Drugs and Behavior

1
Drugs and Behavior

• Chapter 1
• Basic Pharmacology

2
Drug

• drug is any substance that alters the physiology
  of the body, but is not a food or nutrient
• Definition sometimes excludes toxins
• Definition often accounts for the intention of
  the user

3

• Examples
• Vitamin C - in pills
• - in fruits and
  vegetables
• Caffeine - taste or CNS effect
• Nicotine taste of CNS effect

4
Drug names

• Chemical Name
• 7-cloro-1,3-dihydro-1-methyl-5-phenyl-2H-benzod
  iazepin-2-one
• Generic Name (nonproprietary Name)
• diazepam
• SKF 10047
• Trade name (proprietary name)
• Valium

5
Formulation

• Trade name refers to the formulation, i.e. the
  way a medicine is made
• Includes both the active ingredient and the
  excipients, i.e., the non-active ingredients such
  as coloring and binding agents and fillers

6
Compendium of Pharmaceuticals and Specialities
(CPS)
7
Describing drug doses

• Doses mg/kg (body weight)
• Concentration at the site of action

8
Dose Response Curve (DRC)

• Horizonral axis dose
• Vertical axis
• Frequency of effect
• Extent of effect

9
(No Transcript)
10
LD50 and ED50

• LD50 medial lethal dose
• Dose that kills half of the subjects
• ED50 median effective dose
• Dose that causes half the maximum effect.

11
ED50 and LD50
12
Drug Safety

• Therapeutic Index
• TI LD50/ED50
• The higher the number, the safer the drug

13
Potency

• When describing drugs with similar effect, the
  more potent drug is the one which produces the
  effect at the lowest dose.

14
Effectiveness (Efficacy)

• The maximum effect a drug will produce, i.e., The
  drug that causes the greatest maximum effect has
  the greatest effectiveness.

15
Primary Effects and Side Effects

• Primary or main effect
• The effect you want

16
Primary Effects and Side Effects

• Side effect
• All other effects
• May be useful or harmful

17
Drug Interactions

• Antagonism
• Where one drug shifts the DRC of another drug to
  the right

18
Drug Interactions

• Additive effect
• Where one drug shifts the DRC of another drug to
  the left as much as could be expected if the
  effect of both drugs were being added together.

19
Drug Interactions

• Superadditive effect (potentiation)
• Where the effect of one drug shifts the DRC of
  another drug to the left further than would be
  expected if the effects of the drugs were being
  added together.

20
DRUG INTERACTIONS
When mixing two drugs
Potentiation or superadditive The whole effect
is greater than the sum of the effects
Antagonism One drug diminished the effects of the
other
Additive Effects Each drug effect is added
21
Drug Interactions

• Drugs can interact both in terms of potency and
  effectiveness

22
Pharmacokinetics

• How drugs get to and from their site of action
• Absorption How drugs get into the blood
• Distribution Where drugs go in the body
• Excretion or Elimination How drugs leave the
  body

23
Absorption

• Routes of administration
• Parenteral
• Oral
• Inhalation
• transdermal

24
Parenteral administration

• Drugs are dissolved in a vehicle.
• Injected through a hollow needle and left in a
  bolus.
• Catheter chronically implanted tube through
  which drugs are administered
• Usually into a vein.
• Cannula rigid catheter, usually into the brain.

25
Parenteral Subcutaneous, s.c. Intramuscular,
i.m. Intraperitoneal, i.p Intravenous, i.v.
26
Subcutaneous, s.c.
27
Intramuscular, i.m.
28
Intraparetoneal, i.p.
29

• i.p. injection in a rat

30
Intravenous, i.v.
31
Other parenteral routes

• Intracerebroventricular (i.c.v.) Injections
• Brain and spinal cord are surrounded with
  cerebrospinal fluid
• Ventricles are spaces in the brain filled with
  cerebrospinal fluid
• i.c.v. injections are directly into ventricles of
  brain via cannula

32
catheter

• Tube implanted into the body. Usually into a
  vein.

33
cannula

• Like a catheter, but rigid.
• Often implanted into a ventricle in the brain, or
  some brain region.

