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Pharmacology > Block #1 > Flashcards

Block #1 Flashcards

1
Q

Pharmacodynamics

A

site and mechanism of action (drug affecting body)

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2
Q

Pharmacokinetics

A

qualitative and quantitative description of what happens to drug in body over time (body affecting drug)
o Absorption, distribution, metabolism, excretion
o Basis for dosing decisions

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3
Q

Drug tolerance vs drug resistance

A

Tolerance: acquired insensitivity; requires prior exposure

Drug resistance: lack of response to new drug, often in mutant bacterial/cancer cells

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4
Q

List and describe the properties of an ideal drug

A 
•Efficacy
o	Produces given response
o	Important property!
•Safety
o	Minimal potential to cause injury (even at high doses or prolonged periods)
o	No drug is completely safe
•Selectivity
o	Produces only response for which it is given (no side effects)
o	From receptors
•Reversibility
•Predictability
•Ease of administration
•No interactions with other drugs
•Low cost
•Chemical stability
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5
Q

Describe the process of drug development and testing, including details of the various phases of drug testing

A
  1. In vitro studies with Lead Compound
  2. Animal testing: efficacy, selectivity, mechanism
  3. Clinical testing
    a. Phase I: 20-100 healthy subjects (is it safe, pharmokinetics)
    b. Phase II: 100-200 Patients (does it work in patients)
    c. Phase III: thousands of patients (does it work, double blind)
  4. Marketing: Phase IV: post-marketing surveillance
    a. Patent expires after 20 years
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6
Q

Assignment of Pregnancy Risk Categories

A

o Category A: no demonstrated risk to fetus
o Category B: No risk in animal studies, unknown in humans OR risk in animal studies but not in humans
o Category C: risk in animal studies, no studies in humans, but benefits outweigh potential risks
o Category D: evidence of human risk, but benefits outweigh risks
o Category X: human fetal risks outweigh potential benefits

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7
Q

Describe factors that influence drug action

A

•Physiologic
o Body weight & size, age, gender differences in lean: fat mass
•Pathologic
o Renal insufficiency, hepatic disease, acid/base balance, altered electrolyte status
•Genetic variables
o Variations in biotransformation, functional proteins/enzymes/receptors

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8
Q

Explain the basis for allergic reactions to drugs

A
  • Requires previous exposure
  • Only molecules greater than 1 kilodalton
  • Usually have to be covalently linked to a macromolecule like a protein (hapten-protein complex)
  • Manifestations are unrelated to pharmacological effect
  • Anaphylactic shock: allergic reaction resulting in histamine release, causing edema, bronchiolar constriction, heart failure, death
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9
Q

Discuss differences between specific and nonspecific drug action

A

•Nonspecific:
o Act by physicochemical processes
• Metal chelators, osmotic diuretics, acids, bases
o Activity occurs at high concentrations
o Varied structures produce similar effects through same mechanism
o Slight change to chemical structure not much affect activity
•Specific
o Acts on receptors, enzymes, transporters or other cell components
o Activity at low concentrations
o Similar chemical structures have similar effects BUT slight modifications may produce much altered activity

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10
Q

Name the four major receptor classes

A
  • nuclear receptors
  • ligand-regulated transmembrane enzymes
  • ion channels
  • G-protein coupled receptors
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11
Q

Nuclear Receptors

A

a. Lipid soluble
b. Intracellular receptor, stimulates gene transcription
c. Lag period of minutes to hours, but effects can last for hours to days.
d. Ex. Steroids & thyroid hormone

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12
Q

Ligand-regulated transmembrane enzymes

A

a. Ligand binds extracellular domain, stimulates conformational change
b. Receptors dimerize, autophosphorylate
c. Ex. Tyrosine kinase, cytokine receptors with JAK/STAT

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13
Q

Ion Channels

A

a. Increase transmembrane conductance of ion, so alter membrane electrical potential
b. Rapid signaling
c. Ex. Nicotinic acetylcholine receptor

