Some Basic Pharmacology

1
Some Basic Pharmacology
Feb 14, 2005
2
Pharmacokinetics

• Movement of Drugs their metabolites thru a
  Biological System
• Absorption - how drug gets from external to
  internal
• Distribution - circulation to targets
• Metabolism - inactivation (biotransformation)
• Elimination - of waste products

3
The concentration of a compound at its target
site is affected by the extents and rates of ADME

4
Absorption

• Routes Administration
• Major factor in onset duration of drugs
  pharmacological effects
• Affect concentration of drug at site of action
• Passage across membranes

5

• CONs
• First-pass metabolism
• GI distress, vomit
• Drug must be soluble in GI able to pass
  membranes to enter blood
• Need patient cooperation
• Absorption varies due to
• Genetics
• Gastric contents (Grapefruit juice)
• Gender size

• PROs
• Safe
• Self-admin
• Economical
• Easy to recall

6
Injection

• Intravenous (IV) - intra within, vena
  vein
• Intramuscular (IM) - muscle
• Subcutaneous (SC) - under skin
• Intraperitoneal (IP) - abdominal cavity

7
IV

• PROs
• Fast (dispersed equally 1min)
• Dose levels readily titrated
• If drug poorly absorbed GI
• Patient is uncooperative or unconscious
• No first pass metabolism
• CONS
• Rapid onset, no time for drug recall!
• Rapid infusion drug mass resulting in
  arrhythmias, arrest, BP /or respiratory
  depression, convulsions
• Contamination/infection (HIV, hepatitis)
• Clogged vessel if drugs insoluble or comes out of
  solution

8
THE REST

• IM. - slow, even absorption
• SC - absorption depends on blood flow to site.
  Hormones often in pellets.
• IP - rapid, even absorption. Risk of infection
  puncture of organ. Painful.

9
(No Transcript)
10
Inhalation
PROs

• Absorption rapid - large capillary mucous
  membrane surface
• No 1st pass
• Speedy route lungs-heart-brain
• Volatile gases - diffuse in and out of blood
  (anesthetic, nitrous oxide)
• Smoking (THC, opium, cocaine,nicotine) -
  smokeborne particles dissolve on membrane
  diffuse thru capillary walls, dont diffuse out
  of lungs

• CONs FAST, DANDGEROUS Dosing difficult (lung
  capacity)
• Irritants - pneumonia
• Not much known about long term effects of
  particulate matter - cause membrane damage (Tar
  paves lungs)

11
Transdermal

• Thru the skin
• Must be lipid soluble
• Even, slow rate of absorption
• Nicotine
• Scopolamine(motion)
• Estrogen
• Fentanyl (chronic pain)
• Clonidine (hypertension)
• nitroglycerine
• Some compounds can poison thru the skin
  (malathion)

Mucous Membranes Rectal
12
Drug Transport Across Membranes

• Passive Diffusion (most drugs)
• concentration gradient (no energy requirements)
• affected by lipid solubility, molecular
  weight/shape ionization
• Transport Proteins
• Requires energy (ATP, proton gradient transporter
  etc)

13
Diffusion Across Membranes
lipid solubility

• pH affects ionization
• Unionized - mix freely w/ nonpolar lipid layers
• Ion trapping
• Ionized - are bound to H2O molecules dont
  readily move through different components of
  membrane
• Thus, pH significant effect on proportion of
  drug present in its lipid soluble form

14
pH of body compartment affects amount of ionized
vs. unionized (diffusable) drug , thus
distribution and drug action
Phencyclidine produces cyclic coma PCP weak base
15
Membranes to Cross

• Capillary vessels
• Cell membranes
• Blood brain barrier
• Placental barrier

16
Once in blood, drugs exchanged in equilibrium
betwn capillaries body tissue

• Absorption rate influenced by vasularization
  ease of flow through membrane
• Note brain 20 blood that leaves heart
• Endothelial cell pores larger than most drug
  molecules (9-15nM), thus transport of molecules
  betwn plasma body tissue independent of lipid
  solubility
• Pinocytosis for larger molecules

17
Blood Brain Barrier

• Lipid soluble readily distributed in brain tissue
• Not Intact
• Area Postrema
• Hypothalamus
• Pineal Gland
• Passive diffusion of ionized/H2O soluble poor
• Capillaries
• Tight junctions
• Few pinocytotic vesicles
• Astrocytes
• Transporters for glucose, amino acids etc

