what are the three types of routes of drug administration?
=-enteral (systemic) -parenteral (systemic and Local) -topical (Local and systemic)
what is enteral drug administration?
by way of alimentary canal
Is Parenteral drug administration through alimentary canal?
no
what is topical drug administration?
applied tot body surface
what are the three Enteral routes?
=-oral ingestion (Most common)-sublingual/buccal (Not swallowed)-rectal route (Mostly in children)
what are the advantages of oral ingestion?
=-Most often used, auto administration -safest, Most convenient, Most economical -daily intake for a Long period of time
what are the disadvantages of oral ingestion?
=-emesis (irritation of GI Mucosa) -cooperation of patient-poor erratic absorption - some drugs -presence of food, gastric juice and other drugs -metabolized by intestine and liver before reaching systemic circulation (First pass metabolism)
What is first pass metabolism?
only a proportion (less than 100%) of the drug reaches the systemic circulation because it is metabolized by intestine and liver first
what are the advantages of sublingual/buccal drug administration?
=- fast absorption -avoid First pass metabolism -convenient and no swallowing
what are the disadvantages of sublingual/buccal drug administration?
=-quantity limited (small surface area) -bitter Taste and irritation to Mucosa -VERY few drugs can be absorbed
what drug is an example for sublingual/buccal drug administration? and what is it used for?
nitroglycerin; used for angina
what are the advantages of rectal route drug administration?
=-suitable for children -for unconscious and vomiting patients -partially avoid First pass metabolism
what are the disadvantages for rectal route drug administration?
=-inconvenient and embarrassing -absorption is slow and erratic -cause inflammation and irritation
what are the three most important parenteral routes-injections?
=-intravenous (IV): into veins-subcutaneous (SC): under skin -Intramuscular (IM): into muscles
name all 7 types of parenteral route injections
=-intravenous (IV): into veins-subcutaneous (SC): under skin -Intramuscular (IM): into muscles -Intradermal (ID): into dermis-intra-arterial (ia): into arteries -Intrathecal (it): cerebrospinal fluid -Intraperitoneal (IP): peritoneal cavity
what are the advantages to intravenous injections?
-deliver a precise dose quickly -in a well-controlled manner -no barrier to absorption (100%) -suitable for irritating solutions
what are the disadvantages of intravenous injections?
=-difficult to Administer especially in obese patients -phlebitis and increased chance of Infection -rapid onset of adverse reactions: monitoring required -once drive is Inject, There is often no Recall
what is a subcutaneous injection?
injection into fatty tissue just beneath the skin
what are the advantages of subcutaneous injections?
=-slow and constant absorption -useful for Protein drugs
what is a common protein drug that is administered through subcutaneous injections?
insulin
what are the disadvantages of subcutaneous injections?
-slow absorption, not useful in emergency -suitable for only non-irritant drugs -only for small volume (normally <1ml)
what are intramuscular injections?
injection into skeletal muscles beneath the fat
what are the advantages to intramuscular injection?
-absorbed into bloodstream quickly -oily prep and irritants can be given-hold larger volume than SC-useful for most vaccines (flu and COVID-19)
what are the disadvantages to intramuscular injections?
=-Local pain, irritation and abscess-accidental intravenous injection -damage to Peripheral nerve: injection nerve Palsy
out of intravenous, subcutaneous and intramuscular routes, put them in order from greatest to least for the following topics: difficulty to administer quick onset of action tolerance of irritantsmax injection volume
IV>IM>SC for all of them
what is the main purpose for intradermal injections? and one example
diagnostic; example: TB test
what is the main purpose for intra-arterial injections?
localized anti tumor treatment
what is the main purpose for intrathecal injections (cerebrospinal fluid)? and an example of what it is used to treat
anesthesia, treatment of CNS infection such as meningitis
what is the main purpose of intraperitoneal injections, and one example for when it is used?
infusion of fluid; dialysis
what are the four types of topical routes of drug administration?
=-inhalation (via lung)-cutaneous (Local effects) -transdermal (systemic) -other mucous membranes
when can inhalation drug administration be used and what kind of disease can be treated this way?
=-gaseous agents to achieve general anesthesia.-aerosols to treat asthma, pneumonia, Cystic fibrosis
how does inhalation drug administration work?
absorbed via the alveolar-epithelial membrane
what are the advantages to inhalation drug administration?