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14
Q

G-protein coupled receptors

A

a. Serpentine/ 7 transmembrane receptors
b. Use second messengers: cAMP, Ca2+, phosphoinositides
c. Cell surface receptor binds ligand, activates G protein
i. Binding and hydrolysis of GTP
d. G protein changes activity of effector (ex. adenylyl cyclase)
e. Amplification of signal

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15
Q

Types of G protein subunits

A

Mediate effects of types sets of receptors to specific effectors
oGs: stimulates adenylyl cyclase, increases cAMP
oGi: inhibits adenylyl cyclase, decreases cAMP; opens cardiac K+ channels to decrease HR
oGq: stimulates phospholipase C, increases IP3, DAG, & cytoplasmic Ca2+

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16
Q

Describe two major second messenger systems modulated by G proteins.

A

ocAMP
• Gs stimulates adenylyl cyclase to make cAMP
• Initiates phosphorylation cascade by binding regulatory dimers so active catalytic chains of kinases
• Degraded/regulated by phosphodiesterases or phosphatases

oCa2+-phosphoinositide
•	Gq stimulates PLC
•	Converts PIP2 to DAG, IP3
•	DAG: stimulates PKC, phosphorylation
•	IP3: releases of Ca2+, promotes calmodulin activity
•	Regulated by phosphatases, Ca2+ pumps
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17
Q

Describe short- and long-term mechanisms involved in receptor regulation

A

Desensitization: diminishing response even with agonist present
•Short-term desensitization:
o from phosphorylation of receptor via G protein-coupled receptor kinase (GRK)
o prevents interaction with G proteins
o receptor instead binds to b-arrestin, decreases signal
o when agonist removed, dephosphorylation occurs via phosphatases
•Long-term desensitization
o Receptors degraded in lysosomes

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18
Q

Explain the bimolecular binding equilibrium

A

•Drug + Receptor ←→ Drug-receptor complex
•Assumptions:
o 1 drug molecule binds one receptor
o reversible binding
o [D] much greater than [R]
o steady state reaction (association rate = dissociation rate)

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19
Q

Meaning of KD

A
  • equilibrium dissociation constant (units are Molar)
  • KD= [D][R]/[DR]
  • If [D]= KD, then 50% binding sites occupied
  • Or, concentration of drug to occupy 50% receptors
  • Low KD means tight binding/high affinity
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20
Q

Describe the importance of various physicochemical forces and stereochemistry in drug binding

A

Binding depends on complementarities between drug and receptor:
o Ionic bonds: long range, weak
o Covalent bonds: short range, strong
o Hydrogen bonds: short range, weak, directional
o Van der Waals force: short range, weak
o Chemical structure: shape complementarities
o Hydrophobic interactions: H2O exclusion
o Repulsive forces: steric, ionic, dipole

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21
Q

Dose-Response Curves

A

Magnitude of drug effect or % response as function of dose
•Graded responses
o Continuum of response
o Plot response vs dose
•Quantal responses
o Response is either/or value (only 2 possibilities)
o Plot %response (fraction of patients who respond) vs dose

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22
Q

Define ED50 and EC50

A

•ED50: effective dose for 50% response
o Use to measure drug safety

•EC50: effective concentration for 50% response

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23
Q

Explain receptor reserves and how they are demonstrated

A

•A fractional occupation of total number of receptors generates max response
•Demonstrate with irreversible antagonists
o Add some antagonist, still get max response
o Eventually, exceed receptor capacity and get decrease max response

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24
Q

Efficacy

A
  • ability to produce a given response

- more important than potency in therapeutics

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25
Q

Potency

A

oDose required to produce specific response
oDifferent drugs may need different dose to reach same response
oED50 or EC50
oDepends on receptor affinity and efficiency of response

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26
Q

Therapeutic Index

A

(TI) = TD50/ED50
o Dose producing toxicity in 50% population
o Dose producing response in 50% population

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27
Q

Certain Safety Factor

A

(CSF) = TD1/ED99

o More useful measure than TI

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28
Q

Differentiate among agonists, partial agonists, antagonists, and inverse agonists