18
BBB Therapeutic Issues

• Drugs that utilize transporters to cross BBB
  compete w/ other chemicals that use the same
  transporter
• L-dopa transported by large amino acid pump
  competes w/ other large neutral amino acids (e.g.
  tryptophan)
• Can be advantageous
• Diphenoxylate (morphine-like) doesnt cross due
  to poor lipid solubility. Antidirheal effects
  PNS w/o CNS effects

19
Other Barriers to Drug Diffusion

• Depot binding - bind to inactive sites where no
  effect
• Influences tx effects
• Plasma protein
• Hydrophobics others that dont freely dissolve
  in blood
• non-selective, so drugs compete w/ other drugs
  endoegenous substances
• Muscle, bone, fat
• Varies betwn people
• Genetics
• Disease status

Significant amt of depot binding due to albumin
20
Diazepam

• 99 binds w/ blood proteins
• Equilibrium reached so as 1 thats unbound
  diffuses out of blood, bound molecules free
  themselves to maintain proportion
• Most DZP ends up in fat where its slowly
  released (drug hangover?)
• Low steady level of drug

21
Metabolism Excretion
22
Routes

• Liver - metabolism (a.k.a. biotransformation)
• Kidneys - most psychoactive drugs too lipid
  soluble for urine excretion, must be transformed
• Lungs -volatile agents, ETOH
• Skin

23
Liver

• Cytochrome p-450 Family
• Structurally similar, functionally different (50
  in humans)
• Metabolize chemically diverse group of substances
• Non-specific (can biotransform numerous drugs
  toxins)

24
Biotransformation

• Phase I - oxidation, hydrolysis, reduction
• Results in polar metabolite which is eliminated
  in urine
• Active metabolites
• Phase II - conjugation w/
• glucuronic acid
• Sulfate
• Acetate
• Amino acid
• If no site for conjugation, phase I first
• Inactive metabolites

Active metabolite
hydrolysis
If aspirin not hydrolyzed, pain relieving effects
reduced
INDUCTION capacity of metabolism can increase
2-3X via increase in production of enzymes
25
First Pass Metabolism

• Enzymes in gastric mucosa
• Portal system to liver

Collects blood from intestine channels to liver
26
Renal Excretion

• Nephron
• Fluid into Bowmans capsule to tubules to
  collection ducts
• Blood cells plasma proteins left in blood
• 1 liter/min
• 99.9 fluid reabsorbed including lipid soluble
  drugs (follow conc. Gradient out of nephron back
  into plasma)

glomerulus
27
Time Course, half-life, Steady State

• Time course
• Predict optimal dose
• Maintain therapeutic levels

28
Drug Half-Life

• Time course of drug described by half-life - time
  it takes for plasma concentration to fall to 50
  of its peak level.

By 6 half-lives, 98.4 of drug eliminated
29
Steady State Plasma Level
Conc. of drug after equilibrium betwn
absorption/distribution metabolism/excretion
phases.
30
Efficacy Potency
Intensity of Effect
A
B
Dosage (mg/kg)
31
Effective and Lethal Dosage

• ED50 - dose that has desired effect in 50 of
  subjects
• LD50 - lethal dose for 50 (or if human study
  TD50)
• Therapeutic Index - index of relative safety
  ratio of LD50/ ED50 (higherbetter)
• 20 relatively safe
• 100 preferred

32
ED LD Curves
TI5 LD50 (10mg/kg) is 5X the ED50 (2mg/kg)
Safe
TI is the same, LD slope different At 5mg/kg,
10 have died!
Unsafe
33
TOLERANCE

• Decreased response to drug after repeated
  exposure to that drug..it takes bigger doses to
  get initial biological effect

• main types
• Metabolic
• Cellular
• Behavioral

34
Metabolic

• Drug induces production of enzymes that
  metabolize it. Increased enzyme means more drug
  is required to achieve an effect.
• Not permanent

35
Cellular

• Neurons compensate for constant presence of drug
• More on mechanism mediating Cellular tolerance
  when we cover drugs of abuse

Post
36
Behavioral

• Conditioned tolerance
• Pavlovian Conditioning - CS UCS CR (usually
  compensatory in nature)
• Rats large dose of heroin in novel or usual
  environment.96 died in novel room, 32 in usual
• Learn to perform better under influence

Heroin overdoses -evidence that some overdoses
may be due conditioned tolerance
37
Sensitization

• Enhancement of drug effects after repeated
  administration
• Persistent augmentation to drug can last after
  long periods of abstinence