Introduction to Pharmacology PDF

Introduction to Pharmacology  Course objectives General principles of pharmacology  Pharmacokinetics  Pharmacodynamics  Factors affecting drug responses Drugs affecting the peripheral nervous system  Function of the autonomic nervous system  Course Activities an...

Introduction to Pharmacology  Course objectives General principles of pharmacology  Pharmacokinetics  Pharmacodynamics  Factors affecting drug responses Drugs affecting the peripheral nervous system  Function of the autonomic nervous system  Course Activities and Assessment Lectures - 11 Tutorial – 6 CONASS – 40% Practical assignment (20%) Test 1 (20%) FAA – 60% Lab report (25%) Test 2 (35%) Pharmacokinetics I: Drug administration and permeation By end of this lecture.. Describe the various common routes used for administering drugs. Explain the general advantages and disadvantages of each route. Explain and give examples for the choice of route(s) used for administering a particular drug for a particular condition. Describe the various ways by which a drug crosses a cell membrane and gets transported around in the body.  Pharmacology Pharmacology is the study of drugs, their uses, and how they affect organisms. Pharmacokinetics Pharmacodynamics Describes what the body does to a Describes what the drug does to the drug body  Pharmacokinetics Pharmacokinetics is the aspect of pharmacology dealing with how drugs reach their site of action and are removed from the body. The processes that govern the rate of accumulation and removal of drug from an organism. The route of administration critically influences ADME.  Pharmacokinetics Drug transport across membrane Drug Drug absorption Drug distribution Drug Drug excretion Clinical administration biotransformation pharmacokinetics Routes of drug administration  Local routes: Topical Drug applied to the skin or mucous membrane at various site for localised action Passive diffusion through stratum corneum, sweat glands and hair follicles for skin application. Skin is considered as an important route of administration of drugs for both local and systemic effects  Local routes: Topical Oral cavity  Topical medications- first line of therapy in many conditions such as vesiculobullous diseases, oral infections like candidiasis, herpes simplex, potentially malignant disorders, neuropathic pain, and oral mucositis  Clotrimazole as lozenges for oral candidiasis  Xylocaine spray for local anaesthesia Rectum  Medications administered per rectum are ideal for local or systemic treatment- rectal mucosa has a blood and lymph supply that is capable of effective systemic absorption.  Evacuant enema (soap water)  Suppositories for bowel evacuation Eye  Placed in the eye (by the ocular route)  Ocular drugs are almost always used for their local effects.  Liquid eye drops, gel, ointment, and solid inserts  Artificial tears are used to relieve dry eyes.  To dilate pupils - phenylephrine and tropicamide) produce a local effect (acting directly on the eyes) after they are absorbed through the cornea and conjunctiva.  To treat glaucoma such as acetazolamide and betaxolol  Some of these drugs then enter the bloodstream and may cause unwanted side effects on other parts of the body. Ear  Placed in the ear (by the otic route)  Drugs used to treat ear inflammation and infection can be applied directly to the affected ears.  Drugs that can be given by the otic route include hydrocortisone (to relieve inflammation), ciprofloxacin (to treat infection), and benzocaine (to numb the ear). Nasal route  Sprayed into the nose and absorbed through the nasal membranes (nasally)  Breathed into the lungs, usually through the mouth (by inhalation) or mouth and nose (by nebulization)  Drugs that can be administered by the nasal route include nicotine (for smoking cessation), calcitonin (for osteoporosis), sumatriptan (for migraine headaches), and corticosteroids (for allergies).  Systemic enteral: Oral Advantages Disadvantages  Oral (PO) administration is Convenient and well Not suitable for emergency the most frequently used accepted route of administration because of its simplicity and Painless Highly irritant drugs (less desirable for drugs convenience, which improve that are irritating to the GI tract) patient compliance. Mostly safe Unabsorbed drugs (e.g aminoglycosides), Repeated and prolonged Less desirable for patient who is vomiting or  Administered in the form use unable to swallow of tablets, capsules, Can be self-administered Drug must be acid stable or protected from caplets, syrup , gastric acid (e.g., by enteric coatings) suspension and etc Not suitable for peptide drug e.g insulin Cheaper Not suitable for drugs with high first pass metabolism  Systemic enteral: Sublingual and Buccal  Sublingual (under the tongue)  Buccal (between gum and cheek)  Drugs must be lipophilic and are absorbed rapidly.  Compounded in the form of small, quick- dissolving tablets, sprays, lozenges, or liquid suspensions.  