Pharm Kinetics

Describe the difference in plasma concentration w/ time for the dif. drug routes

List the advantages and disadvantages of IV admin

Advantages of IV Admin.

• immediately enters circulation

• rapidly distributed to tissues

• Rapid response

• Permits instant dosage titration

• Useful drug is destroyed by gastric contents or heavily

• metabolized by first pass effect

• Allows maintenance of constant blood Levels

• Large quantities can be administered for a long time

• Reduced irritation due to diluting/buffering by blood

• Always Available (unconscious patients)

---

Disadvantages

• drug cannot be removed

• Too Rapid Injections = serious reactions 

• too much drug arrives @ Target organs 

• Not easy self-admin

• Must use sterile technique

• Pt. Discomfort 

• Complications (irritation,allergy, etc) difficult management

Describe Bioavailability

• Define

• Affected by?

• Definition:

  • proportion (fraction) of unchanged drug -> systemic circulation.

• Affected by 

  • first-pass metabolism, 

  • drug formulation 

  • route of administration.

• NOTE: 100% w/ IV admin.

What is first pass hepatic metabolism in regards to drugs

Oral Admin → GI Absorption →Hepatic portal circulation → rapid and extensive metabolism → decrease # of unchanged drug reaching systemic circulation

List and describe the factors that influences bioavailability

1. Drug solubility:

   • Lipophilic drugs = more absorbed.

   • Molecular weight/size

2. Chemical Instability:

   • Susceptibility to pH of gastric juice

3. Drug formulation:

   • Particle size, salt form etc

1. Draw out the graph depicting the difference between injections and oral drugs

2. What is the formula for Bioavailability

Describe Steady state:

• Definition?

• Mathematical Formula?

• Draw out the graph depicting this

• Definition:

  • Rate of drug elimination balances drug input rate.

    • [Plasma] = constant.

• Mathematically:

  • 4-5 half-lives to reach steady state.

  • 3.33 half life = 90%

1. What is the THERAPEUTIC WINDOW

2. What determines this?

3. What window = toxic?

• Definition:

  • safe “opening” btw minimum therapeutic and toxic concentrations

• Determined by:

  • minimum [effective]

    • Determines the desired trough level

  • minimum [toxic]

    • Determines the permissible peak plasma concentration

• Therapeutic index <10 = toxic

Describe Drug Absorption:

• Definition

• Rate + Efficacy

• Mechs of Absorption?

Drug Absorption

• Definition:

  • Transfer of drug from site of administration to blood stream

• Rate + efficacy:

  • Depends on Route of Admin

  • Complete absorption after IV administration

• Four mechanisms of absorption

  1. Passive diffusion

  2. Active transport

  3. Facilitated diffusion

  4. Pinocytosis

• NOTE: REVIEW IF NEEDED

1. Describe the Non/Ionization of Weak Acids/Bases:

   • Env of best absorption?

   • Location in GI?

   • EX?

2. Describe how ionization leads to excretion?

Non/Ionization of Weak Acids/Bases:

• Weak acids 

  • Best absorbed in an acidic environment

    • PROX of Small Int.

  • Ex: Aspirin, Digoxin, Ketoconazole 

• Weak bases 

  • Best absorbed in a basic environment

    • Distal of Small Int.

  • EX: Quinidine, Morphine, Lidocaine 

---

NOTE:

• Non ionized = lipid soluble

• Ionized = water soluble ->  excreted

1. Describe Drug Distribution:

   • Definition

   • Depends on?

   • Relationship to Albumin?

2. Describe the complications of highly bound drugs

   • %?

   • Mech

   • Specific Types of Drugs

   • clinical Example

3. Describe Volume of distribution:

   • Definition

   • Formula?

• Definition:

  • Process by which drug reversibly leaves blood stream -> interstitium (ECF)

• Depends on 

  • blood flow

  • capillary permeability

  • drug binding

• Relationship to Albumin

  • Drugs usually bind to albumin-reversible binding 

    • Only free (unbound) drug is available for action

---

Complications of Highly bound drugs 

• (> 80%)

• Mech: Competes for binding to available sites ->  drug displacement into plasma -> toxicity

• Specific Types:

  • NSAID’s

  • Sulfonamides

  • Digoxin

  • Warfarin

• Clinical Example:

  • Sulfonamides contraindicated in neonates -> Bilirubin displacement -> (kernicterus)

---

Volume of distribution:

• Definition:

  • # of drug in body in relations to [drug] in blood/plasma/water (unbound drug)

• Formula:

  • Vd = Dose/Co (concentration)

Describe Drug Metabolism (Biotransformation):

• Effect on drugs

• Site?

• Affected by?

• Consequences?

• Effect on drugs:

  1. Terminates pharmacological action (inactivation) -> drug removal

  2. Can activate some drugs (prodrugs)

• Site: @ Liver

---

Affected by:

• Prior administration of drug/s

• Physiological status (eg. nutritional)

• Age

• Genetics

• Liver Function

---

Consequences 

• Produces inactive metabolites

• Metabolites w/ increased or decreased potencies

• Metabolites w/ different pharmacological actions

• Toxic metabolites

• Active metabolites

Describe Phase 1 of Biotransformation:

• Enzymes used? Clinical Relevance?