A

•Agonists: activate receptor to initiate sequence of events leading to response
•Full agonist: creates maximal response
•Partial agonist: has less efficacy than full agonist (response less than maximal)
o When combined with full agonist, appears to be an antagonist because competes for receptor binding sites
•Antagonist: does not activate receptor when binds
o No intrinsic efficacy (but not necessarily no biological effect)
o Blunts effects of agonists
•Inverse agonists: decrease constitutive activity
o Inhibit agonist -dependent and -independent receptor activity
o Stabilize inactive form of receptor

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29
Q

Competitive Antagonism

A 
o	Competes for binding site on receptor
o	Surmountable
Dose-Response Curve:
o	No change on max possible effect
o	Shifts curve right (higher agonist concentrations)
o	ED50 increases
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30
Q

Noncompetitive Antagonism

A 
o	Produces nonfunctional complex or has post-receptor site of action
o	Insurmountable
Dose-Response Curve:
o	Decreased maximum effect
o	ED50 unchanged
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31
Q

Irreversible Antagonist

A 
(type of noncompetitive)
o	Forms covalent antagonist-receptor complex
Dose-Response Curve:
o	Decreased maximum effect
o	ED50 unchanged
32
Q

Chemical Antagonist

A

o Antagonist directly chemically alters agonist

o Ex. Calcium binds tetracycline, so not absorbed in gut

33
Q

Therapeutic Window

A

Range of doses between minimum efficacy and minimum toxic dose

34
Q

Describe the mechanisms of drug movement across biological membranes

A 
•Filtration
o	Passive
o	Body has both small and large pores
•Diffusion
o	Passive, from high to low concentration
o	Lipophilic molecules
o	Fick’s Law: Rate of molecular movement = (concentration gradient) x (permeability coefficient/thickness) x (Area)
o	Affected by local pH
•Transport by special carriers
o	Facilitated diffusion
•	Need a carrier but no energy expenditure
•	Specific, saturable
oActive transport
•	Moves against gradient
•	equires energy
•	Specific, saturable  
•	Ex. P-gylcoprotein (MDR-1)
•Endocytosis or pinocytosis
35
Q

diffusion-limited absorption

A

o When a drug has difficulty passing across a membrane

o Affected by thickness, area, local pH

36
Q

perfusion-limited absorption

A

o Small, lipophilic drugs moving across thin membranes

o Faster the flow, faster the absorption

37
Q

Characterize the difference between a weak acid and a weak base

A

•Weak acid donates a proton; protonated form is uncharged and can cross membrane
o AH → A- + H+
•Weak base accepts a proton; unprotonated form can cross
o B + H+ → BH+

38
Q

Describe the relationship between pH, pKa, and a drug’s membrane permeability

A

•H-H equation: pKa – pH = log [protonated]/[unprotonated]
o When pKa = pH, 50% in protonated form
• Ion trapping: uncharged form can cross membrane; charged form cannot
o So different rates of absorption depending on local pH

39
Q

Enteric routes of drug administration

A

oOral
• Common, safe, easy, patient-friendly, economical
• BUT: slower onset, variable absorption, first-pass effect
• Affected by: pH partitioning, gastric emptying time
oSublingual
• Lipophilic substances, onset within minutes
• Avoids first-pass effect
oRectal (suppositories, enemas)
• Useful if patient is vomiting or unconscious
• Decreased first-pass effect (about half of absorbed drug bypasses liver)

40
Q

Parenteral routes of drug administration

A

oSubcutaneous
• Slow absorption can provide sustained effect
• But not suitable for large volumes or irritating substances
oIntramuscular
• Rapid absorption of drugs in aqueous solutions
• Can use for poorly soluble drugs
• Faster absorbed since higher blood flow
• Can tolerate more or irritating substances
• Used for anaphylaxis tx (epinephrine) and vaccines
• Soreness common
oIntravenous
• Bypasses absorption phase so highly accurate
• Good for large volumes, irritating substances
• Not good for oily solutions or insoluble drugs
oTopical
• Can deliver drug at or beneath point of application
• Systemic effect with transdermal delivery
oIntra-arterial
• Chemotherapeutic or diagnostic agents
oIntrathecal (into CSF)
• For spinal anesthesia
• CNS infections or chemotherapy; bypasses BBB
oPulmonary
• Gaseous and volatile drugs, aerosols
• Large SA, so rapid absorption
• To reach alveoli, particles need to be under 1 um
• If 1- 5 um, ciliary action sweeps particles to GI tract
• Important for local application of drugs

