Pharmacology - 1 - General Principles

Question 1

List the routes of administration for drugs.

Answer 1

1. Enteral
   
   • ingestion
     
     • 1st pass effect
     • absorption occurs via PASSIVE diffusion
2. Parenteral
   
   • IV
     
     • Absorption NOT involved
   • Subcutaneous + IM
     
     • slower, absorption involved
3. Other
   
   • inhalation
     
     • rapid/large SA
   • transdermal
     
     • via patch
   • topicall
     
     • local effect

Question 2

Describe the absorption patterns, advantages and limitations of drug administration by each of the routes.

Answer 2

(See Chart)

Question 3

Describe the 4 processes whereby drugs cross cell membranes.

Answer 3

1. Passive diffusion
   
   • drug must be water & lipid soluble
   • transfer = proportional to:
     
     • [con] gradient
     • partition coefficient
     • cell SA
     • pH difference for ionic compounds
2. Active transport
   
   1. requires ATP
   2. moves drug AGAINST electrochemical gradient
   3. Saturable
   4. Selective
   5. Drug can COMPETE for transport
3. Aqueous diffusion
   
   • lumen –> interstitum
     
     • filtration thru pores
   • across epithelium membrane tight jxn & endothelial lining of blood vessels
   • driven by [con] of permeating drug
   • drugs bound to large plasma proteins = DO NOT PERMEATE vascular aqueous pores
   • brain, testes, other tissues do not have pores
4. Transporter proteins
   
   • mediate drug efflux
   • sites of active transport
     
     • liver
     • kidney
     • intestines
   • p-glycoprotein & multi-drug-resistance type 1 (MDR1) transporter mediate efflux from select sites

Question 4

Describe the physicochemical factors that affect absorption of drugs.

Answer 4

1. molecular size
   
   • # & type of atoms + arrangement in space
2. partition coefficient
   
   • measure of overall polarity
3. ionic character
   
   1. only NON-IONIZED form of drug can CROSS MEMBRANE
      
      1. chemicals exist in the IONIZED form when exposed to an environment with OPPOSITE pH
      2. ex: weak acid are ionized at high pH (basic)
4. effect of pH - Henderson/Hasselbach equation
   
   1. Weak acid: HA + H2O -> H3O+ + A- (conjugate base)
      
      1. pKa 4.4
   2. Weak base: B + H3O+ -> H2O + BH+ (conjugate acid)
      
      1. pKa 8.4

Question 5

Given the pka of a drug, be able to determine the relative proportions of unionized and ionized drug at a given pH.

Answer 5

• For instance, a +1 unit difference between pH and pKa for
  
  • weak acid
    
    • r_esults in the drug being 90% ionized_;
  • weak base
    
    • 90% ionized
• A +3 or -3 unit difference
  
  • a weak acid and weak base, respectively will result
    
    • drug being essentially completely ionized

Question 6

What is ion trapping?

Answer 6

• distribution of weak acid/weak base at steady state
  
  • acidic drug will accumulate on the more BASIC side of the membrane
  • basic drug will accumulate on the more ACIDIC side of membrane

Question 7

Describe the factors that affect distribution of a drug to its site of action or other sites.

Answer 7

1. Physicochemical properties of drug
   
   • size, part, coeff, charge
2. Rate of blood flow to tissue capillaries
   
   • more rapid rate = helps maintain concentration gradient
     
     • favoring absorption
3. Capillary structure
   
   • differences in capillary integrity:
     
     • endothelium of kidney = large pores
     • endothelium of liver = incomplete
     • endothelium of CNS = no pores
       
       • lipid soluble drugs readily penetrate into CNS, ionized or polar drugs do NOT
4. Degree of binding to plasma proteins
   
   • drugs bound to plasma proteins will REMAIN in plasma
   • not available for absorption or excretion
5. Other factors…
   
   • age
   • gender
   • disease state
   • body composition

Question 8

Describe how plasma proteins, tissues and fat can act as reservoirs for drugs.

Answer 8

1. Plasma proteins
   
   • acidic drugs can bind to ALBUMIN
2. Tissues
   
   • binding of drugs = reversible
     
     • via protein, phospholipid, nuclear protein binding
     • serves as reservoir
3. Fat
   
   • lipid-soluble drugs are stored by physicial solution in NEUTRAL FAT
     
     • reservoir for lipid-soluble drugs

Question 9

Describe the processes whereby drugs are excreted/reabsorbed by the kidney.

Answer 9

Elimination of drugs occures thru processes of

• drug excretion (by kidney)
• drug metabolism (by liver)

Methods:

1. Renal excretion
   
   1. glomerular filtration
      
      • only unbound drug filtered
   2. active tubular secretion
      
      • drug affed to tubular fluid (urine)
      • transports exist
   3. passive reabsorption
      
      • nonionized forms of weak acids & bases
      • depends on pH
        
        • urine = alkaline = weak acids ionized & excreted rapidly
        • urine = acidic = weak acid ionization = reduced = excretion reduced

Question 10

Explain the effects of altering urine pH on the excretion of weak acids and weak bases.

Answer 10

When the tubular urine is made more alkaline, weak acids are
largely ionized and thus are excreted more rapidly and to a
greater extent. When the tubular urine is acidic, the fraction of
weakly acidic drugs ionized is reduced, and excretion is
reduced as well.
(b) Alkalinization and acidification have opposite effects on excretion

Question 11

Describe phase I and phase II metabolism of drugs and how these reactions facilitate excretion of drugs.

Answer 11

Reactions of drug metabolism:

• Lipophilic —–> Hydrophilic

Phase I = drug

• microsomal ezymes
• catalyzed by p450
• lipid soluble substrate
• inducible

Oxidation / Reduction/ Hydrolysis

Phase II = Conjugates

• glucuronidation
• sulfation

Question 12

Describe the concept of the superfamily of CYP P450 enzymes.

Answer 12

CYP enzymes

• catalyze PHASE I reactions
  
  • hydrolysis / oxidation / reduction
• CYP2C, 2D, 3A, 3A4 = most important
  
  • catalyze about half of clinically used drugs

Question 13

Using specific examples, explain how drug interactions can occur = with respect to the metabolism of drugs.

Answer 13

Inhibition of CYP

• inhibit metabolism of a drug
• reduce clearance
• increase plasma [con]
• –> decrease dose

Activation of CYP

• promote metabolism of a drug
• increase clearance
• decrease plasma [con]
• –> increase dose

Question 14

List potential outcomes of metabolism of drugs.

Answer 14

ACTIVE

1. inactive metabolite (most drugs)
2. active metabolite
3. toxic metabolite

PRODRUG (INACTIVE)

1. active drug

Question 15

List the factors that influence the rate of drug metabolism.

Answer 15

Factors that influence rate of biotransformation:

1. enzyme inducers
2. enzyme inhibitors
3. age
   
   • infants = less developed liver enzymes
4. liver fxn/disease
5. diet
   
   • grapefruit juice = inhibits CYP in GI tract
   • increase bioavailability of drug
6. genetic factors
   
   • fast/slow acetylators of isoniazid (tx of TB)
   • metabolism of warfrin (anticuagulant)
7. gender

Question 16

Define the first-pass effect.

Answer 16

• Oral administration
  
  • intestines
  • hepatic portal vein
  • liver
    
    • biotransformation
  • systemic circulation
    
    • lower degree of bioavailabilty due to transformation in gut/liver
• IV
  
  • skips 1st pass
  • goes directly into systemic circulation