de gregorio

Pharmacokinetics

• Active chemical substances can produce a physiological response when interacting with an organism
• Pharmaceutical formulation consists of the active component plus any added excipients
• Xenobiotics are foreign compounds to which organisms are exposed
• Chemical drug names include 7-chloro-1,3-dihydro...
• Generic drug names include diazepam
• Brand drug names include valium
• Drug forms include solid pills, tablets, powders and suppositories
• Drug forms also include liquid solutions, lotions, syrups, and emulsions
• Factors affecting drug response are age, mass, sex, pathology, and timing of administration

Full or Empty Stomach and Drug Response

• Drugs are better absorbed on an empty stomach but it can irritate the stomach
• Drugs taken on a full stomach neutralize the compound but interact with certain foods, which can prevent absorption
• To take drugs before meals, administer 30 minutes before
• To take drugs after meals, administer 30 minutes after
• To take drugs away from meals, administer 4-6 hours after

Pharmacokinetics: ADME

• Absorption is the movement of a drug from its site of administration into the bloodstream
• Distribution is the movement of a drug from the bloodstream into tissues
• Metabolism is the process by which the body breaks down drugs
• Excretion is the elimination of drugs from the body
• Systemic administration determines the routes of drug administration
• Determining the maximum safe dose of a drug optimizes effectiveness

Routes of Administration

• Systemic routes include enteral, parenteral and transdermal
• Local routes include skin topical, intra-arterial, and subcutaneous

Systemic Routes

• Enteral includes oral, sublingual and rectal
• Oral route advantages include pain-free, easy to take, and cheap
• Oral route disadvantages include not so efficient, first-pass effect, irritation, slow, and unpleasant taste
• Sublingual route advantages include rapidly absorbed by highly vascularized mucosa, cheap, and no first-pass effect
• Sublingual route disadvantages include bitter taste and irritation to the oral mucosa
• Buccal route advantages include avoiding the first-pass effect, quick onset, and sterile
• Buccal route disadvantages include loss in case of swallowing, only a small amount absorbed, and irritation of gum
• Rectal route advantages include use in children, limited first-pass effect, and high concentrations
• Rectal route disadvantages include slow absorption and irritation of mucosa

Parental Routes

• Parental routes bypass the alimentary canal
• Intravenous advantages include use in emergencies, 100% bioavailability, large quantities, no vomiting or diarrhea, and rapid delivery
• Intravenous disadvantages include uncomfortable administration, risk of thromboembolism, infections, pain, potential air embolism, and it's expensive
• Intramuscular advantages include uniform absorption and it's fast
• Intramuscular disadvantages include local pain, limited volume (10 mL), risk of infections, and risk of damaging nerves
• Subcutaneous advantages include slow absorption, prolonged action, and implant capsules
• It also includes a controlled release of medication administration

Determining Therapeutic Route

• Consider physical and chemical properties
• Determine the site of desired action (topic)
• Evaluate the rate and extent of absorption and the rapidity of response
• Note the condition of patient (non-responsive -> injection)
• Intravenous administration is more precise than oral administration

Bioavailability

• Bioavailability is the fraction of a drug that reaches the systemic circulation after a specific route of administration
• 100% bioavailability is intravenous

Assessing Bioavailability

• Pharmacokinetics methods include blood analysis and excretion data
• Pharmacodynamics methods include acute pharmacological response
• Cmax is the max level of drug concentration in bloodstream after administration
• Tmax is the time taken from drug to reach its max plasma concentration
• Two drugs are bioequivalent when they show comparable bioavailability and similar times to achieve peak blood concentrations, ensuring an alternative version of a drug is as safe and effective as the original

Requirements for Equivalent Drugs

• Contain the same active ingredient
• Share the same pharmaceutical form
• Route of administration
• Unit dosage
• Similar absorption characteristics
• 20% lower cost than the original

Pharmaceutical and Therapeutic Equivalence

• Pharmaceutical equivalence: drugs with the same dosage form, identical active ingredients, and same route of administration
• Therapeutic equivalence: drugs that are pharmaceutically equivalent and similar clinical effect

