FAR 381. Learning opportunities 1 -10 PDF

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Summary

General principlesPharmacologyStudy of the effects of drugs on the function of organisms  Breakdown of term  “Pharmakon” = remedy/poison  “-logia” = study of  Pharmacology includes  Naturally derived medicines  Synthetic compounds Bio-engineered moleculesPharmacological treatment Disease man...

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General principles

Pharmacology Study of the effects of drugs on the function of organisms  Breakdown of term  “Pharmakon” = remedy/poison  “-logia” = study of  Pharmacology includes  Naturally derived medicines  Synthetic compounds  Bio-engineered molecules

Pharmacological treatment 

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Disease management aims to restore homeostasis in diseased states o Physical therapy o Psychotherapy o Surgery o Medicines Disease management often requires biological interactions o Ensures alleviation of a disease’s specific characteristics

Drugs and medicines 

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Drug o

Chemical substance of known structure, other than a nutrient or essential ingredient, which produces a biological effect in living organisms o Must be administered, not released endogenously o Medicines, research tools or recreational (illicit drugs) Medicine o Chemical preparation of an agent administered with the intention of producing a therapeutic effect Various types to accommodate bioactivity and use o Small molecules (e.g., adrenaline or atropine)  Chemically synthesized or extracted from source o Biopharmaceuticals (e.g., monoclonal antibodies)  Large proteins produced through biotechnology o Gases (e.g., sevoflurane or halothane)  Volatile substances that make ideal anaesthetics Generic name/active compound o Chemical name or identification of compound (e.g., paracetamol) Trade name o Name of medicine given by manufacturer (e.g., panado) Generic drugs o Don’t confuse with a generic name!!!

Generic drugs Copies of innovator/originator drug (original), with the same pharmacological characteristics 

Myths o Poorly made  A few manufacturing companies have poor GMP  Strictly regulated and dealt with legally o Impure chemicals used o Results in treatment failure o Not regulated

Different Extensive animal/human research More expensive

Different Less animal/human research Less expensive (20-80%) Different appearance Different inactive ingredients (e.g., flavourings, preservatives)

Original

The copy

Same Active ingredient Dosage form and strength Route of administration Bioequivalence (same rate and extent of absorption)

Drug discovery  o o o o o

Several sources Natural (e.g., microorganisms, aquatic organisms, plants) Serendipitous discovery Chemical synthesis In silico design In silico fishing

Drug development  Pre-clinical assessment (±4 years) o Drugs undergo extensive in vitro and in vivo testing o Potential drugs are further subjected to clinical trials  o o o o o

Clinical trials (±12 years in total, high failure rate) Phase I: safety in humans (10 –20 healthy volunteers) Phase II: efficacy in humans (100 –200 patients) Phase III: confirmation of phase I and II in larger population group (> 1000 patients) Approval: granted based on safety and efficacy Phase IV: post-marketing phase

Medicinal formulations  o o o o o o o o o o

Various forms exist depending on route or use Capsules Tablets Creams/ointments/gels Emulsions Solutions (eye drops, injections) Powders Patches Suppositories Syrups Gases

Compliance  Patient’s adherence to a recommended treatment  Non-compliance may lead to treatment failure Contraindication  An indication where drug usage should be avoided (illness, characteristic or interactions)

Drug-drug or drug-food interactions  Activity altered due to interaction with drugs or food 

Typically leads to adverse effects or treatment failure

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May be beneficial in certain circumstances

Side effect  Any unwanted effects that a drug may elicit, but not necessarily harmful 

May often be beneficial in another circumstance

Toxicity/adverse effects  Detrimental effects to the patient

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May result in reduced quality of life or death

Routes of administration

ocular aural Nasal inhalation Oral Sub-lingual Buccal inhalation Topical transdermal

Rectal Vaginal

Injectables Subcutaneous Intramuscular Intravenous Intradermal

Oral administration Most used, where formulation is swallowed from oral cavity o GIT absorption  Drug needs to dissolve in GIT  Liquids often easier absorbed due to soluble nature  Subjected to harsh environmental factors (e.g., acid, enzymes, first-pass effect)  Degrades or converts compounds  Must pass through biological membranes for absorption  Small intestines are the primary site of absorption due to absorptive surface (villi and microvilli) o

