Pharmacokinetics 1 Absorption + Distribution PDF

Pharmacokinetics 1 Absorption + Distribution Stephen Evans PhD  Concentration of drug that interacts with the target is influenced by how the drug passes through the body. Pharmacokinetics can be Pharmacokine...

Pharmacokinetics 1 Absorption + Distribution Stephen Evans PhD  Concentration of drug that interacts with the target is influenced by how the drug passes through the body. Pharmacokinetics can be Pharmacokine described as “what the body tics does to the drug” Key processes are Absorption, Distribution , Metabolism and Excretion (ADME).  Absorption Important factor for all routes of drug administration except intravenous route. (directly into systemic circulation) Oral doses may be solid form (tablet, capsule or powder). Liquid form (solution or suspension) Solid dosage forms must disintegrate and undergo dissolution before being available for absorption. Absorption faster for liquids, elixirs, syrups> suspensions>powders> capsules> tablets> coated tablets> enteric coated tablets and sustained (controlled or “slow” release formulations. Absorption across biological membranes Drugs must cross a membrane and enter blood vessels on other side membranes typically consist of a lipid bilayer, containing protein irregularly through it. Proteins provide structural order, may act as carriers (transporters), enzymes, receptors, ion channels or antigenic sites. Lipid soluble drugs readily pass through the lipid membrane, while ionized (charged drugs have difficulty. Aquaporins permit the passage of small uncharged water-soluble substances such as urea and water (too small for drugs). Passive diffusion Most drugs cross membranes by passive diffusion. Passive diffusion: movement from a higher concentration to a region of lower concentration until equilibrium is established both side of the membrane. Influenced by the surface area of the membrane exposed to the drug, concentration gradient of the drug, its lipid-water partition coefficient and for acidic and basic drugs diffusion influenced by the ionization state.  Requires involvement of a membrane protein for movement across a biological membrane. May be active (requires energy) or facilitated (energy not required). Carrier mediated Active transport can enable movement against a concentration gradient or transport electrochemical gradient in the case of ions (e.g. sodium-potassium pump). Amino acids, glucose, some vitamins, neurotransmitters and ions are transported via this method. Also important for drug absorption, distribution and elimination.  Classified into Two superfamilies, particularly important in transport of drugs in the kidney, GI tract, liver and blood-stream. ATP binding cassette (ABC) transporter. Membrane Solute carrier (SLC) transporter. transporter ABC transporters require the hydrolysis of ATP as energy source to pump sI substrate across membranes. Seven sub-classes best known is the efflux transporter P-glycoprotein (P-gp; also MDR1 which stands for “multi-drug resistance”, P-gp found in intestine, liver, blood-brain barrier, placenta and testes and has been associated with resistance to cytotoxic chemotherapy drugs (doxorubicin, paclitaxel and vincristine).  Membrane transporters II SLC transporters include the uptake transporters: Organic anion transporting polypeptides (OATPs). Organic cation transporters (OCTs) and organic anion transporter (OATs). Major role in hepatic uptake of compounds. Bile acids, sulfate and glucuronide conjugates and drugs such as fexofendadine, rifampicin and the statins (atorvastatin, pravastatin and rosuvastatin). OATs and OCTs contribute to uptake of drugs in the liver and kidney such as furosemide and metformin and ranitidine. Variables that affect drug absorption Nature of the cell Solubility membrane Greater the solubility the more rapidly Larger surface area the greater the it will be absorbed. absorption and more rapid the effects Chemicals and minerals that form (e.g. pulmonary epithelium and inhaled drugs such as gasesous anaesthetics). insoluble precipitates such as barium salts or drugs that are resins (chloresytramine) are not absorbed. Blood flow to the site of Ionisation administration Significant determinant of rate and extent Many drugs are weak acids and bases of absorption. and are present in both un-ionized and sublingual route (rich blood supply) ionized (charged state). sub-cutaneous route in poor vascular charged state is water soluble and does not readily diffuse across site will delay absorption. membranes. food increase splanchnic blood flow basic drugs are more ionized in an and can enhance oral absorption of acidic environment such as drugs. stomach. acidic drugs are more ionized in a more basic (less acidic environment). Formulation Drug formulations can be manipulated to achieve a desirable absorption profile. Coating with a resin or placed in matrix from which its slowly released. Enteric coatings on drugs used to: Prevent decomposition of chemically sensitive drugs to gastric acid (e.g. erythromycin unstable at acidic pH). Prevent dilution of drug before it reaches the small intestine. Prevent nausea and vomiting induced by the effect of drug in stomach. Provide delayed release of drug. Routes of drug administration Drug can enter circulation either by direct injection (intravenous) or absorption from extravascular sites. Oral (enteral). Parenteral -includes subcutaneous, intramuscular, intravenous, intrathecal or epidermal. Inhalation. Topical. Rectal. Drug-eluting stents, nanoparticles. Oral route Most common route of drug administration. Safe. Convenient. Economical. Frequent changes in GIT environment by food, emotion, physical activity and other medications may make absorption unreliable or slow. May be absorbed from several sites within the GIT, and or metabolized by enzymes (not appropriate for recombinant protein-drugs).  