Flashcards
aug 24
Flashcards do conjunto (102)
- 1Drug DistributionOnce the drug is in the systemic circulation, they are carried by the blood to the target site (usually the n receptor) for drug action and to other tissues as well, where side eects or adverse reactions can occur.
Drug molecules are distributed to organs of elimination, such as the liver and kidney, and to other tissues, such as the brain, skin, and muscle. - 2drugs can move thru membrane withactive transport
passive tranport (faciltated and passive) - 3passive tranport2 types: facilitated difussion and passive diffusion
NO external energy is utilized. - 4active transportThe transport of certain substances across the biological membranes requires energy to transport against the concentration gradient (i.e. low to high concentration).
Some drug molecules structurally resemble certain endogenous substances that are carried across biological membranes via specialized carrier proteins. - 5faciliatted diffsionlarge water soulable polar molecules
transport proteins/carrier proteins used - 6passIVE diffusionsmall lipid, non polar molecules
from high conc to low conce - 7major driving forceconcentration gradient is one of the major driving force that compels drug molecules
to cross biological membranes (i.e. from a higher concentration to a lower concentration). - 8Whatis ion trapping?At equilibrium, an acidic
drug will accumulate on themore basic side of the membrane and a basic drug
more on the more acidic
side. - 9OR AL (EN TER AL)Most preferred route for administration
Surface area of stomach < intestine
Weak acids absorb better than weak bases in stomach
Small Intestine: Large surface area, High blood perfusion, High capacity for absorption
Drugs can be subjected to rst pass metabolism that alters bioavailability
Peptide based drugs (e.g. biologicals) cannot be administered via this route. - 10B UCC AL (EN TER AL)Buccal tablets are small and dissolve slowly, usually placed between the gum and the cheek.
Small surface area, slow dissolution of tablet
Better absorption for WEAKLY BASIC drugs like nicotine (WEAK BASE; pKa = 8.5)
no first-pass metabolism via this route - 11Better absorption for WEAKLY BASIC drugs like nicotinemouth pH : 6-7
gastrointestinal tract pH : 1-5
relatively lower ionization in mouth compared to stomach - 12SUB LIN GUALSublingual tablets are small
are applied under tongue
dissolve rapidly in mouth to release drug content
Route is ideal for drugs that are:
not ionized in mouth
are highly lipid soluble (i.e. lipophilic)
rapidly dissolve - 13Extensive blood supply supply under tongue favors rapid drug absorption. For examplenitroglycerine (used for angina pain) that has a small moleciular size and is lipophilic in
nature.
NO first-pass metabolism via this route - 14R ECTALSuppositories works well in unconscious or non-compliant patients
PARTIAL avoidance of first-pass metabolism : superior rectal vein that feeds to the liver
Absorption for some drugs can be incomplete and irregular. Irritation of rectal mucosa is a possibility with some irritant drugs - 15intravenousDirect administration into the vein during emergency; rapid eect; bypasses absorption component
NO rst-pass metabolism
Drugs with very high molecular weight and drugs that remain ionized at any pH (e.g. quaternary ammonium compounds like tubocurarine and atracurium) are given
by i.v. route. - 16part 2Entire drug quantity enters the vasculature: Bioavailability = 100%
Can control drug delivery via infusion
NEVER administer INSOLUBLE DRUGS OR OILS via this route - 17intramuscularEasy administration v/s intravenous route
Intramuscular: rate of absorption is good
Used for more irritating drugs, larger volumes
Absorption of a drug can vary depending on the muscle site (higher absorption from
deltoid v/s thigh). The decreasing order of vascularity: Deltoid (arm) > thigh > buttock. - 18subcutanousVascularity for subcutanceous tissue < muscle - slow absorption of drugs (sustained release eect), as rate of absorption depends on blood ow to site.
No rst-pass metabolism
This route is ONLY for non-irritating drugs (necrosis can occur with irritant drugs)
INSULIN and monoclonal antibody injections is a very good example for this route - 19inhaleddelivery to lungs
Extensive surface area – rapid absorption
Route can be used for local eect in the lung (bronchodilators for asthma) as well as for
systemic eect (inhaled insulin)
NO rst-pass metabolism - 20topicalMucous Membrane/Skin:
Absorption through mucosa is rapid
Absorption through skin is slow
Applies Fick's law of diusion - 21part 2Rate of diusion across skin is proportional to the surface area (A) and inversely
proportional to stratum corneum thickness (dx).