Factors affecting GIT absorption  Gastrointestinal motility  Affects how long drug stays in GIT lumen  Absorption typically better the sooner a drug reaches the small intestines

 Splanchnic blood flow  Rich blood flow from GIT lumen increases absorption  Food and drug interactions  Alters drug absorption through interactions  Solid meals delay gastric emptying 

Particle size, formulation, and physicochemical factors

 Absorption profile dependent on drug characteristics (e.g., solubility, charge, size, chemistry)  Formulation may offer time delay or protection

Advantages  Convenient and cheap  Typically, higher compliance rates  Comfortable preparation for most individuals  Various formulations available Disadvantages  Needs to survive stomach acidity, digestive enzymes, and bacterial enzymes (i.e., first-pass effect)  Subject to food interactions  Inappropriate for unconscious, non-compliant or vomiting patients

Sublingual administration Absorption directly from the oral cavity by placement under tongue Advantages over oral administration  Rapidly absorbed due to blood supply, thus quick onset  Useful for drugs unstable at gastric pH or GIT enzyme systems  Bypasses first-pass effect Disadvantages over oral administration  May cause oral irritation

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Forms  o  o  o

Saliva-soluble drugs only

Soluble tablets Tablets dissolve with little residue in oral cavity Drops or spray Concentrated solution dripped or sprayed under tongue Lozenge Metred and patient-controlled rate of dissolution

Administration to epithelium Administration of solubilised drugs to different epithelial surfaces of the body  Cutaneous: epithelium of the skin  Nasal: mucosa overlying nasal-associated lymphoid tissue  Eye: epithelium of the conjunctival sac  Lungs: inhalation to alveoli Administered to skin for localised effect or trans-dermal absorption to systemic circulation The skin barrier  Hydrophobic (water-insoluble) barrier

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Drugs must have moderate lipophilicity (fat-soluble) to cross cells either transcellularly or intercellularly Highly hydrophilic drugs have low permeation, and thus remain on the surface Can use permeability enhancers (e.g., DMSO)

Topical cutaneous administration Preparation applied to skin and works locally Advantages  Ease of use  Little systemic absorption occurs due to intact skin and dermis, thus low risk of systemic side effects Disadvantages  Accurate dose cannot be specified  Skin irritation or discomfort of use  Lipophilic preparations may enter circulation Transdermal cutaneous administration Preparation on patch/implant allows for transfer of drug into systemic circulation Advantages  Controlled state of drug delivery  Bypasses first-pass effect Disadvantages  Too slow for emergencies  Skin irritation or discomfort of use  Affected by condition of skin and circulation Nasal administration Preparation applied to nasal mucosa for localised effects in the nose or sinuses Advantages

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Fast relief of nasal symptoms; less systemic effects

Disadvantages if used chronically

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Rebound congestion

Forms

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Nasal sprays or drops

Ocular administration Preparation applied to conjunctiva for localised effects within the eye Advantages

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Produces less systemic effects

Disadvantages

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May be unpleasant to the eye Cloudy vision

Forms

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Eye drops or lotion

Pulmonary inhalation administration Gaseous drug inhaled into lungs for localised effect Advantages

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Rapid adjustment to plasma concentration Localised to lungs with less systemic side effects

Disadvantages  Unpleasant taste or oral irritation Forms  Metered-dose inhalers or nebulizers

Rectal administration Preparation inserted into rectum for localised or systemic effect Advantages over oral administration  Faster onset and higher bioavailability  Bypasses two-thirds of first pass effect  Can be used when patient nauseous/vomiting  Alternative to oral administration in home setting Disadvantages  Unreliable absorptive profile, and uncomfortable Forms  o  o  o

Suppository Drug delivery system into the rectum Enema Liquid-drug delivery system into the rectum and/or colon Rectal catheter Placed into rectum for continuous use