Action of Drugs

• Some drugs induces pharmacological effects but have a therapeutic effect
• If a drug interacts with a receptor activating it, it has a pharmacological effect (agonist -> ++ effect)
• If a drug interacts with a receptor blocking it, it has a therapeutic effect (antagonists -> + effect)
• First-pass effect: the greater the FPE, the less the agent will reach the systemic circulation when administered orally, reducing the efficacy of the drug

Absorption

• Absorption is the process of movement of unchanged drug from the site of administration to the systemic circulation
• Effectiveness is a drug's assessment by its concentration at site of action and it's difficult to measure

Oral Absorption

• Factors affecting oral absorption include physiological factors such as the nature of cell membrane
• Also includes, physical-chemical factors such as nature of the drug
• Includes formulation factors such as clothes wrapping the drug
• Passport control is the cell membrane

Mechanisms of Drug Absorption

• Passive diffusion is from high to low concentration, extremely lipophilic drugs and no ATP needed
• Greater the area and lesser the thickness of the membrane, the faster the diffusion
• Sink condition is the concentration of drug at absorption site is greater than its concentration in the plasma
• It implies that a drug can have a lesser or a higher volume of distribution
• For high volume, a drug is less concentrated in the plasma and more in the body
• Amount of drug in the plasma determines the bioavailability
• For example, between a drug with a volume of distribution of 200 mL and one of 1L, the drug which will stay more in the body and less in the plasma (so more effective) is the one with the volume of distribution of 1L
• Pore transport: involves proteins with a canal, driving force is the osmotic pressure difference across the membrane
• Absorption of water, gaseous channels, low molecular weight/size and water-soluble drugs

Further Mechanisms of Drug Absorption

• Ion-pair transport: absorption of compounds which ionize at pH values (passive)
• Carrier-mediated transport: involves a carrier which reversibly binds to solute
• Facilitated diffusion: no ATP needed, the driving force is the concentration gradient aided by integral membrane proteins
• Absorption of simple sugars, steroids, amino acids, pyrimidines
• Active transport: requires ATP, from low to a high concentrated area
• Primary uniport: direct ATP requirement, only 1 ion in only 1 direction
• Secondary antiport and symport: the energy used in transporting an ion which aids the transport of another ion (coupled)
• Symport is the same direction, antiport is both directions

Endocytosis

• Endocytosis involves engulfing molecules; vesicular transport
• Phagocytosis engulfs microbes or very small molecules
• Transcytosis engulfs very big molecules like insulin
• Pinocytosis engulfs liquids or very small molecules, it's non-specific, ATP needed (oil soluble vitamins, uptake of nutrients)

Rate of Absorption

• Factors affecting the rate of absorption include drugs solubility, dissolution rate
• The solubility of a drug in the GI tract fluid is fundamental the drug must be solubilized there and must release its particles
• A drug must be lipophilic in order to be absorbed, since we also need a lipophilic drug in order to be absorbed
• The higher the surface area, the higher the abs. and diss. rate
• Partition coefficient: the ratio of unionized drug distributed between organic phase and aqueous phase at equilibrium
• A drug with a high partition coefficient will be more lipophilic for any value higher than 1
• The partition of a drug molecule between two phases can be quantified by a partition coefficient

Factors Related to a Patient

• Formulation factors include disintegration time, manufacturing variables, dosage form and stability of the drug
• Patient related factors include GI tract pH, gastritis, increased acid production, and rise in pH for altered absorption
• They also include age for infants developing biological systems
• As well as blood flow through the GI tract
• Sometimes a full stomach is better for NSAIDs
• Intestinal transit is the residence time of a drug in the small intestine and its delay is wanted to prolong the effect of the drug

Distribution

• Distribution is the reversible transfer of drugs between one compartment and another, which is between the blood and tissues
• Passive distribution: the driving force is the concentration gradient between blood and extravascular tissue which is not uniform throughout the body