Creams, gels and lotions are applied on skin. Transdermal patches can be used to achieve sustained eect of drugs. - 22"rst-pass eect"The process or the rst passage of the drug through the liver via hepatic-portal circulation that decreases the available amount of the drug in the general circulation
- 23Drug DistributionOnce the drug is in the systemic circulation, they are carried by the blood to the target site (usually the receptor) for drug action and to other tissues as well, where side eects or adverse reactions can occur.
Drug molecules are distributed to organs of elimination, such as the liver and kidney, and to other tissues, such as the brain, skin, and muscle - 24Average body wt assumed in pharmacokinetics70 kg
- 25Volume of distribution (VD)proportionality factor that relates the amount of drug within the body (DB or dose administered) to the corresponding plasma concentration (Cp).
In other words, the volume of distribution is the apparent volume into which the drug is needed to be dissolved to provide the same concentration as it currently is in plasma. - 26There are two anatomical deviations from the normal capillary structure that often leads to a variation from normal tissue permeabilityperfusion-rate limited and permeability-limited distribution.
- 27perfusion-rate limitedUnder these two special anatomical variations, drug permeability is greatly INCREASED in RENAL capillaries (fenestrated) and HEPATIC capillaries (Sinusoids).
Here drugs are VERY extensively distributed out of these capillary beds.
Under such circumstances cellular membranes DO NOT act as anatomical barriers, - 28permeability-limited distribution.nother anatomical variation where the drug permeability is EXTENSIVELY REDUCED as in the BRAIN capillaries. Brain capillaries seem to have an IMPERMEABLE wall that restricts transfer of drug molecules across it.
- 29So what passes through this barrier?ONLY lipid soluble drug molecules pass through these capillaries and the water soluble drugs are restricted entry into the brain. This is the basis of the blood brain barrier (BBB).
Under such circumstances the distribution of polar drug molecules across the BBB is slow and is governed by the rate of diffusion that occurs across the barrier and is called as permeability-limited distribution. - 30The factors that can alter extent of distribution of a drug areDrug Factors (Lipid solubility, pH/pKa)
Plasma protein binding
Intracellular binding
Elimination of drug (drug removal) - 31PLASMA PROTEIN Ssample of your blood in a tube containing an anticoagulant (agent that prevents blood coagulation) and spins it down in a centrifuge, this is what will be observed. There will be two distinct layers, a bottom layer of packed cells (~45%) and a pale straw colored a supernatant called plasma (~55%).
- 32The plasma comprises of the following componentsmajority being water ~92%
7% plasma proteins
1% inorganic salts - 33ALB UMINOf all plasma proteins the most abundant protein is albumin (~60%) that is responsible for maintaining osmotic pressure, water balance and also transporting drugs within the circulation.
- 34Albumin has an average molecular size of67 Kda. Most weakly acidic drugs have a preference to bind to this plasma protein
- 35α1-acid glycoproteinhave a relatively lower abundance (0.4-1.0 g/L) and are responsible for binding and transporting weakly basic drugs withing
the circulation. The average molecular size is around 42 Kda. - 36Lipoproteinsrelatively larger molecules compared to albumin and alfa1-acid glycoproteins. The average molecular size for lipoproteins ranges between 200 - 2400 Kda.
These proteins are responsible for binding electrically neutral species. Their relative abundance in our body can be variable. - 37Irreversible drug-protein bindingresult of chemical activation of the drug and irreversible attachment to the protein or macromolecule by covalent chemical bonding.
The affinity of the drug to the protein is very strong and stable and very difficult to break. - 38These types of irreversible drug binding accounts forcertain types of drug toxicity that occur over a long time period, as in chemical carcinogenesis, or within a relatively short time period with drugs that form reactive chemical intermediates (e.g. hepatotoxicity associated with high doses of acetaminophen).
- 39The blood capillaries at the brain barrier are enclosed by theflattened ‘end-feet’ of astrocytic cells (glial cells), which also act as a partial, active, barrier. As a result, substances leaving the blood must traverse not only the capillary endothelium, but also the astrocytic sheath in order to reach the interstitial fluid of brain tissue.
- 40.Water, carbon dioxide, oxygen, and most lipid-soluble substances such as alcohol and anesthetics.
- 41The brain gets all nutrients required for its normal function. The brain receivesmacronutrients (e.g. glucose and amino acids), micronutrients (e.g. vitamins) and ions via specialized transporter proteins that utilize active carrier-mediated transport mechanisms.
Water is transported via water channels called aquaporins.
Oxygen and carbon dioxide can diffuse freely through endothelial cells via transcellular transport (or simple diffusion). - 42lipid solubilityIf a drug molecule is water soluble or not lipophilic, then it's entry into the brain is restricted at the BBB.
- 43Permeability glycoprotein transporters (P-gp)ATP-dependent efflux pumps with broad substrate specificity.