=-Almost instantaneous absorption -Avoidance of hepatic First pass loss -Local applications (minimal side effects)
what are the disadvantages to inhalation drug administration?
=-special apparatus is required (nebulizer) -difficult to Control the Exact dosage -irritation of the Respiratory tract May occur (cough)
what is cutaneous route drug administration used for?
=-Local effects-treatment of superficial skin disorders such as eczema, Infection, psoriasis, itchiness
what is transdermal route drug administration used for?
=-systemic effects - used for smoking cessation, contraception, pain relief, and motion sickness relief-delivered slowly and continuously
what are four other mucous membranes used in topical drug administration?
=-nasal-vaginal-ocular-otic
Can you take insulin orally?
no, because it is a protein tat will be broken down into an amino acid that won't be effective
what is he risk of IV injection of insulin?
could risk going into hyperglycemic shock and CNS crashes first which can cause damage to the brain
can insulin be used as a transdermal patch?
no , because it is a protein which is hydrophilic and wouldn't be able to go through the lipid bilayer.
What is pharmacokinetics?
ADME the study of bodily absorption, distribution, metabolism, and excretion of drugs
what is absorption (pharmacokinetics)?
the movement of a drug into the bloodstream after administration
what does drug absorption depend on?
drug's physicochemical properties, formulation, and route of administration
what are the four different ways a drug can cross a cel membrane?
=-passive diffusion -facilitated diffusion -active transport-pinocytosis
What is bioavailability?
(< or equal to 100) the fraction of administer dose of unchanged drug that reaches the systemic circulation (absorbed)
what is the equation for solving bioavailability?
Bioavailability = mass (absorbed) / mass (administered)
what is the bioavailability of IV route?
100% because it goes directly into circulation
100 mg of drug A is administered. 50 mg of drug A is absorbed. what is the bioavailability. is it IV route?
50/100= 0.5 = 50% no because IV is 100%
bioavailability of drug A is 50%. 30 mg of drug A is absorbed. how much is administered?
30/x =.5 x= 60 mg
standard IV dose of a drug A is 100mg. the bioavailability of oral form of drug A is 50%. to ensure the same amount of absorption is achieved, what is should the oral dose be?
IV: 100 (mass administered) x 1 (bioavailability: 100%) = 100mg (mass absorbed)oral: 100 mg (mass absorbed)/ 5 bioavailability:50%) = 200 mg (mass administered)
what is distribution (pharmacokinetics) determined by?
drug distribution is determined by the drug's physicochemical properties, cardiac output, regional blood flow, capillary permeability, binding to plasma protein, and tissue reservoirs
does ideal distribution happen often?
no, rarely
what is drug binding; plasma protein?
when drugs are associated with plasma protein and make a drug protein complex
is drug binding: plasma protein reversible?
yes, there is a drug reservoir and the drug protein complex can dissociate and be administered throughout the body
are bound drugs (to plasma proteins) biologically inactive or active?
biologically inactive
are free drugs (not bound to plasma proteins) biologically inactive or active?
biologically active
what does sequestration on drug binding (to plasma protein) affect?
distribution, metabolism, excretion and action of drug
what is drug binding: tissue binding?
drugs that are associated with tissue elements. slow the rate of elimination/excretion.
where is the drug reservoir for drug binding: tissue binding?
muscle, fat, bone
what are two specific examples of drug binding: tissue binding?
1. tetracycline-bone2. barbiturates-fat
what is the redistribution of drug binding: tissue binding?
from its sites of action into other tissues or sites
wha does the volume of distribution indicate?
indicate how extensively drug is distributed to the rest of the body compared to plasma
What is volume of distribution?
theoretic fluid volume that would be required to contain the amount of drug present in the body at the same concentration a in the plasm
what is the equation for determining volume of distribution?
Vd= drug absorbed (mg)/ plasma [drug] (mg/L)
100 mg of drug A is admonished IV. plasma concentration is 5 mg/L. what is the volume of distribution (Vd)?
vd= 100mg/5 (mg/L)= 20L
what factors affect volume of distribution?
size and lipid solubility of drug, plasma protein binding, tissue-binding, and health status
what does a small Vd mean?
drug is confined to blood
what does a large Vd mean?
drug is confined to the tissue
what is excretion (Pharmacokinetics)?
removal of drug from the body (filtration + reabsorption + secretion)
how is drug excretion done?
primarily carried out by renal and biliary pathways
what are the three steps for renal excretion?