Most common sublingual medication is the nitroglycerin tablet  Others - narcotic pain relief, migraine pain relief, blood pressure control, and mental decline due to dementia  Systemic enteral: Sublingual and Buccal  Advantages Bypass gastric and hepatic metabolism Rapid absorption Drug stability – pH in mouth relatively neutral Action can be terminated by spitting out the tablet Self-administered Buccal formulations can provide extended-release options to provide long-lasting effects.  Disadvantages Inconvenient- holding the dose in the mouth Small doses only can be accommodated easily Flow of saliva may wash away the drug into the stomach Not suitable for children  Systemic enteral: Rectal  Used for local as well as systemic effect  Preferred when quick therapeutic response is required.  Found to achieve better plasma levels and therapeutic effectiveness when compared with orally or intramuscularly administered drugs of similar dose  Drugs administered are absorbed through two different vascular systems, one of which delivers agents to the liver while the second bypasses the liver.  Example: acetaminophen (for fever), diazepam (for seizures), and laxatives (for constipation).  Systemic enteral: Rectal Advantages Disadvantages Little or no first pass effect Small surface area Higher concentration rapidly Absorption is slow and erratic achieved, drug is readily absorbed Useful in situations in which the Inconvenient and less patient patient is unable to take medication compliance orally (e.g unconscious, vomiting, convulsing) Irritation or inflammation of rectal mucosa can occur  Gastric Feeding  Enteral feeding refers to intake of food via the gastrointestinal (GI) tract.  Nutrition taken through the mouth or through a tube that goes directly to the stomach or small intestine  necessary for someone who physically can’t eat, can’t eat safely, or if their caloric requirements are increased beyond their ability to eat.  Examples: o cancer, which may cause fatigue, nausea, and vomiting that make it difficult to eat o failure to thrive or inability to eat in young children or infants o a stroke, which may impair ability to swallow  Parenteral  The word parenteral was derived from the two words ‘‘para’’ and ‘‘enteron’’ means to avoid the intestine  Preparations intended for injection through the skin or other external boundary tissue, so that the active substances can be administered directly into a blood vessel, organ, tissue, or lesion.  Subcutaneous, intramuscular, intravenous, intradermal and intraarterial  Conventional parenteral formulations include solutions, suspensions and emulsions  Parenteral administration is preferred at times over other drug-administrations routes, such as in emergency situations of cardiac arrest and anaphylactic shock  Examples: aminoglycoside antibiotics, such as gentamicin. The injectable route may be chosen to provide a highly localized effect, injection of drugs, such as steroids, into joint spaces (intra-articular injection), intra-ocular injections to treat eye diseases or intrathecal injections where medicines are administered into the spinal column to deliver drugs into the cerebrospinal fluid  Parenteral: Intravenous (IV)  Avoids the first-pass drug effect resulting in direct entry of drug into the systemic circulation and consequently an immediate drug effect.  Administration of drugs via IV infusion is necessary when longer/continuous systemic exposures are required to elicit a therapeutic effect.  Intravenously administered drugs are given either as a “bolus” (within 1–30 min) or an infusion over a period of many hours.  Bolus IV administration is rarely used and is restricted to emergency situations where a critical rapid, but restricted duration of drug action is required. Thiopental is an example of a short acting bolus IV injected drug.  Examples: cancer chemotherapeutics, antibiotics, antifungals, and antinociceptive drugs.  Drugs in the form of suspensions or oily solutions cannot generally be given intravenously – ONLY WATER SOLUBLE  Parenteral: Intravenous (IV)  Advantages  Intravenous (and intra-arterial) drug administration provides the most complete drug availability with a minimal delay by control of the administration rate, constant plasma concentrations can be obtained at a required level  Unexpected side effects observed during the administration period can be halted by stopping the infusion (pleading for an extended infusion time)  Compounds that are poorly absorbed by the gastrointestinal tract  Compounds that are unacceptably painful when administered intramuscularly or subcutaneously  Irritating and non-isotonic solutions can be administered intravenously since the intima of the vein are insensitive.  Highly irritant drugs, e.g. anticancer drugs can be given because they get diluted in blood.  Parenteral: Intravenous (IV)  Disadvantages  Pain at the site of injection.  Once the drug is injected, its action cannot be halted and the drug cannot be removed by various methods like forced emesis or binding of charcoal (activated) as introduction of any particulate matter or any other substance can lead to fatal embolism.  