PBS 1.2 Objectives
27. Differentiate between lipid and water soluble drugs in regards to drug metabolism.
Lipid soluble: - metabolite = h2o soluble - CYP450 in Smooth ER of hepatocytes
22. Describe the various ways that drugs are metabolized and eliminated from the body.
Major determinant of duration of action of drug Metabolism: - via CYP450s in smooth ER of hepatocytes - limited GI, kidney, blood - lipid soluble drugs > h2o soluble for excretion Excretion: - via urine in kidneys - h2o soluble drugs & drug metabolites - (could also be exhalation via lungs, biliary via GI, sweat, saliva, breast milk)
7. Define and differentiate between: p. Drug metabolites versus active metabolites
Metabolite -what drug is broken into after metabolism (usually by liver) - Active Metabolite add to pharmacologic effects
30. Describe genetic factors that can influence drug metabolism.
Pharmacogenomics: - variability in CYPisozymes & Phase II metabolism
28. Differentiate between the phases of drug biotransformation (phase I and phase II metabolism) and be able to describe the general reaction types involved in each.
Phase I: - oxidation - CYP450s Phase II: - conjugation - Transferases (cytosol)
7. Define and differentiate between: q. Pro-drug
Pro-drug is when drug is only activated by metabolism
8. Compare and contrast quantal versus graded dose/response curves.
Quantal - binary (all-or-none) - effect = present or absent - potency in terms of efficacy Graded - cumulative - response to drug by individual
24. Describe when steady state is generally achieved.
Rate of drug admin = rate of drug elim - achieved after 5t(1/2) Time to reach [plasma drug] -depends only on t(1/2) drug - independent of dose May need to reach steady state quickly > loading dose =(VTC)/F - drug w/ narrow therapeutic window, large fluctuations are problem, minimized by... - slow abspt'n rate (controlled release formulat'n) - decrease dosing interval (small doses @ ^fq)
7. Define and differentiate between: c. Pharmacogenetics
Study of variation in individual's gene coding for drug metabolizing enzymes
7. Define and differentiate between: e. Bioavailability
The fraction of the drug which reaches systemic circulation
7. Define and differentiate between: m. Efficacy
how well a drug produces a response
7. Define and differentiate between: n. Tachyphylaxis
loss of drug effectiveness over short time (min/hr)
13. Differentiate between intracellular enzymes as they relate to drug binding
(extracellular receptor) - aspirin inhibits cyclooxygenases that synth prostaglandins -> analgesic, anticoag, antipyretic effects - hyperlipidemias (statins) inhibit enzyme in cholesterol synthesis - hypertension (ACE inhibitors) inhibit enzyme needed for formation of angiotensin - tyrosine kinase receptor (binds insulin)
1. Define e. Proprietary (brand) name
Brand name is given by the manufacturer, is trademarked, and best recognized by patients
7. Define and differentiate between: o. Drug tolerance
gradual loss of drug effectiveness (days/week)
31. Describe the role of P-glycoproteins and their relationship to drug metabolism.
- expel drug mols from intestinal mucosa into lumen of GI tract - opposite direction to drug absorption - inhibitors of can ^ drug absorption & ↓ excretion of some drugs - verapamil & grapefruit juice
13. Differentiate between intracellular receptors
- located in cytoplasm & on binding hormones - translocated to nucleus -increase/decrease gene transcription anti-inflammatory steroid hormones: - (prednisone) Thyroid hormone (thyroxine) -change gene expression - used in cancer drugs & some antibiotics
7. Define and differentiate between: l. Potency
- measure of quantity of drug needed to activate a receptor - usually determined as amount of drug needed to cause a half maximal response (EC50)
29. Compare and contrast the cytochrome P isoenzyme inducers with cytochrome P isoenzyme inhibitors and how this might affect drug metabolism and be relevant to drug-drug interactions.
- multiple inducers correspond w/ mult. CYP families (max induction after days of drug tx & similar time to regress after withdrawal of inducer) Inducers: ^ drug metabolizing capacity bc ^ CYPisozymes ^ rate of CL ^ risk of inadequate tx Inhibitors: ↓ drug metabolizing capacity bc ↓ CYPisozymes ↓ rate of CL ^ risk of side effects & toxicity
13. Differentiate between G-coupled receptors
- muscarinic - metabolic & catabolic actions (respond to NTs, hormones, autocoids & cytokines) -largest protein family expressed in human genome - single subunit (w/ 7 transmem-spanning domains) Gs - stimulation of adenylyl cyclase - includes receptors for adrenergic amines, glucagon, histamine Gi - inhibition of adenylyl cyclase - includes receptors for acetylcholine, adrenergic amines, & opiods Gq - increase IP3, DAG, Ca2+ - includes receptors for ACh, rhodopsin & serotonin
13. Differentiate between ligand-gated ion channels
- nicotinic, glutamate, GABA - CNS & PNS, skeletal myoneural junction, heart -made of subunits (usually 4 transmem-spanning domains) -target for disorders of cardiac rhythm -targeted by local anesthetics Na+ channels responsible for action potential -> prevent Na+ influx (depolarization) -> inhibition of conduction of pain signals
21. Describe the physiology of the first-pass effect and be able to identify routes of drug administration that are/are not subject to this effect.