1. glomerular filtration: only unbound drug can be filtered2. tubular reabsorption: favors unionized and lipophilic drugs 3. active secretion: energy required secretion of drug, penicillin
what compromises renal function and decrease excretion?
CRD and aging
in renal excretion, most drugs are what kind of acids and bases?
weak acids or bases
in acidic urine, drug is in R-COOH form. is the acidic drug reabsorbed or excreted? while the basic drug is reabsorbed or excreted?
acidic drug is reabsorbed; basic drug is excreted
in basic urine, drug is in R-COO- form. is the acidic drug reabsorbed or excreted? while the basic drug is reabsorbed or excreted?
acidic drug is excreted; basic drug is reabsorbed
how are drugs excreted biliary (fecal)?
1. drug metabolites (lipophilic) excreted in the bile 2. drugs metabolites secrete directly into the lumen 3. un-absorbed orally ingested drugs excreted in feces
what is enterohepatic circulation in binary excretion?
a drug secreted in bile is reabsorbed into the circulation from the intestine. this cycle decreases excretion and prolongs action
what are other routes of excretion?
1. sweat, saliva, tears- quantitatively unimportant 2. saliva drug concentration may be used to determine plasma drug concentration 3. lactation: relevant to nursing baby 4. pulmonary: gaseous anesthetics and ethanol
what kind of drugs are easier for absorption? lipophilic or hydrophilic drugs?
lipophilic drugs
what kind of drugs are easier for excretion? lipophilic or hydrophilic drugs?
hydrophilic drugs (ultimate goal)
metabolism outcomes: what is deactivation?
(most drugs) active drugs are metabolized to inactive drugs
metabolism outcomes: what is activation?
inactive drugs (prodrug) becomes an active drug
metabolism outcomes: what is detoxification?
toxic drug becomes non toxic metabolite
metabolite outcomes: what is toxification? what is one example?
(rare) non toxic becomes toxic; acetaminophen
where is the principal site of drug metabolism?
liver
metabolism I'm the liver is carried out by what kind of cells, and where in the cell does the reaction occur?
hepatocytes, site of the reaction is in the smooth ER
what is first pass metabolism for?
absorption
what is systemic metabolism for?
distribution
what kind of drug administration will undergo first pass metabolism?
drugs taken by oral or rectal routes
how many phases are in hepatic metabolism?
2
what are the reactions that occur in phase one?
OXIDATION,reduction and hydrolysis
what is the key enzyme in phase 1 of hepatic metabolism
CYP 450
what structural changes occur in phase 1 of hepatic metabolism?
cleavage and addition of polar groups
what is the outcome of phase 1 of hepatic metabolism?
more polar; ready for phase II
what is the reaction that occurs in phase II of hepatic metabolism?
conjugation
what is the key enzyme of phase II of hepatic metabolism?
transferases
what structural changes occur in phase II of hepatic metabolism?
attach endogenous small molecules
what is the outcome of phase II of hepatic metabolism?
lots more water soluble for excretion
how does drug interaction effect phase I of hepatic metabolism?
CYP450 enzymes can be induced or inhibited by many drugs and substances
what I the non CYP450 enzyme in phase I of hepatic metabolism?
alcohol dehydrogenase
besides CYP450, what are the top CYP enzymes?
CYP3A4 and CYP2D6
what is the purpose of oxidation, reduction and hydrolysis in phase I of hepatic metabolism
unmask or addition of functional groups, and change biological properties suitable for phase II
what is conjugation in phase II of Hepatic metabolism?
attach endogenous small molecules (sulfate, glycerine, glucuronic acid, acetate) to the drug; increases water solubility for excretion
what is the most common conjugation reaction for phase II, and where does the product get excreted and secreted?
glucuronidation ; secreted in bile or excreted in urine
do all drugs go through both phases?
no
what are 6 factors that affect drug metabolism?
=-liver condition and pathology -Enzyme inhibition/induction -genetic factor-gender and hormone -age -diet and environmental factors
What is cirrhosis?
scarring of the liver; makes its hard as a rock and eventually nonfunctional
what are three causes of cirrhosis?