Thin lining, rich blood supply and slightly acidic pH. Little absorption occurs in the mouth. Drugs that dissolve rapidly in salivary excretions can Absorption be given by sublingual or buccal routes. Sublingual- placed under tongue to permit from oral dissolution, e.g fentanyl patient advised to refrain as long as possible from swallowing saliva, drug cavity enters the systemic circulation without entering the hepatic-portal system and thus bypasses the liver and first-pass metabolism. Absorption is rapid and effects may become apparent with 2 minutes. Buccal- placed between teeth and mucous membrane of the cheek, some hormones and enzyme preparations administered by this route.  Rich blood supply, but thick layer of mucus, tight intracellular junctions and small surface area (relative to other sites). Not a major site. GI absorption is determined by a large extent to Absorption the amount of time a drug remains in the stomach. from the Slow gastric emptying decrease rate of absorption in the small intestine. stomach Drugs administered on an empty stomach with sufficient water enable faster absorption. Sitting upright for 30 mins after oral dosing will help reduce gastric emptying time (also reduces oesophageal irritation and lodging). Drugs that cause gastric irritation are usually given with food. Absorption from small intestine Highly vascularized, many villi (large surface area), permeable absorption surface compared to stomach. Lipid soluble forms readily absorbed. Dynamic nature of equilibrium: more unionized drug then becomes available for absorption. Weak acids and basic drugs are well absorbed after oral administration.  Small surface area. Extensive vascularity enables drug absorption. Veins of the rectum include the superior, middle and inferior veins. Only the superior vein connects into Absorption the hepatic portal vein, approximately 50% of absorbed drug from escapes first pass metabolism. rectum Can be used for both local and systemic administration. Useful in unconscious individuals, fasting patients or those unable to swallow or with severe vomiting. Disadvantages, interruption due to defecation, local drug irritation, drug retention uncertain, patient acceptability. Parenteral route – by injection Subcutaneous- Beneath skin into connective tissue or fat under the dermis. Non-irritating drugs. Rate of absorption slow, can provide sustained effect. Intramuscular- Into the muscle, most often fully soluble in aqueous solution. More rapid absorption than SC route due to greater tissue blood flow. Procaine penicillin is poorly soluble, injected as an aqueous suspension that’s slowly absorbed, has a prolonged duration of action. Some steroid hormones synthesized as chemical esters to increase solubility in oil for use as depot injection. Parenteral route cont… Intravenous- produces immediate pharmacological response (100% bioavailability). Adverse effects may occur as a result of the rapid attainment of a high plasma concentration. Given as small bolus doses or by constant or intermittent infusions administered slowly to prevent adverse effects. Intrathecal- injected into the subarachnoid space, bypassing the blood- brain barrier, spinal anaesthesia, treatment of acute infection of the CNS. Epidural- injection on or outside the dura mater that surrounds the spinal column.  Inhalation- large Topical route- include skin surface area, mucous membranes, eyes, ears, nose. Other routes alveolar membrane is Skin- local or systemic effects thin, rich capillary network. (transdermal patches), Passage across outer hard avoids first pass layer extraction by the (stratum corneum) rate- liver. limiting in dermal absorption, Metered-dosed lipophilic drugs diffuse freely, Inhalers produce a more rapid absorption mainly local effect through abraded or burnt with reduced skin. systemic adverse Cutaneous blood flow or effects compared hydrating skin increases with po admin. absorption, role of massaging, warming skin and occlusive dressing placement can enhance this. Eyes,ears and nose Eyes- topical administration of ophthalmic drugs produce a local effect on the conjunctiva or anterior chamber. Systemic absorption through the naso-lacrimal canal ( bypasses liver), adverse effects from corticosteroids. Suspensions and ointments may promote distribution of drug over the surface of the eye. Ears- drops into the auditory canal to treat local infection, inflammatory conditions or help remove wax in the external ear. Nose- drops administered or sprays onto nasal mucosa, primarily for sinus conditions from viral infections or hay- fever.  Definition “ Bioavailability (F) is defined as the rate and extent to which the active moiety of a drug is absorbed from a drug product and reached the circulation”. Once the drug crosses the membrane of the GIT, it enters the hepatic portal vein which carries the blood containing the drug to liver Bioavailability (main site of drug metabolism). The drug may pass through the liver unmetabolized and enter the circulation as the intact parent drug or may undergo metabolism. The extent to which a drug is metabolized or extracted by the liver is highly variable. Factors affecting bioavailability Factors affecting bioavailability In this example, 80 mg of the original 100 mg dose is absorbed intact into the portal circulation. (The fraction absorbed is 0.8.) The hepatic extraction ratio is 0.75; that is, 60 mg is extracted in the first pass through the liver, and 20 mg escapes extraction and is available for distribution via the systemic circulation. The bioavailability is F = f g × f H , which is 0.8 × 0.25 = 0.2 (20%).  