across the membrane, hence easily absorbed. Ionized forms are lipid insoluble, water soluble & can not cross the membrane, hence poorly absorbed. Concentration of ionized and non-ionized form of a drug is determined by pH of the medium and pKa of a drug. pKa – is the pH at which half (50%) the drug is in its ionized form. pKa usually low for acidic drugs & high for basic drugs. Patients related factors by oral route ❑ Surface area. ❑ Motility of GIT: Drugs are better absorbed in normal GIT movement. ❑ Blood supply at the absorptive area. ❑ Presence of food: ▪ More absorption in empty stomach. ▪ Antacid prevents absorption of tetracycline. ▪ Milk (Ca) - can reduce tetracycline absorption. ▪ Food – reduce the absorption of ampicillin. ▪ Fatty diets - ↑the absorption of griseofulvin. Patients related factors by oral route ❑ Gastric emptying time: ▪ ↑gastric emptying time → ↓ rate of absorption food & drugs. ▪ Metoclopramide increases gastric motility and accelerates gastric emptying and hence aid in rapid absorption. ▪ While fatty meal, antimotility drugs (atropine), exercise & stress can slow gastric emptying and delay the rate of absorption and onset of action. ❑ Destruction of drug in GIT: ▪ Benzyl penicillin is destroyed by gastric HCL. ▪ Insulin is destroyed by proteolytic enzymes. Patients related factors by oral route ❑ Nature of drug & pH of the media (GIT) ▪ Acidic drug in acidic pH more absorption (in stomach). ▪ Acidic drug in alkaline pH less absorption (in intestine). ▪ Basic drug in acidic pH less absorption (in stomach). ▪ Basic drug in alkaline pH more absorption (in intestine). ❑ First-pass metabolism / pre-systemic elimination ▪ ↑first pass metabolism → ↓ absorption Parental site (except IV) Site of injection: o IM→ more absorption. o SC → less than IM. Blood flow to absorptive area: o Muscle (IM) → more absorption. o Subcutaneous tissue (SC) → less absorption. Formulation: o Sustained release formulation → slow absorption. o Aqueous solution → rapidly absorption. Torniquet →↓ Blood supply →↓ absorption. Application of heat massage →↑ Blood flow →↑ absorption. Drug Absorption - Summary Most drug absorption occurs through passive absorption. Lipid soluble drugs are more readily absorbed than non-lipid soluble drugs. Non-polar drugs are more readily absorbed than polar drugs. Non-ionized drugs are more readily absorbed than ionized drugs. Basic drugs are more readily absorbed in the small intestine than acid drugs; acid drugs in the stomach. Overall, most of the drug absorption occurs in the small intestine, especially the duodenum. Distribution ▪ Drug distribution is the process by which a drug reversibly leaves the blood stream and enters interstitium (extracellular fluid, ECF) and/ or the cell of the tissues. ▪ Distribution is represented by a parameter called volume of distribution (Vd). ▪ Major compartment of distribution: ❖ Fluid compartment (70%): Plasma compartment, ECF, total body water (TBW). ❖ Solid compartment (30%): bone, muscle, fat (25% of TBW). Factors affecting drug distribution Lipid solubility of drugs ❑ Drugs with high lipid solubility → widely distributed in the body (High Vd). Ionization at physiological pH ❑ Polar/ionized drug – less lipid solubility – readily extracellular distribution. ❑ Nonpolar/unionized drug – high lipid solubility – readily intracellular distribution. Plasma protein binding ❑ Plasma protein that are responsible for drug binding: – Albumin: Usually binds with acidic drugs e.g., phenytoin, warfarin. – α1 glycoprotein: Usually binds with basic drugs e.g., prazosin, verapamil. – Other special plasma proteins: thyroid binding globulin (TBG), corticosteroid binding globulin (CBG). ❑ Protein bound drug are inactive & acts as reservoir. ❑ They are not responsible for the pharmacological actions of drug. Factors affecting drug distribution Tissue protein binding (storage of drugs in tissues) ❑ Drugs with high lipid solubility → widely distributed in the body (High Vd). Capillary permeability ❑ In liver and spleen: endothelial cells have high intercellular pores, through which even large plasma protein can pass; as a result, majority of drugs enter liver and spleen. Factors affecting drug distribution Capillary permeability ❑ Blood brain barrier (BBB): In brain, capillary endothelium is continuous with tight junctions; as a result, all the drugs can not enter the brain (restricted entry). ❑ This barrier restricts the entry of water soluble / lipid insoluble drugs like streptomycin, neostigmine, etc. ❑ Highly lipid soluble drugs can easily cross BBB & enter CNS, e.g.: thiopentone. Factors affecting drug distribution Capillary permeability ❑ Passage across placenta: Lipid soluble drugs can easily cross placental membranes whereas polar/water soluble drugs poorly cross placental membrane. ❑ However, placental barrier is incomplete compared to BBB. ❑ Water soluble drugs at high concentration can crosses placental barrier & enter fetal circulation. ❑ Drugs which enter fetal circulation can produce adverse effects on growing fetus or newborns (teratogenicity). *Care should be exercised while prescribing drugs to pregnant women. Recommended reading Katzung Bertram G. (2018) Basic & Clinical pharmacology, (14th Edition), Mcgraw Hill. Whalen,K., Finkel, R. (2019 )Lippincott Illustrated Reviews: Pharmacology (7th Edition), Wolters Kluwer. Rang HP, (2020)Dale’s Pharmacology, (9th Edition), Elsevier,. Brunton. L.L., Hilal-Dandan. R., Knollmann. B.C., (2018) Goodman & Gilman's: The Pharmacological Basis of Therapeutics, (13th Edition), Mcgraw Hill. Tripati, K.D. (2016) Essentials of Pharmacology for Dentistry, (3rd edition) Jaypee Brothers. Tripati, K.D. (2019) Essentials of Medical Pharmacology, (8th Edition) Jaypee Brothers. Rang, H.P., M.M and Ritter, J.M.(1999) Pharmacology (4th Edition), Churchill Livingstone. Katjung B.G. (2000) Basic and Clinical Pharmacology, (8th Edition), Appleton and Lange. Page, C.P., Curtis, M.J., Sutter, M.C., Walker, M.J.A and Hoffman, B.B. (2002) Integrated Pharmacology. (2nd Edition), Mosby. Seymour.R, John G. Meechan and Yates. M., Pharmacology and Dental Therapeutics (3rd edition) Oxford publication.