=-Alcohol abuse-Viral hepatitis -fat accumulation
what does cirrhosis do to the liver?
=-decreases functional mass (Enzyme Activity) -hypoalbuminaemia (lower plasma binding)-reduced hepatic blood flow (Local and systemic)
what is in inhibitions in relations to metabolism?
decrease in enzyme production and activity. enzyme is inhibited by drugs and other compounds
what enzyme turns statin into a metabolite?
CYP3A4
what inhibits CYP3A4?
zantac
what is induction in relation to metabolism?
increase in enzyme (CYP450 and transferases) production that is induced by drug and other compounds
what enzyme turns oral contraceptive into metabolites?
CYP3A4
what induces CYP3A4?
phenytoin
what is drug interaction on a kinetic level?
one drug affects the metabolism (enzyme) of the other drug
what is an example of a drug that has an enzyme that is induced by alcohol?
acetaminophen
when shouldn't you drink alcohol and take tylenol?
both alcohol and acetaminophen use CYP450 as a metabolic enzyme, which will then product too much NAPQI. NAPQI is a toxic metabolite and will cause liver failure and possibly death
what is the enzyme used to metabolize codeine to morphine?
CYP2D6
codeine and morphine: which is inactive and active?
codeine is inactive and morphine is active
What is polymorphism?
multiple forms of a single gene
what is CYP2D6 polymorphism?
different forms and functions
what happens when codeine is poorly metabolized?
not enough morphine is made and there will be a lack of therapeutic effects
what happens when codeine is ultra-rapidly metabolized?
morphine is made too quickly and there is a risk of opioid overdose
how does gender and hormones effect metabolism?
=-males and females differ in their response to drugs -anatomic difference (surface area, water content, fat mass, and muscle mass)-variations in regulation of CYP450, Most probably through endogenous hormones-sex Specific conditions that impact DRUG metabolism (oral contraceptives, period, pregnancy, menopause)
what is neonates?
lack of fully developed enzymatic system
how does being elderly effect metabolism?
decreased enzymatic activity due to smaller active liver mass, decreased liver blood flow and altered plasma binding of drugs
what are clinical implications that affect metabolism?
difficulty in metabolizing drugs, higher level of prolonged action, and toxicity
what is gray baby syndrome?
a syndrome due to toxicity of antibiotic CHLORAMPHENICOL in the newborn and premature babies, due to lack of liver enzymes to metabolize this drug
what enzymatic alteration does chargrilled meat have on metabolism?
CYP1A induction
what enzymatic alteration does grapefruit juice have on metabolism?
CYP1A/3A inhibition
what enzymatic alteration does smoking have on metabolism?
enzymatic induction
what enzymatic alteration does exposure to pesticides have on metabolism?
enzymatic induction
what is prodrug?
drugs that become active after metabolism
metabolism activates cortisone into?
hydrocortisone
metabolism activates codeine into?
morphine
metabolism activates acetylsalicylic acid into?
salicylic acid
metabolism activates levodopa into?
dopamine
metabolism activates chloral hydrate into?
trichloroethanal
what is clinical pharmacokinetics?
the safe and effective therapeutic management of drugs and individual patient
what is the primary goal of clinical pharmacokinetics?
enhancing efficacy and decreasing toxicity of a patient's drug therapy
what is the fundamental hypothesis of clinical pharmacokinetics?
a relationship exists between the effects (therapeutic and toxic) of a drug and the accessible concentration of the drug (e.g. in plasma)
what is the kinetic of absorption and elimination?
=-First order and zero order elimination -elimination half- life and clearance -volume of distribution and bioavailability -DRUG effects: steady state, loading dose and maintenance
what is first order elimination?
-enzyme > drug -the higher the plasm [drug] the hight the rate of elimination -rathe of elimination is proportional to the plasma [drug]
what is the zero order elimination?
-enzyme <_ drug -the hight the plasma [drug], the rate of elimination constant -the rate of elimination is independent to the plasm [drug]
the half life is _______ for first order eliminations
constant
what is the shape of a first order elimination on a linear scale?
negative curved slope
what is the shape of a first order elimination on a logarithmic scale?
negative slope
half life question: half life of drug is 2 hours. at time 0 plasma concentration of drug A is 100 mg/L. after 4 hours what is he plasma concentration?