- part of absorption - takes places in liver with oral admin'd drugs - some drugs rapidly metabolized so decreased bioavailability *buccal & sublingual admin bypasss hepatic-portal route
7. Define and differentiate between: d. Volume of distribution
- reflection of ability of drug to distribute throughout the body tissues - drugs distributed into total body water have V(d) = 0.6 L/kg • water soluble (aspirin) - drug with V(d) > 40-42 L/kg are sequestered in fats (ie. can't be measured in [plasma] • lipid soluble (morphine)
7. Define and differentiate between: f. Elimination half-life
- time required for blood level to decrease by 50% -can predict duration and intensity
7. Define and differentiate between: h. Clearance
- volume blood cleared/time - L/hr - Elimination/[plasma] - kinetic characteristic of a [drug] and its elimination from the blood - constant in 1st order elimination
15. Compare and contrast up-regulation and down-regulation of receptors.
-body wants to maintain homeostasis if blocking channel with drug -> body will ^ # receptors till max receptors reached (during which time dosage of drug must also be ^ to maintain effect - both can work on receptors or ligands - leads to super sensitivity
7. Define and differentiate between: g. First order & zero order elimination
1st order elimination: - drugs with rate of elimination/[plasma] is proportional Zero-order elimination: - drugs with rate of elimination = constant
7. Define and differentiate between: j. Therapeutic window/index
= plasma drug level above [min effective] but below [min toxic]
25. Describe how clearance of a drug affects its half-life.
= rt elemination/[drug plamsa] ^ clearance = ^ elimination? - primarily occurs in kidneys & liver - constant in 1st order elimination - as blood level ↓ rt of removal ↓ *unless elim mech impaired - if CL ↓ then t(1/2) ^ so dose must be ↓ to avoid toxicity - if CL ^ then t(1/2) ↓ so dose must be ^ to maintain effective drug levels
11. Compare and contrast the differences between agonists (full and partial) and antagonist (competitive and non-competitive) and be able to describe their effects on dose/response curves.
Agonists: stimulate receptor full - fully stimulate receptor partial - partially stimulate receptor Antagonist: prevent receptor stimulation competitive - binds to receptor site & changes potency non-competitive - binds to allosteric sit & changes efficacy
1. Define c. Chemical name
Chemical name describes the chemical formulation of drug (used by pharmacists)
14. Describe the mechanisms for the development of receptor desensitization, tachyphylaxis, and tolerance.
Desensitization - continuous use of drug can result in reduced response -> must increase dose to obtain original effect Tolerance - decreased response over greater time Tachyphylaxis - decrease response over short period of time
20. Differentiate between "bound drug molecules" and "free drug molecules".
Distribution: tissue dist = lipophilicity/drug, bloodflow to organ, ability of drug to bind blood protein (albumen) only free drug mols can cross mem and enter tissue [free drug] determines mag of pharmacologic effect ***some drugs can be displaced from plasma proteins by other drugs -> ^ effects***
10. Differentiate terms such as efficacy, potency and therapeutic index as they relate to drug therapy.
Efficacy - dose/response relationship Potency - comparative dose/response relationship (ie. drug A is more potent than drug B bc smaller dose = greater effect) Therapeutic index - comparative efficacy vs. toxicity
9. Differentiate between the Emax, the EC50, the TD50, the ED50 and the therapeutic index (T.I.)
Emax = dose needed for max effect EC50 = dose needed for 50% effect ED50 = median effective dose TD50 = median toxic dose
2. Describe and define the following oral preparations of drugs and be able to utilize this information to recommend a preparation for a patient. a. Tablets
Form • hard pill, mixture of powdered drug + inert ingredients • fillers, lubricants, adhesives, disintegrates Function • ↑stability • delivery of drug can be immediate or delayed release • facilitate solubizat'n when tablet reaches GI fluid • variable bioavailability in different formulat'ns ̶ different rate & extent of disintegrat'n/dissolut'n
2. Describe and define the following oral preparations of drugs and be able to utilize this information to recommend a preparation for a patient. b. Capsules
Form • hard/soft gelatin shell enclosing powder/liquid med • hard = powdered • soft = liquid • regulates release of drug from pharm product
2. Describe and define the following oral preparations of drugs and be able to utilize this information to recommend a preparation for a patient. c. Solutions
Form • liquid pharmaceutical preparation • small particles (ions/molecules) ̶ homogeneous ̶ solution fully mixed Function • oral, parenteral, other routes of admin • convenient for pediatric/other pts who can't swallow pills/tablets • Cons - measured each time dose administered