Injectable routes Preparation injected into various areas for rapid distribution of drug to site required o Intramuscular – 90° angle o Subcutaneous – 45° angle o Intravenous – 35° angle

Intravenous Preparation injected directly into systemic circulation Advantages  Fastest, best control and most certain route  Bypasses first-pass effect Disadvantages  Invasive and uncomfortable procedure  Scarring of veins  Drug must be hydrophilic Specific indications  Rapid action required or emergency procedure  Drug causes tissue irritation  Drug has poor absorption profile Subcutaneous Preparation injected directly under the skin Advantages  Bypasses first-pass effect  Can be given by patient  Complete absorption Disadvantages  Pain and tissue damage  Slow absorption route Intramuscular Preparation injected into the muscle Advantages  Bypasses first-pass effect  High vascularity allows for quicker absorption  Depot formulations for non-compliant or out-patients  Sometimes used in emergencies at home Disadvantages  Pain and tissue damage, requires training/trained staff  Injection site affects absorption and may be erratic Subcutaneous and intramuscular Absorption limited by  Diffusion through tissue  Removal by local blood flow Methods for increasing absorption  Hyaluronidase breaks down extracellular matrix Methods for delaying absorption

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Poorly soluble or solid forms injected Vasoconstrictors at site of injection

Pharmacokinetics Study of time course of drug concentration in the body “What the body does to the drug” Aspects of drug input and output (LADMET)  Absorption  Distribution  Metabolism elimination  Excretion

Crete events that occur simultaneously Absorption: movement of the drug from the site of administration to the blood circulation Distribution: diffusion of transport of drug from intravascular space to extravascular space Metabolism: chemical conversion or transformation of drugs into compounds for easier elimination Excretion: elimination of unchanged drug or metabolite from body via excretory system

ABSORPTION

Movement of solubilised drug from administration site into systemic circulation, across biological membranes Absorption affects … of action  Onset, duration, and intensity Transport classified according to energy dependency into two major types  Passive (does not require energy)  Active (requires energy) Passive transport  Drug molecule penetrates lipid bilayer o Along concentration gradient o No cellular energy used  Along concentration gradient o Movement from high to low concentration  Different subtypes o Simple diffusion Most frequently used by drugs o Facilitated diffusion o Filtration and osmosis o Bulk flow Simple diffusion  Direct movement of drug through semi-permeable membrane until equilibrium reached o Along concentration gradient o No cellular energy used  Physicochemical factors affecting simple diffusion o Solubility  Lipophilic molecules pass through lipid bilayers more easily than hydrophilic molecules  Lipophilic molecules  Dissolve easily in lipids  Tend to cross lipid bilayers freely  Generally higher permeation into cells  Needs to dissolve slightly in water to be absorbed  Otherwise, cannot pass through hydrophilic heads  Extremely lipophilic molecules  Cannot dissolve in aqueous compartments  Reduced absorption  Hydrophilic molecules  Dissolve easily in water due to hydrogen bonds  Cannot dissolve in lipophilic compartments  Does not pass-through lipophilic tails  Reduced absorption o Size  Small, low-molecular weight molecules pass through lipid bilayer more easily than larger ones o Ionisation

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Ionisation state alter solubility of compounds Weak acids and bases ionise at different pH ranges Unionised/uncharged molecules  More lipophilic  Higher membrane permeability Ionised/charged molecules  Positive or negative charge  Tend to form hydrogen bonds  Less lipophilic  Low membrane permeability

Ionisation is dependent on Ph of environment pKa of drug and status as weak acid or base

pKa - pH where drug is equally ionised and unionised weak acids – ionised if pKa < pH weak bases – ionised if pKa > pH

Unionised molecules  Move across membranes to other systems  Action (if possible) more dispersed

Rule of thumb! Weak acids are typically more unionised in acidic regions Weak bases are typically more unionised in alkaline regions