4 hours = 2 hours x 2 =2 half lives. after 2 half life, fraction of the drug remaining is 1/4 plasma [Drug]= 100 mg/L x (1/4) = 25 mg/L
half life question: half life of a drug A is 3 hours. at time 0, plasma concentration of drug A is 80 mg/L. after how many hours will the plasma concentration drop to 10 mg/L?
it takes 3 half lives to drop to 1/8time= half life x 3 3 hours x 3 = 9 hours
what is the clinical relevance of half life?
=-How fast the DRUG will be Eliminated from the body -How much DRUG is left in the body after a certain amount of time -select the appropriate DRUG based on half life-estimate the dosage and How often the DRUG should be administered
the shorter the half life of the drug, what does that mean for the elimination?
the shorter the half life, the quicker the elimination
how is elimination of a drug affected by a longer half life?
the longer the half life, the slower the elimination
what is clearance?
the volume of plasma from which a drug is completely filtered and removed per unit time
what are the units for clearance?
mL/min
what does a high clearance mean?
higher amount of drug lost in urine, and higher the elimination
what does a low clearance mean?
less drug lost in the urine, and less elimination
what is the volume of distribution?
indicate how extensively drug is distributed to the rest of the body compared to the plasma small Vd: confined to the blood large Vd: confined to the tissue
what is the relationship between half-life, clearance and volume of distribution and Ke
Ke = clearance/ Vd half life= 0.693/Ketherefore, half-life = (0.693 x Vd)/ clearance
what is Ke?
first order elimination rate constant
what is steady state drug concentration?
concentration(ss) will be achieved when a drug is administered a a constant rate (repeated dosing)
what is the elimination half life
the time it takes for the plasma drug concentration to be reduced by 50%
for iv infuse, what does the dosing rate equal?
infusion rate
for oral route, dosing rate equals?
bioavailability of the drug (<_1) x (dose/ dose interval)
what is the therapeutic goal of dosage regimens?
maintain steady state drug levels within the therapeutic range
what its the therapeutic range?
the range between the minimum effective conc. and the minimum toxic conc.
what is the loading dose?
dose given at the onset of therapy with aim of achieving the target concentration rapidly
what is the equation for loading dose of drug(IV)?
volume distribution x plasma concentration
what is maintenance dose?
a series of respective doses or as continuous infusion to maintain a steady state concentration of drug
what is the interaction between drugs?
the effect of a drug maybe increased, decreased or otherwise altered by concurrent administration of another compound
what is antagonism?
effects of drug A is reduced or even diminished by drug B (penicillin and tetracycline)
what is potentiation?
effect of drug A is greater with presence of drug B; A and B have different MOA (succinylcholine and neostigmine)
what is summation?
combined effect of drug A and of drug B is the sum of their individual effect; drug A and B have identical or similar MOA (morpine and meperidine)
what is synergism?
combined effect of drug A and drug B is greater than sum of their individual effect; drug A and B have different MOA
what is pharmacokinetic interaction?
influence of one drug on the ADME of another drug
what is pharmacodynamic interaction?
independent of any change in the quantitative dispassion of another drug
what is the interaction outcome of tetracycline and oral iron supplements?
antagonism (form insoluble chelate of tetracycline, prevents absorption)
what is interaction of digoxin and quinidine?
potentiation (inhibition transporter of digoxin, reduced renal clearance, increase conc of digoxin, increase toxicity)
what are interaction bette metoprolol and nitroglycerin>
synergism : profound vasodilation and therefore profound hypotension
what is the drug interaction of aspiring and warfarin?
synergism: increased gastrointestinal bleeding almost fourfold
what is the adverse drug reaction: toxicity?
-extension effects: toxicity as and extension of therapeutic effects (overdose -acts on target organ -predictable and dose related -example hypoglycemia caused by insulin
what is the adverse drug reaction: side effect?
=-adverse effect that occurs within the therapeutic dose range of the DRUG -acts on non target organ-predicable and dose related -example: muscle wasting caused by Lipitor
what is the adverse drug reaction : idiosyncratic reaction?