1. Define d. Nonproprietary (generic) name
Generic name is usually a shortening of chemical name and is used by providers
23. Compare and contrast first order elimination with zero order elimination.
Rate of elimination directly proportional to plasma level (exponential decay) -elimination half-life = constant regardless of amount of drug in body - blood level decreases by 50% during each half life
26. Describe factors that might affect drug clearance and how this might influence decisions regarding dosing.
Requires altered dose &/or dosing interval for maintenance dosing: - renal/hepatic disfunction: ↓ CL - change in renal function - GFR: ^/↓ in CL - Active secretion: ^ in CL -pH: ^/↓ in CL (depending on drug weak acid/base) - other drugs (drug-drug interactions) - induction of drug metabolizing enzymes: ^ CL - inhibition of drug metabolizing enzymes: ↓ CL
32. Describe how the elimination of a drug influences dosing and treatment indications.
^ elimination = ^ dosing
16. Describe the basic pharmacokinetic principles governing absorption, distribution, and elimination of drugs and apply these principles in the therapeutic management of patients.
absorption : - 1st order or 0 order distribution: -binding to plasma proteins - volume of distribution - structural barriers of dist. elimination: - metabolism & excretion (kidneys)
12. Differentiate between the three types of drug antagonism (chemical antagonists, physiologic antagonists, and pharmacologic antagonists).
chemical antagonist: -compounds bind directly with drug molecules thus preventing their interaction with receptors - dimercaprol for chelating heavy metals physiological antagonists: - activates different receptor that exerts opposing effects -inhibitor antagonist of enzyme that breaks NT down -> rate of NT release unchanged but NT not being broken down = more NT present in synapse = more signaling (even though drug inhibitory) pharmacologic antagonists: - binds same receptor and blocks activating effect - full v partial
7. Define and differentiate between: i. Steady state
rate of drug admin = rate of rug elimination - with continuous drug admin, steady state is achieved after 5 half-lives of a drug
1. Define a. Toxic effects
response to substance contributing to adverse effects
7. Define and differentiate between: k. Dose response curves
shows the relationship between drug dose & magnitude of its effect
1. Define b. Adverse effects
undesirable effects (usually related to drug)
18. Describe the effect that pH has on the permeation of drugs and describe how the ionization of molecules influences permeation of biomembranes.
weak acid = ionized in basic envt weak base = ionized in acidic envt Why do we care? only unionized forms of drugs are lipid-soluble and can cross biomem.
7. Define and differentiate between: r. Toxic metabolite
when drug metabolite can damage/kill cells
3. Describe the routes of drug administration and be able to provide an example of how a drug would be administered in such a way and when such a route might be preferred, including the following: b. Parenteral administration
• admin'd w/ needle & syringe/IV infusion pump Methods • intravenous (IV) ̶ bypasses absorption > immediate effect ̶ RAPID ̶ 100% bioavailibility Cons ̶ > risks for toxicity ̶ most dangerous ̶ > $ compared to other routes Intramuscular ̶ solution(rapid absrpt'n rt) ̶ suspension (sustained absrpt'n rt) ̶ faster than subQ bc > bloodflow to muscles ̶ slower than IV Cons ̶ possibly painful ̶ can cause bleeding (prblm if pt. on anntcoag) • Subcutaneous ̶ suspention, solution, pellets ̶ slower than IV & IM Cons ̶ not for drugs that irritate cutaneous tissues ̶ must be given in large doses • Intrathecal ̶ injection through thecal covering of SC into subarachnoid space ̶ for admin of drugs that w/n cross BBB ̶ ex. = antibiotic for meningitis • Intra-articular ̶ tx of arthritis • intradermal ̶ allergy tests
2. Describe and define the following oral preparations of drugs and be able to utilize this information to recommend a preparation for a patient. d. Suspensions
• larger particles • heterogeneous (may look cloudy/murky) • not fully mixed • non-transparent
2. Describe and define the following oral preparations of drugs and be able to utilize this information to recommend a preparation for a patient. e. Syrups
• sweetened aqueous solution/suspension • more palatable
2. Describe and define the following oral preparations of drugs and be able to utilize this information to recommend a preparation for a patient. f. Elixirs
• sweetened aqueous-alcoholic solution • alcohol acts as solvent for drugs not soluble to h2o alone