Extravasation of some drugs can cause injury, necrosis, and sloughing of tissues.  Severe adverse effect especially when organs such as liver, heart, brain are involved in toxicity.  Local irritation may cause phlebitis.  Self-medication is not possible.  High probability of bacterial contamination.  IV injection may induce hemolysis and other similar conditions if the drug is administered too rapidly.  Parenteral: Intramuscular (IM)  injection into the striated muscle  The most commonly used sites are the deltoid, dorsogluteal, rectus femoris, vastus lateralis, and ventrogluteal muscles.  moderately rapid onset of action, usually within 5 to 10 minutes.  Muscles with high blood flows (e.g., deltoid) provide faster absorption rates than muscles with lesser flows (e.g., gluteus maximus).  Bioavailability via the IM route of administration is 100%  Water soluble drugs (i.e., insulin for diabetes and epinephrine for anaphylactic shock) diffuse quicker whereas drugs dissolved in an oil based vehicle diffuse slower.  Parenteral: Intramuscular (IM) Advantages Disadvantages Absorption is more rapid as compared to oral Possibility of improper deposition of drug route preparation in nerves, fats, blood vessels, or between muscle bundles in connective sheaths less pain than the IV route Aseptic conditions are needed Mild irritants, depot injections, soluble substances, Painful and may cause abscess at the site of and suspensions can be given by this route, as injection. particles pose no risk of blocking capillaries like the intravenous route. Convenient route in administering drugs in animals Self-administration is not possible that are difficult to restrain Released drug is transported by the lymph before Injury to the nerves leading to paresis of the muscle it enters the circulation. that the nerve supplies  Parenteral: Subcutaneous (SC)  Subcutaneous (SC) injection is similar to intramuscular administration of drugs- Volumes administered are restricted (human 1.5–3.5 mL to minimize pain at the injection site).  Medication given this way is usually absorbed more slowly than if injected into a vein, sometimes over a period of 24 hours.  Examples of drug: Insulin, epinephrine, drugs for nausea and vomiting (Reglan) and dexamethasone, some vaccine and allergy shots.  Parenteral: Subcutaneous (SC) Advantages Disadvantages good route of administration especially in skin Suitable for nonirritant drugs only infections safer than intravenous and intramuscular routes Drug absorption is slow; hence it is not suitable for emergency Self-administration is possible as the injection need Only small volumes can be administered not be penetrated deeply Larger number of possible injection sites for Degradation at injection site multiple dosing Low risk of systemic infection Retention at injection site can lead to local adverse reactions Least painful of the parenteral administration routes  Inhalation route  offers the best potential for optimal delivery to the lungs with reduction in systemic side effects.  Drugs for inhalation require a dedicated device for delivery.  Three main types are available: dry-powder inhalers (DPI), pressurized metered-dose inhalers (pMDI), and nebulizers.  Delivery of drug to the airway mucosa by inhalation therapy depends on many factors: pattern of breathing, the geometry of lungs and airways (often altered in patients with lung disease), and the size of the aerosol particles.  Inhalation route Advantages Disadvantages Fewer systemic side effects Drug irritation and toxicity Direct delivery of the medication to the affected Most addictive route (drug can enter the brain area in the desired form is possible quickly) Protein-containing solutions can be nebulized. Some patients may have difficulty using inhalers. Effective for patients with respiratory problems Drug solubility issues can be solved by using lipid, water, or lipid/water emulsions as drug carriers (viscous drug formulations can also be nebulized)  Transdermal  Technique that provides drug absorption via the skin principally by diffusion, for local internal and systemic effects.  The efficacy of transdermal delivery is equivalent to that of a continuous IV infusion  Chiefly take the form of textile bandage, textile sheet, compression therapy hosiery, electrospinning mats and ion-exchange fibers  Examples: estradiol, fentanyl, lidocaine and testosterone; combination patches containing more than one drug for contraception and hormone replacement; and iontophoretic and ultrasonic delivery systems for analgesia Other routes Drug permeation  Drug permeation  Permeation: is the movement of drug molecules in to and within the biological environment. It involves several processes of drug transport across the cell membranes.  To reach their site of action they have to permeate from one compartment to another by crossing the different barriers.  So, the drugs have to cross the cell membranes.  