41
Q

Identify factors that affect drug distribution

A
  • Blood flow
  • Affinity of cells for drug
  • Ability of drug to cross membranes
  • Liver: enterohepatic cycling of drugs excreted into bile
42
Q

Describe ABC transporters and their role in drug distribution

A
  • “ATP-Binding Cassette” transporters
  • Transmembrane proteins that actively extrude a variety of substances from cells
  • Broad and overlapping substrate specificities
  • Expressed in liver, kidney, GI, testes, placenta
  • Affect uptake, distribution, and elimination of drugs
  • Ex. ABCB1/P-glycoprotein: amphipathic anion, nonconjugated neutral or weakly basic lipophilic substrates
43
Q

Enterohepatic Cycling

A
  • Circulation of modified drugs from liver into bile into intestine
  • Gut flora change drug back to original
  • Drug is reabsorbed, goes back to liver via hepatic portal vein
  • Significance: gut flora can change drug distribution; drugs can become hepatotoxic
44
Q

Explain the concept of apparent volume of distribution

A
  • Apparent volume (Vd) = (amount drug in the body)/(concentration measured in blood)
  • Higher the apparent volume, the more drug in the tissues
45
Q

Name two drug-binding proteins in plasma and know their drug binding characteristics

A
  • Albumin: binds weak acids; lower levels in infants <1 year and people with liver disease leading to altered drug distribution
  • Α1-acid glycoprotein: binds weak bases
46
Q

Name the blood-organ barriers that exist in the body and describe their effects on drug distribution

A

•Blood-brain
o Tight junctions between capillary endothelial cells
o Lipophilic compounds can pass
•Blood-thymus
o Tight junctions between capillary endothelial cells
o Isolates lymphoid cells in cortex, but not medulla
•Blood-testis
o Tight junctions between Sertoli cells
o Isolates spermatocytes from blood
o Sertoli cells protect and nourish spermatocytes
•Blood-ocular:
o Blood-aqueous: isolates aqueous chamber from blood
• Tight junctions between ciliary non-pigmented epithelial cells
o Blood-retinal: isolates retinal cells from blood
• Tight junctions between retinal pigmented epithelial cells

47
Q

Explain how drugs distribute into the CSF and across the placenta

A 
•CSF
o	Few cells/mL, extremely low protein
o	Lipophilic molecules can cross BBB
o	Constant flow, any xenobiotic in CNS can exit with CSF to veins
o	Organic acid and base transporters
•Placenta
o	NOT a barrier
o	Amino acids: active transport
o	Glucose: facilitated diffusion
o	Most drugs: simple diffusion
•	Still can cross if bound to plasma proteins
•	Permeable to albumin, IgG, sometimes even RBCs
48
Q

Describe the first-pass effect

A

Drug concentration is reduced before it reaches systemic circulation
o Absorption by GI → hepatic portal vein → liver → rest of body
o Reduces bioavailability

49
Q

Define Phase 1 reactions

A

•Functionalization reactions
o Oxidative and reduction reactions: create new functional groups
o Hydrolytic reactions: cleave esters, amides and epoxides; reveal carboxylic acids, alcohols, and amines
•Changes chemical structure to become more polar → more soluble

50
Q

Name the five major isoforms of cytochrome P450 (CYPs) enzymes

A
  • Major Phase I enzyme family
  • Require NADPH and O2 to function
  • CYP1A2
  • CYP2C9
  • CYP2C19
  • CYP2D6
  • CYP3A4 (metabolizes about ½ of current drugs)
51
Q