Steps of Distribution

• These include a drug free in the EC fluid
• Followed by the drug passes through the capillary endothelium
• And ends with a drugs acts on tissues which is reversible
• Factors affecting distribution include tissue permeability, physicochemical properties, molecular size, pKa, and solubility in water and oil
• Physiological barriers include simple capillary endothelial barrier and simple cell membrane barrier

Physiological Barriers

• The blood testis barrier (BTB): tight junctions
• Only lipid soluble non-ionized compounds can enter such as volatile anesthetics and narcotic analgesic
• Includes case of inflammation leads to permeability changes
• The blood-CSF barrier involves tight junctions and the choroid plexus
• Only lipid soluble non-ionized compounds can enter
• The blood-placental barrier separates maternal and fetal blood
• Only drugs <1000 Daltons and moderate lipophilicity can pass through passive diffusion, active transport, and pinocytosis
• Including ethanol, sulfonamides, gaseous anesthetics, steroids, narcotics, and anticonvulsants

Cellular Reservoirs, Metabolism and Albumin

• Cellular reservoirs: forms when drugs get stuck in the tissues (depending on their permeability and lipophilicity)
• Thanks to them, the effect of the drug can be longer and more efficient
• But they're also toxic if the reservoir forms in a non-target tissue
• For example, fat and plasma drugs bind to plasma proteins (albumin), but the problem is that they won't distribute equally
• Albumin has 4 binding sites
• These include Warfarin, diazepam, digitoxin and tamoxifen
• Multiple drugs can bind to albumin which creates competition
• Apparent volume of distribution is the total space available in the body to contain the administered amount of drug
• It's not a realistic volume
• Drugs that are more lipid soluble will cross the cell membrane more easily which will be absorbed more and effectively

Drug Redistribution and Metabolism

• Highly lipophilic substances initially get distributed to more vascularized organs, and later to the less vascularized ones
• Metabolism transforms a drug into a different shape, so it can be more suitably eliminated
• A drug must display a good balance between hydrophilicity and lipophilicity
• High lipophilic drug well absorbed, meaning it is harder to solubilize
• It's rare that drugs are excreted in an unchanged form
• The metabolism is essential to make the drug more hydrophilic (more polar)
• However, even after metabolism, some metabolites can still display biological activity or potential toxic activity

Phases of Metabolism

• 1. Functionalization: convert the original drug into a more polar metabolite by introducing or unmasking a functional group through the ER such as oxidation, reduction reactions, and hydroxylation
• It can generate more polar compounds or toxic metabolites
• For example, acetaminophen which is a paracetamol can create a quinone imine that causes necrosis of liver cells
• Pro-drugs are pharmacologically inactive compounds, which are converted into an active metabolite only through Phase 1
• Advantages include increased absorption, the active has an unpleasant taste, decreased toxicity, decreased metabolic in activation, increased chemical stability, and prolonged or shortened action
• 2. Conjugation: establishes covalent linkages between the functional group on the initial compound and an endogenous substrate through the cytosol
• It includes glutathione conjugation, acetylation, and methylation
• After Phase 2 the drug is ready to be excreted since it has become water-soluble which is also deactivation of the toxic metabolite
• For example, Paracetamol turns into a para-amino benzoquinone imine
• Overdose is max 3g in 24h which is when Glutathione is notable to detoxify
• Liver toxicity solutions involve the administration of exogenous Glutathione and the administration of acetylcysteine

Elimination

• Hoffman elimination: sometimes it's the only option for few drugs, where the drug inactivates spontaneously, such as atracurium which is used in anesthesia
• Isoforms: drugs like warfarin occur as optical isomers, one of which may be metabolized faster