 Ph partitioning effect and cellular retention o Important for drugs that need to accumulate in specific location to exert mechanism of action (e.g., local anaesthetics) Ionised molecules  Get retained within their environment  Action exerted at that site Although pH partitioning is important, it is not the major determinant of GIT absorption  Small intestines have the best absorptive surface o Stomach’s absorptive surface small relative to intestines  Not ideal for absorption o Intestinal absorptive surface higher because of villi and microvilli

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Most of GIT absorption occurs in small intestines regardless of ionisation state

Facilitated diffusion  Drug molecule transported across bilayer o Along concentration gradient o No cellular energy used o Facilitators (carriers/transporters) required Active transport  Drug molecule penetrates lipid bilayer o Against concentration gradient o Cellular energy (ATP) used o Facilitators (carriers/transporters) required  Against concentration gradient o Movement from low to high concentration  Two types classified by usage of cellular energy o Primary (direct usage of ATP)  ATP binds to receptor  ATP converted to ADP, release energy for transport  ADP free o Secondary (indirect usage of ATP)  Transport occurs via electrochemical gradient established by primary transport (if ions transported)  Molecule transported along with ions against gradient Specialised transport (active and facilitated)  Specific towards molecule o Only specific structures recognised  Saturable system o Finite amount of facilitators o Transported if facilitators available o If nonavailable, no transport occurs until available, creating bottleneck  Types of drugs transported o Non-diffusible or hydrophilic

Bioavailability Fraction of administered drug that reaches systemic circulation unchanged Relative comparison – IV always 100% bioavailable Bioavailability (%) = x 100

Factors affecting bioavailability

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All ADME processes may alter drug’s presence

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Bioavailability does not infer the strength of a drug o Only measures amount of unchanged drug available after absorption into the systemic compartment, not its activity o Pro-drugs only active once metabolised or activated, so needs to be changed to be therapeutically useful o Importance of bioavailability  Dosage needs to be effective  Changes that may occur if bioavailability altered due to disease or interactions

DISTRIBUTION Movement of drug from systemic circulation throughout the body to, ideally, the site(s) of action 

Affected by the physicochemical properties of the drug o Determines extent of distribution o Widespread, organ-specific or localised o Spreads to major fluid compartments of the body  Plasma (circulatory fluid)  Interstitial fluid (fluid between cells)  Intracellular fluid (fluid in cells) o Circulatory system is the first compartment to which distribution occurs

Transport in circulatory system Drugs dissolves in plasma and/or binds to plasma proteins 

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Plasma proteins in blood o Albumin o Lipoproteins o Acid glycoprotein o Alpha, beta, and gamma-globulin Function of albumin o Maintains colloidal osmotic pressure of blood o Carrier for hydrophobic molecules o Drug/molecule binding Hydrophilic drug transported freely in plasma (can dissolve)

Lipophilic drug dissolves to lower degree in plasma (until aqueous compartment saturated) Free fraction available in plasma

Undissolved drug binds to hydrophobic pockets of plasma protein as bound fraction

Hydrophobic pockets of plasma protein unbound (empty) action pharmacologically active Elicits biological effect Transported across cellular systems Gets metabolised Gets excreted

Bound fraction gets released as free fraction is secreted (replaces free fraction)

armacologically inert t because cannot fit into g targets Does not get transported Does not get metabolised Is not excreted and not filtered by kidneys Systematically released as free fraction cleared (sustained release)

Clinical implications of plasma protein binding  If highly bound, free fraction is decreased  If plasma proteins saturated or depleted, free fraction is increased  Drug displacement may occur during drug interaction

Drug-drug interaction Drugs with higher affinity for plasma proteins will eject lower affinity drugs, increasing free fraction

Factors that affect plasma protein binding  Plasma protein concentration o Amount available to be bound o Can be saturated if drug concentration high enough  Free drug concentration o Influences release of bound drug to maintain equilibrium  Affinity for binding sites o Influences how easily drugs bind to plasma proteins o Drugs with high affinity may displace low affinity drugs

Important! High plasma protein binding does not infer poor activity. Warfarin is >97% plasma protein bound, so only 90% of steady state concentration (Css) achieved after fourto-five t1/2 o Time-course of drug elimination  If drug administration stopped,...