This protein not only has protective function to keep toxic drugs out of the brain, but also becomes a major hurdle in delivering drugs to tumor sites where it is overexpressed. - 44The blood vessels of the fetus and mother are separated by a number of tissue layers, which, collectively, constitute theplacental barrier.
Interchange of drugs between the maternal and fetal circulation takes place primarily in the placenta, which connects the embryo or fetus with the maternal uterine wall. - 45The characteristics of diffusion of drugs from maternal blood to fetal blood in the capillaries of the villi are very similar to the passage of drugs across any epithelial barrier.lipid solubility
degree of ionization
molecular size - 46The rate and direction of this exchange is related to theconcentration gradients and the rate of delivery to the intervillous spaces and villi
- 47Influx transportersperform physiological functions facilitating the transfer of nutrients and normal metabolites across the placenta. However, many xenobiotics can be transported into the fetal tissue sue to structural resemblances to physiological substrates.
- 48Efflux transportersdo restrict entry of xenobiotics into the fetoplacental unit.
- 4911β-hydroxysteroid dehydrogenase II enzymecan inactivate prednisolone to prednisone.
- 50Adverse Effectis an unwanted or harmful reaction (e.g., tissue damage) following the administration of a drug or combination of drugs. Usually requires the drug be discontinued or the dose reduced.
- 51Side Effectis any effect caused by a drug other than the intended therapeutic effect, whether beneficial, neutral or harmful (e.g., ankle edema with vasodilators)
- 52Drug Toxicitydescribes adverse effects of a drug that occur because the dose or plasma concentrations are above the therapeutic range, either unintentionally or intentionally (drug overdose).
- 53Causes of Human PoisoningTherapeutic drug toxicity
Exploratory exposure by young children
Environmental exposure
Occupational exposure
Recreational abuse
Medication error (Prescribing)
Purposeful administration for self-harm
Purposeful administration to harm another - 54Human Poisoning is done mostly bydrugs in the house
- 55Pain medications lead the list of the most common substances implicated in adult poison exposures.
- 56what determines the toxic responseDose
- 57.The extent of adverse effects depends upon the concentration and interaction of the active toxic drug/chemical with its target site
Bioactivation of drugs/chemicals to reactive metabolites - 58DoseThe amount of drug or chemical entering the body
Usually given as: mg of drug or chemical/kg body weight = mg/kg - 59Dose is dependent upon (5 FACTORS):Concentration
Properties of the toxicant
Frequency of exposure (e.g., once vs. multiple)
Duration of exposure (e.g., hr vs. day vs. week)
Route of exposure (e.g., oral, inhalation, IV) - 60What is a Toxic ResponseChange from normal state
could be on the molecular, cellular, organ, or organism level--the symptoms - 61TYPES:Local vs. Systemic
Reversible vs. Irreversible
Immediate vs. Delayed
Graded (individual) vs. Quantal (population) - 62Graded (individual) vs. Quantal (population)degrees of the same damage vs. all or none
Quantal dose-response is extremely important in toxicology and used to determine the median toxic (TD) or lethal (LD) dose of a drug or chemical - 63Dose-Response RelationshipAs the dose of a toxicant increases, so does the response.
- 640-1 Denotes theNO-OBSERVED-ADVERSE-EFFECT-LEVEL (NOAEL).
- 65ED50Median Effective dose at which 50% of the population responds
- 66TD50Median Toxic dose at which 50% of the population responds
- 67LD50Median Lethal dose at which 50% of the population responds
- 68Therapeutic Index (TI)LD50/ED50
- 69ExposurePrimary Routes: GI, Respiratory Tract & Skin
- 70ADMEAbsorption, Distribution, Metabolism, and Excretion
Once a living organism has been exposed to a toxic substance, the compound must get into the body and to its target site in an active form in order to cause an adverse effect. - 71MetabolismAdverse effects depend on duration of active drug or chemical at the target site
- 721o objective-make a drug or chemical more water soluble and easier to excrete
decrease lipid solubility --> decrease amount of toxic agent at target site
increase ionization --> increase excretion rate --> decrease toxicity - 73BioactivationBiotransformation can result in the formation of reactive metabolites
- 74BiotransformationPhase I--Make the toxic agent more water soluble (cytochrome P450s)
Phase II--Links with a soluble endogenous agent (conjugation) - 75Management of Intoxicated PatientSymptomatic and supportive care are the cornerstone in the management of the intoxicated patient.
There are limited circumstances and toxins in which antidotal therapy is used.