• Effect of inhibition/inducers of cytochrome P450? List out the substances that can do them 

Phase 1 Biotransformation:

Enzymes Used:

• Non-microsomal enzyme 

  • Hydrolysis (succinylcholine, amide local anesthetics) + alcohol metabolism

• Microsomal enzymes 

  • cytochrome P450 isoenzymes

    • NOTE: most abundant = 3A4

• NOTE: Clinical Relevance:

  • Genetic polymorphisms may exist

    • EX: pseudocholinesterases metabolize succinylcholine -> extended muscle paralysis.

---

Inhibition vs induction:

• Inhibition -> reduced meta. -> toxicity

  • Ex:

    • grapefruit juice, 

      • Inhibits statin meta -> rhabdomylosis and renal failure!

    • Cimetidine,

      • Inhibits 2C9-diazepam toxicity

    • omeprazole,

    • macrolide antibiotics (erythromycin) azole antifungals,

    • acute alcohol.

• Induction -> increase meta -> treat. Fail

  • EX:

    • barbiturates, 

    • all anticonvulsants (except valproate), 

    • rifampin, 

      • Induces  3A4 -> oral contraceptive fail

    • chronic alcohol.

      • may cause acetaminophen toxicity.

Describe phase 2 of Biotransformations:

• Enzymes used? Ex of medications for each enzymes?

• End result?

Phase II:

• Enzymes used:

  • Glucuronyl transferase (glucoronidation)

    • EX: 

      • Morphine -> Morphine 6b-glucoronide (6X more potent)

      • Chloramphenicol contraindicated in neonates (gray baby syndrome)

  • Sulfotransferase (sulfate conjugation)

    • EX: acetaminophen, methyldopa

  • Transacylases (amino acid conjugation)

  • Glutathione conjugation

    • Ex: Acetaminophen

  • Acetylation

    • EX: Hydralazine, Isoniazid, Procainamide (HIP)

      • HIP Drugs-SLE syndrome in slow acetylators!!

• Result:

  • Inactivation + increased water solubility = increased excretion

List and describe the impact of different phenotypes on drug metabolism

What are the Potential consequences of polymorphic drug metabolism

• Increased/decreased effective dose

• Extended/shortened therapeutic effect

• Adverse drug reactions and drug toxicity

• Metabolism by alternative, deleterious pathways

• Exacerbated drug-drug interactions

• Lack of pro-drug activation

[REVIEW] net renal excretion

1. What is the formula for Renal Elimination

2. Describe Clearance

   • Define

   • Formula?

Renal Elimination

• Formula:

  • Rate of elimination = (GFR) + active secretion – reabsorption

  • GFR = 120 (normally)

---

Clearance (Cl): 

Definition:

• volume of blood cleared of drug per unit of time

Formula:

• Cl = free fraction × GFR

  • Cl = GFR if no reabsorption or secretion and no plasma protein binding

    • Protein-bound drug is not cleared

• Cl is constant in first-order kinetics.

Differentiate between First and Zero order elimination rate

• What happens?

• Formula?

First-Order Elimination Rate

• What happens:

  • constant fraction of the drug is eliminated per unit time

  • t1/2 is a constant.

• Formula:

  • drug decreases by half every half-life

    • 80 -> 40 -> 20 every four hrs (T1/2)

---

ZERO -ORDER ELIMINATION RATE

• What Happens:

  • constant amount of drug is eliminated per unit time

    • Independent of [plasma] or # in body

  • half-life (t1/2) is a variable

• Formula:

  • Drug decreases by set amount every half life

    • 80 -> 70 -> 60 every 4 hrs (t1/2)

• Examples:

  • Ethanol “except low blood levels”

  • Phenytoin “high therapeutic doses”

  • Salicylates (toxic doses)

(T/F) Drug Elimination = drug excretion. Explain?

False:

A drug may be eliminated by metabolism long before the modified molecules are excreted from the body. Excretion is the mode of elimination for drugs that are not metabolized

Describe the Effect of Urine pH on renal Excretion:

Effect of Urine pH on renal Excretion:

• Acidification ->  ionization of weak bases -> increases excretion of weak bases

  • EX:  NH4Cl, cranberry juice, vitamin C

    • use NH4Cl last; too potent

• Alkalinization -> ionization of weak acids -> increases excretion of weak acids

  • NaHCO3, acetazolamide.

Differentiate between LD and MD:

• Definition

• Formula?

LOADING DOSE (LD)

• Definition:

  • First dose of drug treatment

  • required to achieve target [] rapidly.

• Higher loading dose = achieves effective blood levels (Cp)

• Formula:

  • (Vd X Cp)/F

    • Vd = volume of distribution

    • Cp= plasma concentration

    • F = bioavailability

---

MAINTENANCE DOSE (MD)

• Definition:

  • Dose rate to achieve + maintain target []

    • @ steady state:  dose rate in = rate of elimination

• Formula:

  • (Cl X Css X t)/ F

    • Cl = clearance

    • Css = concentration-steady state

    • F = bioavailability

    • t – frequency od administration (minutes)