State the major chemical transformations catalyzed by cytochrome P450 enzymes

A
  • Aliphatic and aromatic hydroxylation
  • Alkene and aromatic epoxidation
  • N-, O-, and S-dealkylation
  • N-oxidation and N-hydroxylation
  • Oxidative deamination and desulfuration
  • S-oxidation
  • Oxidative dehalogenation
52
Q

List other enzymes involved in Phase 1 reactions

A
  • Flavin adenine dinucleotide (FAD) monooxygenase
  • Monoamine and diamine oxidase
  • Alcohol dehydrogenase
  • Aldehyde dehydrogenase
  • Xanthine oxidase (in uric acid metabolism)
53
Q

Define Phase 2 reactions

A
  • Conjugation reactions

* Usually couple polar groups to functionalized substrates

54
Q

Name the five major Phase 2 reactions, name the cofactors involved, and describe the role of the cofactors in these reactions.

A

• Glucuronidation
o Uridine disphosphate-glucuronyl transferases (UGTs)
o Mainly in liver; also intestine, kidney, skin
o Adds glucoronic acid to acceptor molecules (hydroxyls, carboxylic acids, thiols, amines)
o Substrates: bilirubin, bile acids, steroid hormones

• Sulfation
o Sulfotransferases
o Liver, intestine, lung, adrenal glands
o Attaches sulfate groups to hydroxyl groups

• Mercapturic acid formation
o Glutathione-S-transferase (GST)
o Liver, kidney, lung, intestine
o Adds glutathione (Gly-Cys-Glu) to acceptors
o Then hydrolysis of glutamate and glycine, then acetylate cysteine to make polar, highly excretable product

• N-, O-, S- methylation
o	Phenylethanolamine-N-methyltransferase
o	Histamine-N-methyltransferase
o	indolethylamine-N-methyltransferase
o	catechol-O-methyltransferase
o	thiol-S-methyltransferases
o	Located in liver, kidneys, lung, brain
o	Adds methyl group from S-adenosyl methionine to acceptor molecules

• Acetylation
o Arylamine N-acetyltransferase
o Important in xenobiotic metabolism
o Catalyzes transfer of acetyl group from AcetylCoA to various amine and hydrazine acceptor molecules

55
Q

Name substances that induce cytochrome P450s.

A
  • Polycyclic aromatic hydrocarbons (from incomplete combustion products)
  • Anticonvulsants: Carbamazepine, Phenobarbital, Phenytoin
  • Glucocorticoids: Dexamethasone, Prednisone, Triamcinolone
  • Peroxisome proliferator activated receptor alpha agonists: Clofibrate, Fenofibrate
  • Rifampin
  • St. John’s Wort
  • HIV drugs: Efavirenz, Nevirapine, Ritonavir
56
Q

Explain how xenobiotics can produce decreases in drug metabolism

A
  • Cofactor depletion
  • Reversible competitive inhibition (substrates for metabolic enzymes compete for binding sites with other drugs and inhibit their metabolism)
  • Covalent inhibition (reactive intermediates covalently modify and inactivate enzymes)
  • “Pseudoirreversible” inhibition: Intermediates dissociate very slowly
57
Q

Name substances that block the metabolism of other drugs.

A

(via reversible competitive inhibition)
o Antibiotics (clarithromycin, erythromycin)
o Gemifibrozil
o Azole-class antifungals (itraconazole, ketoconazole, posaconazole, voriconazole)
o HIV protease inhibitors (indinavir, ritonavir, saquinavir)
o 1st generation H2 antagonists (cimetidine)
o Grapefruit juice (inhibition can last 3 days with regular consumption)

(via covalent inhibition)
o Disulfiram inhibits aldehyde dehydrogenase (treat alcohol abuse)

58
Q

Examples of enzyme inhibitors

A

• MAO inhibitors
o Example: pargyline → ↑ concentration of biogenic monoamines (serotonin, norepinephrine, dopamine)
• Aromatic L-amino acid decarboxylase inhibitors
o Example: carbidopa → longer half-life of levodopa → ↑ plasma concentration and CNS availability → can decrease the dose of levodopa required to treat Parkinson’s disease
• Xanthine oxidase inhibitors
o Example: allopurinol → ↓ uric acid biosynthesis → ↓ gouty deposits
• Peptidase inhibitors
o Example: cilastatin → inhibits renal dehydropeptidase-I, which is responsible for b-lactam inactivation → ↑ therapeutic activity of b-lactam antibiotics

59
Q

Explain how age, environmental factors, diseases, and genetic polymorphisms affect drug metabolism; name three drugs whose metabolism is affected by genetic variation.