Orally administered drugs that are absorbed travel first through the portal vein system and the liver. A high amount of drug can be extracted from the liver eg First-pass Propranolol ( oral dose considerably greater than IV metabolism dose. Morphine undergoes significant first-pass metabolism, higher oral doses needed to compensate e.g, 30mg po is equivalent to 10mg, by iv, im or sc.  When comparing two formulation of the same, bioequivalence refers to an identical concentration of the active ingredient in the same dosage form administered by the same route. Once a patent expires on a drug, other Bioequivale pharmaceutical companies can produce a generic equivalent of the original patented drug nce under a new proprietary name. The generic product must be tested against the original, bioequivalence is achieved if the new product’s parameters describing exposure are within 20% of the original and if there is no clinically important difference between their therapeutic or adverse effects.  Distribution After reaching systemic circulation, drug(s) can be distributed to various interstitial and intracellular compartments within the body, including: blood, bone, fat, total body water and extracellular water. Distribution is defined as the process of reversible transfer of a drug between one location and another (one of which is usually blood) in the body Some drug remain almost exclusively in the blood (e.g. warfarin and penicillin. While others are distributed to organs that are well perfused ( heart, liver and kidneys), the local drug concentration in these organs maybe high initially. Drugs will be distributed more slowly to organs with poor blood supply (e.g. skeletal muscle and fat). Drugs widely distributed in the body include amiodarone, digoxin and morphine. Rate and extent to which drugs enter different body compartments depends on permeability of capillaries, partitioning of drug between vascular and tissue  Proportion of free drug molecules in systemic circulation bind reversibly to proteins and lipoproteins. Plasma protein binding expressed as a percentage of total bound drug or as fraction of unbound (e.g. 75% bound corresponds to an unbound Plasma fraction of 0.25). protein Extent of drug binding depends on affinity binding (attraction) of the drug to the protein, relative concentration of drug and protein and the number of binding sites on the protein. Drugs with high affinity for binding will be more tightly bound (but still reversible), the unbound fraction will be low.  Plasma protein binding continued Saturable process although doses used for most drugs are lower than required for saturation. (Notable exception salicylates for Rheumatoid arthritis: non-linear drug binding). Free drug + protein drug-protein complex Reversible and dynamic process, bound and unbound drug in equilibrium. Only free drug can exert a pharmacological effect. Most important plasma in relation to drug binding is albumin (quinine binds to -acid glycoprotein). Acidic drugs, warfarin, NSAIDs, sulfonamides and some basic drugs (tri-cyclic antidepressants and chlorpromazine bind to albumin. Warfarin is 99% plasma bound, atorvastatin ~98%. Albumin can provide multiple binding sites, two drugs can compete with one another for the same site and displace each other. (a mechanism of some drug- drug interactions). Hypoalbuminaemia (low levels of albumin in blood) may be caused by hepatic dysfunction. (cirrhosis, reduced synthetic function of liver) and can result in more free drug in the circulation and toxicity e.g. phenytoin. Tissue binding Adipose- lipid soluble drugs Bone- Tetracycline have high affinity. antibiotics can adsorb onto Low blood flow results in the bone crystal surface and stable reservoir for limited can depress bone growth in number of drugs e.g. premature infants, also can thiopental sodium (6-12 X discolour teeth in young concentration in fatty tissue children (tetracycline- c.f plasma ( long whole- calcium-orthophosphate body half life). complex. Tissue specific barriers to drug distribution Blood brain barrier (BBB) Placental barrier- separates Endothelial cells of brain blood vessels of mother and capillaries joined by tight fetus junctions, (also astrocytic end Placental enzymes can feet form a near continuous metabolise catecholamines layer over the thick basement inactivating them as they membrane. travel from maternal Lipid soluble drugs can enter circulation to the embryo. into brain and CSF although Lipid soluble drugs more efflux transporters such as P-gp likely to cross, many drugs pump drugs back out. intended to treat mother may During Meningitis infection the also cross the barrier to the inflammatory disruption of BBB fetus. allows distribution of penicillin to CNS tissues.  Called the “apparent” volume of distribution (Vd) is defined as the volume that would contain the total body content of the drug (Q) at concentration equal to that present in the plasma (Cp): Volume of Vd=Q distribution Cp Drugs confined to the plasma compartment have a Vd such as heparin (0.05L/kg of body weight) Highly lipophilic drugs with extensive tissue binding such as amiodarone (66L/kg). Questions???