=-genetically determined abnormal response -normally involves a change in Enzyme Activity -unpredictable and dose related -example: response to codeine in patient that are either poor or ultra rapid metabolizers
what is the drug reaction: drug allergy?
=-abnormal reaction of your Immune system to a Medication -can be mild or severe, even life threatening -unpredictable and Not dose related -example: anaphylaxis caused by penicillin
what is the adverse drug reaction: carcinogenic and teratogenic effects?
=-carinogenic: having the potential to cause cancer (example: estrogen postmenopausal therapy) -teratogenic: causing developmental malformations (First trimester is the Most sensitive) example: thalidomide tragedy and babies with phocomelia
what is the considered low success rate, high cost, and a long time for drug discover and testing phases?
-low success rate: ~ 13.8%- high cost: >1 billion dollars -long time: ~12.5 years
what is the 1906 our food and drug act?
forbade the adulteration and mislabeling of drugs
what is the 1914 harrison narcotic act?
regulated opioid and cocaine
what is the 1938 food, drug, and cosmetic act?
mandate safety and the role of FDA in enforcing it
what its the 1952 durham-humphrey act?
used restriction for certain drugs by Rx only
what is the 1997 FDA Modernization Act?
enhanced FDA mission which faces increasing technological, trade and public health complexities
what is the 2018 support for patients and communities act?
address the nation's opioid overdose epidemics
what is pharmacodynamics?
what the drug does to the body
what are drug receptors (targets)?
any part of a cell, usually proteins, on the cell surface or in the cytoplasm with which a drug interacts to trigger a response or effect
drug receptors includes?
cell receptors- the most important drug targets
what is the signaling molecule?
ligand- growth factors, hormones, neurotransmitters and physiochemical stimulus + drug
what are the proteins that receive signaling?
receptors:-g protein-coupled receptors -ion channel receptors-enzyme-linked receptors -intracellular receptors
how many marketed drugs bind to GPCRs?
between 1/3 and 1/2 of all marketed drugs
what is tachyphylaxis?
a decreased response to a medicine given over a period of time
how are receptors desensitized?
uncoupling, internalization, and reduction in total receptor number
what is the receptor occupancy theory?
pharmacologic response (effect) is proportional to the number of receptors occupied by a drug (increased drug concentration leads to increased response until it reaches a maximal response- ceiling effect )
what is the dose response curve?
the relationship between an effect of a drug and the amount of drug given
what is Emax in dose-response curve?
maximal response to a drug (all the receptors bound)
what is EC50 in a dose-response curve?
[drug] that produces 50% of the maximal response
what is the sigmoid shape in a dose-response curve?
characterized and quantitate the drug activity ( typical shape)
what is affinity?
attraction between a drug and its receptor
what is potency?
amount of drug needed to produce an effect (EC50)
what is efficacy?
a drug's maximal capacity to produce an effect (Emax)
what is agonist? and one example
bind to physiological receptors and MIMIC the effects of the endogenous signaling molecules (efficacy)example: morphine
what is partial agonist? and one example?
partly effective and lower efficacy than agonists, no matter the amount employed (lower efficacy)pentazocine
what is antagonist? and one example
bind to receptors with no effect, but their bi ding blocks the binding of the endogenous agonist (zero efficacy)example: naloxone
what is inverse agonist? and one example
induces a response opposite to that of agonist, reduces basal activity of receptor (negative efficacy)example: nalmefene
what is a competitive antagonist?
=-binding reversible -Decrease potency-same efficacy-parallel shift to right (Naloxone)
what is non-competitive antagonist?
=-binding irreversible -Decrease efficacy-same potency-downward displacement (ketamine)
what is naloxone?
competitive antagonist to treat overdose of opioids -such as the brand narcan
what is therapeutic index?
the ratio of the dose that produces toxicity to the dose that produces a clinically effective response
what is the equation of therapeutic index?
TD50 / ED50 TD50= the dose that is toxic in 50^ of the population ED50 =the dose that is effective in 50% of the population
what does a larger therapeutic index mean?
the drug is safer
therapeutic index question: the TD 50 is 200 mg and the ED50 is 20 mg. what is the TI?
200/20= 10
therapeutic index question: there are two drugs available to treat hypertension. Drug A has a TI of 10 and drug B has a TI of 3. which drug is safer?
Drug A