The route of excretion or detoxification is important for planning treatment
The prevention of toxicity is instituted
when specifically indicated - 76Treatment of Intoxicated PatientReduce Absorption of Toxin
Reduce or Increase (Bioactive drug or chemical) Metabolism
Increase Excretion of Toxin
Neutralize Toxic Effects (e.g., receptor blockers, antibodies) - 77Activated Charcoal(Single-dose)
Effectively adsorbs all drugs or
toxic chemicals except for:
alcohols, mineral acids, cyanide and various metals (iron, lithium, potassium, sodium) - 78Gastric Lavage (1 h)Ingestion - sustained release drugs
Ingestion – xenobiotics not adsorbed by activated charcoal - 79AntidoteAdminister agent that alters the production of a toxic metabolite
- 80Acetaminophen(>100 products): metabolized by P450 to a reactive metabolite that induces hepatotoxicity; greater risk - chronic alcoholics or patients taking drugs that alter P450
- 81Acetaminophenmetabolized by P450 to a reactive metabolite that induces hepatotoxicity; greater risk - chronic alcoholics or patients taking drugs that alter P450
- 82Methanol and ethylene glycolmetabolized to highly toxic acids – metabolic acidosis, blindness, or renal failure
- 83Mechanismorganophosphates phosphorylate serine in the active site of acetylcholinesterase (AChE) to prevent the inactivation of acetylcholine (neurotransmitter) at the neuromuscular junction (NMJ).
- 84AntidoteTreatment with
atropine to block activation of cholinergic receptors at NMJ and pralidoximine (2-
PAM) to restore AChE. - 85Chelating agentsEDTA, Penicillamine, Deferoximine
have the ability to form complexes with heavy metals and prevent or reverse the binding of the metallic cation to ligands in the body. - 86Pure Food and Drug Act of 1906Proof of efficacy not required
Proof of safety not required
Required proper labeling
Limited interstate transport of misbranded/adulterated drugs
Led to the creation of the Food and Drug Administration (FDA) - 87Harris-Kefauver Amendment (1962)Both efficacy and safety must be proven
Required documentation of risk to benefit ratio
Gave the FDA authority to regulate advertising
Began to classify all pre-1962 drugs already on the market as effective, ineffective or needing further study. - 88Preclinical TestingIn vitro
In vivo
Establishes a “proof of concept”
File for Investigational New Drug (IND)
Time required to complete; 3 - 6 years - 89In vitroEfficacy
Toxicity - 90In vivoEfficacy in an animal model
Toxicity in an animal model (multiple species, acute and chronic) - 91Phase ORecent development
“Micro-dosing” using subclinical doses
Studies how the drug behaves in humans
Only 10-15 subjects - 92part 2No data on safety or efficacy
Provides data on pharmacokinetics (absorption, distribution, metabolism and excretion)
No benefit for subject - 93Phase IUses “normal” volunteers (n=20-80)
Ethical concerns regarding risk/reward
Determines safety and biological effects
Efficacy is not studied
Assesses pharmacokinetics (absorption, distribution, metabolism and excretion)
Time required to complete; months – 1 year - 94Phase IIStudies a small number of patients with the targeted disease (≈200-300)
Efficacy is established
Pharmacokinetics is characterized - 95part 2Dose range is determined
Short-term side effects and risks are assessed
Time required to complete; 1 – 2 years - 96Phase IIILarge, multi-site sample of patients (hundreds to thousands)
Different sex/genders, ages and ethnic groups must be included (if appropriate)
Safety and efficacy are established - 97part 2Drug-Drug interactions are assessed
Risk-Benefit information is generated
Time required to complete; 3-5 years
Highest rate of failure is in Phase III - 98Phase IVAdditional uses of the drug are discovered (repurposing)
Post-Marketing Surveillance - 99Post-Marketing SurveillanceIdentify new or unusual adverse reactions
Incidence of adverse effects might be low
Adverse effects might require chronic exposure
Adverse effects might occur in higher frequency in subpopulations (sex/gender, age or ethnic groups) - 100Blackbox Warning (caution especially for people with other conditions)Appears on the package insert for certain prescription drugs
Signifies that the drug carries a significant risk of serious or even life-threatening adverse effects
Does not mean the drug is contraindicated in any way or should be withdrawn from the market
It is a means of communication from the FDA to prescribers to highlight the risk
Serious adverse reactions might be prevented, reduced in frequency or reduced in severity by proper use of the drug - 101How Drugs Are NamedChemical Name
Company Code Name
The Generic Name is assigned by the United States Adopted Names (USAN) Council during clinical testing
The Brand Name is developed by the company (marketing experts) requesting approval - 102Generic Drugs Are better becusMuch Cheaper Than Brand Name Drugs
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- FlashCards sobre aug 24, criado por Shylla T em 24-08-2020.
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