Drug's permeability across biological membranes is a key factor that influences the absorption and distribution  Drugs may cross cell membranes by passive diffusion, facilitated passive diffusion, active transport, and pinocytosis.  Drug's physicochemical properties (such as size and lipophilicity), as well as membrane-based efflux mechanisms, can lead to poor permeability.  Blood Brain Barrier (BBB)  BBB is a dynamic structure that functions as a gatekeeper, protecting the brain against invading organisms and unwanted substances.  Imposes obstruction for delivery of large number of drugs, including antibiotics, antineoplastic agents, and neuropeptides, to pass through the endothelial capillaries to brain  Delivery of many of the drug types is very difficult to carry them into the brain because of fat insoluble nature.  Example: fat-soluble substances dissolve in the cell membrane and cross the barrier (e.g., alcohol, nicotine and caffeine). Water-soluble substances such as penicillin have difficulty in getting through.  Blood capillaries and renal glomerular membrane  Blood vessel wall allow the flow of small molecules (drugs, nutrients) or even whole cells (lymphocytes) in and out of the vessel.  Capillary walls are permeable- Lipid soluble drugs pass through very rapidly. Water soluble compounds penetrate more slowly at a rate more dependent on their size.  Low molecular weight drugs pass through by simple diffusion. For bigger compounds the transfer is slow.  Permeability is greatly increased in the renal capillaries by pores in the membrane of the endothelial cells, and in specialized hepatic capillaries (sinusoids).  Renal tubules  Renal drug transporters, expressed in the basolateral and apical membrane of renal proximal tubules - important role in tubular secretion and reabsorption of drug molecules in the kidney.  Membranes are relatively non-porous – only lipid compounds or non-ionised species (dependent of pH and pKa) are reabsorbed. How do the drug cross the cell membranes? There are only a few ways for a drug to make its way through a living organism: Paracellular diffusion (aqueous) Intracellular diffusion (lipid) Membrane diffusion (usually, aqueous) Active transport / facilitated diffusion  Lipid diffusion/ Passive diffusion  Mechanism by which most drugs cross cell membranes.  Solute will pass from the side where it is more concentrated to the side where it is less concentrated.  The un-ionized form is usually lipid soluble (lipophilic) and diffuses readily across cell membranes.  The ionized form has low lipid solubility (but high water solubility—ie, hydrophilic) and high electrical resistance  cannot penetrate cell membranes easily.  influenced by physical–chemical properties 1) concentration gradient 2) the membrane surface area 3) substance‐specific diffusion coefficient.  The lipophilicity of an organic compound can be described by a partition coefficient, log P  Lipophilicity influences permeability; potency; selectivity; absorption, distribution, metabolism, and excretion (ADME) properties; and toxicity.  Carrier mediated transport  Energy-dependent pathway generally used by small hydrophilic molecules (monosaccharides, amino acids, and peptides)  Carrier-mediated transport can be divided into two types: Passive and active  Mostly for endogenous substrates, but some also transports xenobiotics (e.g. anticancer 5-fluorouracil)  Solute Carrier transport (SLC)  SLC transporters are facilitated or secondary active transporters that translocate soluble molecules across cellular membranes  They facilitate the passive diffusion of specific small molecules, function as exchangers, or utilize ion gradients to drive flow against gradients.  SLCs have an essential role in the absorption, distribution, metabolism, and elimination (ADME) of therapeutic drugs  Example, the peptide transporter PepT1 (SLC15A1) regulates the intestinal absorption of peptide-like drugs, such as β- lactam antibiotics (cefadroxil) and antiviral drugs (valacyclovir) across the cell membrane  Active transport  1) Primary: ATP-coupled – generate energy by themselves (e.g ATP hydrolysis)  2) Secondary: driven by ion gradients – utilize energy stored in voltage and ion gradients generated by primary active transport (e.g Na/K-ATPase).  Symporters (co-transporters)  Antiporters (exchanger)  Mostly occurs against concentration gradients  Saturation can occur  Involves certain pathways such as choline, uracil  Aqueous diffusion/Pinocytosis Aqueous diffusion  Water soluble substances pass through aqueous “pores” (aquaporins) in cell membranes at a rate according to Ficks' Law.  Allows free passage of small water soluble molecules.  No energy and no carrier (e.g urea, Li+, alcohol) Pinocytosis  form of endocytosis involving fluids containing many solutes.  Occurs in cells lining the small intestine and is used primarily for absorption of fat droplets.  Involves a considerable investment of cellular energy in the form of ATP  Examples: Ions, sugar molecules and proteins References