A

• CYP polymorphisms
o DYP2D6 most commonly mutated
o Affects warfarin, omeprazole, codeine, dextromethorphan, most SSRIs, beta-blockers, many antipsychotic agents
• N-acetyl transferase activity
o Isoniazid and procainamide inactivation
o Fast and slow acetylators
• COMT deficiency
o Decreased isoproterenol metabolism
• Thiopurine-S-methyltransferase deficiency
o Azathioprine, 6-mercaptopurine toxicity
• Butyrylcholinesterase (pseudocholinesterase) activity
o Succinylcholine sensitivity
o Succinylcholine resistance
• Age
o Infants: not reach adult levels of metabolizers until weeks to years after birth; hepatic metabolism matures at 1 year
o Elderly: lower hepatic metabolic activity
• Nutritional Status
o Decreased CYP metabolism with protein deficiency
o Decreased CYP metabolism with iron deficiency
• Pathological state (ex. Liver disease)

60
Q

Describe the physiology of the renal tubule.

A

• Glomerular filtration
o Blood→ urine
o Unbound drugs are freely filtered; protein-bound drugs are not
• Passive reabsorption
o Water is reabsorbed so get increased drug concentrations
• Creates concentration gradient for drug
o Lipid soluble drugs reabsorbed to blood
o Polar or ionized drugs remain in urine
• Active transport
o Pumps move organic acids and bases from blood to urine

61
Q

Describe glomerular filtration

A

o 10% of renal blood supply gets filtered
• Normal GFR: 120-130 mL/min
• Renal failure: <14 mL/min
o No cells/proteins larger than 60-75 kD
o Unbound drugs are freely filtered
o Amount of drug filtered depends on GFR and extent of binding to large proteins

62
Q

Describe renal tubular transport

A

o Active transport for Na+, Cl-, HCO3-, glucose, and amino acids
• NOT for drugs
o Endocytosis for filtered proteins
• Get reabsorbed by cells in proximal tubule
o Drugs use passive reabsorption and active secretion
• Passive reabsorption
• H20 follows salt back to blood
• Lipophilic substances diffuse back to blood as concentration increases
• Hydrophilic substances stay in tubule
o Get more concentrated as more water reabsorbed
• Active secretion (transport from plasma to urine)
• ATP-binding cassette transporters
• Organic anion secretion (organic base ionized at physiological pH)
• Organic cation secretion (organic base ionized at physiological pH)
• Effect: transport systems “strip” drugs from bound proteins as drug is secreted into tubules
o More drug dissociates to maintain equilibrium

63
Q

Predict the effect of urine pH on drug excretion given whether the substance is a weak acid or a weak base

A
  • If urine more acidic, greater excretion of weak bases (trapped in urine)
  • If urine more basic, greater excretion of weak acids
64
Q

Use the Cockcroft-Gault equation to estimate renal function

A

• Creatinine Clearance = (140-age) x body weight [kg]/ (serum creatinine [mg/dL] x 72)
o Units: ml/min
o For females, multiply by 0.85
• Normal female: 88-128 mL/min
• Normal male: 97-137 mL/min
• Use to estimate clearance in patients with impaired renal function
o Able to adjust dosing for drugs excreted by kidneys

65
Q

Explain the process of biliary excretion

A

• Bile: made of water, electrolytes, and organic molecules (bile acids, cholesterol, phospholipids, bilirubin)
• Produce 400-800 mL/day
• Active transport from plasma to bile
o Transport systems in canalicular membranes of hepatocytes
o ATP-binding cassette transporters (broad specificity)
o Organic acid and base transporters
o Neutral compound transporters (use ouabain as marker)
o Minimum molecular weight of 275-375
• Conjugation may increase molecular weight above threshold
o Metals: Mn, Hg, Cu, Zn, Cd
o Enterohepatic cycling: drugs excreted in bile may be reabsorbed in intestine