Factors Effecting Metabolism

• Environmental determinants can induce the induction or the inhibition of the reaction
• Enzyme induction is thanks to the exposure to certain substrates
• This leads to acceleration of biotransformation and reduction of unmetabolized drug
• Examples: anticonvulsant drugs such as phenobarbital, carbamazepine
• Consequences: increased rate of metabolism, which leads to decrease in drug plasma concentration and reduced bioavailability with increase in drug effects and toxicity
• These require increasing the dose to maintain effective plasma concentrations
• Tolerance is when you have to enhance the dose to have the same effect and can be caused by auto-induction
• An antidrug is an active synthetic derivative designed to undergo biotransformation to the excretable inactive form upon entry into systemic circulation
• Age, sex and genetic variations also affect a drug's action
• Locally administered drug is deactivated immediately after entering the bloodstream

Excretion

• Drugs and metabolites are irreversibly transferred on the external environment
• Conversion of non-polar compounds into polar lipid-insoluble ones
• Elimination: removal of indigested (unchanged) material from the body non-renal
• Renal excretion: gentamycin can only have renal excretion
• Criteria for renal excretion: the drug must be more hydrophilic, non-volatile, under 500 Da, and metabolized slowly

Renal Excretion

• Sequence of excretion: glomerular filtration, tubular resorption, and tubular secretion
• Glomerular filtration: extremely polar compounds, which are non-discriminant of a protein-free plasma
• It's also unidirectional and non-selective process thanks to the hydrostatic force of blood in capillaries
• Rate of filtration is 120-130 mL/min, measured by creatinine
• Active tubular secretion: not so polar compounds
• It's the selective movement of non-filtered substances from the peritubular capillaries into the tubular lumen mainly in PCT and act, mediated by carriers
• Requires energy since it goes against the concentration gradient
• There are two kinds of mechanisms for this
• One for organic acids/anions (penicilline, salicylates - uric acid)
• One for organic bases/cations (morphine, hexamethonium - catecholamines)
• Not affected by the pH, measured by paraamino-hippuric acid or by the lodopyracet

Tubular Resorption

• Tubular resorption: selective movement of filtered substances from the tubular lumen into peritubular capillaries
• Only non-enough lipophilic compounds all along the renal tubule
• A drug that is completely reabsorbed has a clearance of zero
• Resorption increases the half-life of the drug
• There are two kinds of mechanisms for this: active and passive
• Factors affecting tubular resorption include lipophilicity of the drug
• As well the pH of urine, which depends on diet, drug intake, and pathophysiologhy of patient
• Urine flow rate can be forced with large fluid intake, mannitol or diuretics
• Typically used to treat intoxicated people
• Clearance: a hypothetical volume of body fluids containing the drug, from which the drug is removed completely in a specific period of time
• Renal clearance volume of blood that is completely cleared of the unchanged drug by the kidney per unit time
• The clearance is the ability of our kidneys to clear out blood from all substances and can be measured by a ratio

More Clearance Factors

• The total amount of drug excreted by kidneys into urine can be measured, being constantly released by the body
• Non-renal excretion: biliary - liver factors influencing- physicochemical properties of drug (weight and polarity), nature of biotransformation process, sex, species, disease state, drug interactions
• Its efficacy is tested by sucpnobromophtalein, secreted within 30 min if not: malfunction biliary clearance
• Pulmonary excretion: factors influencing- rate of respiration, solubility of the volatile substances, pulmonary blood flow
• Used for general anesthetics
• Salivary excretion: passive diffusion depending on saliva pH (5.8-8.4) unionized, lipid soluble and soluble drugs are excreted
• Mammary excretion: passive process depending on milk pH (6.4-7.6) weakly basic drugs concentrate more in milk (atropine, antihistaminics)
• Skin excretion: passive excretion (sulfadiazine, benzoic acid)
• Intestinal excretion: through feces, in case of renal failure via intestinal
• Genital excretion

Kinematics of Elimination

• Zero order (linear): constant amount of drug elimination per unit time, regardless the plasma concentration of the drug
• First order (exponential): Constant fraction of drug elimination per unit time, directly proportional to plasma conc. of drug but non-linear elimination
• Elimination approaches saturation over the therapeutic range where plasma concentration increases disproportionately