66
Q

Contrast zero-order and first-order elimination kinetics

A

• Zero order
o Rate of change is independent of drug concentration
• Ex. When enzyme is saturated
o Few drugs in this category (exception is alcohol)
• First order
o Rate of change is directly proportional to drug concentration

67
Q

State the formula for volume of distribution

A

• Vd= apparent volume of distribution determined at time 0
o Small Vd: drug is mostly in blood bound to plasma proteins
o Large Vd: drug is distributed in tissues
• Vd = amount of drug in body/ plasma drug concentration = A/C

68
Q

State conditions that may alter the volume of distribution

A

o Uremia (uric acid in blood), burn patients
• Decreased albumin binding so increased Vd
o Pregnancy, ascites, edema
• Another “compartment” so decreased plasma concentration, higher Vd
o Dehydration
• Increased plasma concentration so increased Vd
o Congestive heart failure, End stage renal disease
• Decreased clearance of drugs excreted by kidneys
• Can increase OR decrease Vd

69
Q

State the first-order elimination formulae in terms of concentration or amount of drug

A 
•	A = dose x e ^ (-ke x t)
•	Ke= elimination rate constant
o	Equal to slope of elimination line
o	Units of time^-1
o	Negative Ke because concentration of drug decreases over time
70
Q

State the elimination half-life formula

A
  • Elimination half-life = time taken for plasma concentration to decrease by one-half
  • General Rule: after 5 half-lives, virtually all of drug is eliminated
  • t(1/2) = 0.7/ Ke
71
Q

Explain the meaning of clearance. State the formulae relating clearance, volume of distribution, elimination rate constant, and half-life

A
  • Clearance = CL = Ke x Vd
  • t(1/2) = (0.7 x Vd)/ CL
  • Units are vol/time
  • Fraction of fluid entering an organ from which all drug is cleared
72
Q

Explain constant-rate infusion and the concept of steady-state plasma concentration

A

• Goal is to maintain a stable plasma concentration (plateau, steady state)
o All drugs infused at same rate and having same clearance will reach same plateau concentration
o When infused at same rate, amount in body at plateau is same for all drugs with same half-life
• Steady state (ss) infusion = (rate of elimination)ss = CL x C(ss)
• Amount in body (ss) = Vd x C(ss)

73
Q

Describe multiple-dose regimens

A

o Drugs taken on fixed dose, fixed time intervals
o A and C(ss) will fluctuate
o Takes 5 half-lives to reach plateau
o To maintain effect, nontoxic drug concentration, can modify size or frequency of dosing

74
Q

Calculate a maintenance dose rate.

A

• Elimination rate determines the maintenance dose rate
• For constant dosing: Dm rate = CL x C(ss) = Ke x Vd x C(ss)
• For intermittent doses: Dm rate = CL x C(ss) x dosing interval (τ)
• To make sure concentrations not go outside of therapeutic window:
o Dm,max= maximum maintenance dose = (Vd/F)(C,upper- C,lower)
o τ, max = maximum dosing interval = [ln (C,upper/ C,lower)]/Ke
o When Dm,max is given very τmax, C(ss) will be the average between C,upper and C, lower
• To calculate dosing interval smaller than τmax but still maintain the same C(ss)
o Dm = (Dm,max/ τmax) x τ

75
Q

Calculate a loading dose

A
  • Used to rapidly achieve a therapeutic level (especially for drugs with a long half-life)
  • A = Vd x desired plasma concentration
76
Q

Describe how bioavailability affects drug dose and know how to adjust the dose accordingly.

A
  • Bioavailability = F= fraction of drug reaching systemic circulation for a particular route of administration
  • IV drugs are 100% bioavailable
  • F = (area under curve of route) / (area under curve of IV)
  • So to correct for bioavailability, divide IV dose by F

Pharmacology (6 decks)

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