34
intrathecal

• Injection into the cerebrospinal fluid in the
  spinal cord

35
Parenteral Absorption Rates
blood stream

• The movement of a drug from the site of
  administration to the blood stream.
• i.v, injections have the fastest absorption.

36
Factors that influence absorption from parenteral
sites

• Blood flow to the area
• capillaries
• bloodgtperitoniumgtmusclesgtskin
• Temperature

37
capillaries
38
diffusion

• A substance will move from an area of high
  concentration to an area of low concentration
  until concentration is even everywhere, i.e.,
  drugs will move down their concentration gradient
• Drugs diffuse from the bolus (high concentration)
  into blood in capillaries through pores.

39
(No Transcript)
40
Inhalation of gasses

• Lungs are an efficient gas exchange system
• Absorb oxygen and release carbon dioxide
• Works by diffusion

41
Inhalation of gasses

• Very rapid absorption
• Very rapid delivery to the brain
• Gasses can move in and out of the body

42
(No Transcript)
43
Inhalation of smoke and solids

• Smoke
• Burning dried plant material
• Tobacco, marijuana, opium
• Drug is vaporized or remains in ash and dissolves
  in the moist surface of the lung
• Diffuses into capillaries
• Cannot revaporize so cannot be exhaled like
  gasses

44
Inhalation of solids

• Drugs in the form of fine powders or droplets
• Cocaine, aerosols (inhalers), tobacco snuff,
  heroin
• May be inhaled into lungs (aerosols) or snorted
  into nose (intranasal administration)

45
Intranasal administration

• Enters nasal cavity and dissolves in mucouse
  membrane. Then diffuses into blood.
• Some enters lungs
• Some runs down throat to stomach

46
(No Transcript)
47
Oral (peroral, p.o.) administration

• Drugs administered to the digestive system are
  usually administered by mouth, but the nose and
  rectum may also be used.
• Some drugs are absorbed by the buccal membranes
  in the mouth (eg. nitroglycerine for angina)

48
Oral administration

• Some absorption from the stomach, but it is
  designed to digest food. It is acidic with a pH
  of about 3.5
• Most absorption is from the small intestine which
  is designed to absorb nutrients from food

49
Oral administration

• In the small intestine drug molecules must pass
  through a tissue barrier to enter the
  capillaries.
• Tissue is made of cells and cells are surrounded
  by a membrane made of lipid (fat) molecules.
• Rate of absorption is therefore controlled by the
  ability of drug molecules to dissolve in lipids,
  i.e. lipid solubility

50
Lipid bilayer of membranes
51
Lipid solubility

• Olive oil partition coefficient
• When a drug is dissolved in a mixture of oil and
  water, different proportions of the drug will end
  up dissolved in the oil and the water.
• A high partition coefficient means that most of
  the drug ended up in the oil
• A low coefficient means that most ended up in the
  water

52

• Highly lipid soluble drugs can diffuse through a
  membrane and be absorbed from the small
  intestine.
• Drugs with low lipid solubility diffuse slowly
  into the blood from the small intestine.
• When molecules of a drug have an electric charge,
  i.e., they are ionized, they are not lipid
  soluble at all.

53
ionization

• When few molecules of a drug are ionized,
  absorption is as fast as the natural lipid
  solubulity of the drug will allow.
• When many molecules of a drug are ionized,
  absorption will be very slow no matter what the
  natural lipid solubulity if the drug is.

54
Want determines the percent of ionized molecules?

• THE DRUG whether it is a weak acid or a base
  (alkaloid).
• THE SOLUTION whether it is an acid or a base,
  i.e., its pH
• pKa of the drug the pH at which half the
  molecules of the drug are ionized

55
pH
56
pKa

• pH of solute at which the molecules of the drug
  are 50 ionized.
• Drugs that are bases have few ionozed molecules
  when dissolved in bases.
• Drugs that are acids have many ionized molecules
  when dissolved in bases

57
pKa
e.g., damital (acid)
pH of solution
0
1
3
5
4
6
7
8
9
10
11
12
13
14
2
0
0
0
1
8
50
95
90
100
100
100
100
100
100
100
Percentage of nonionized molecules determines the
rate of absorption
58
Using pKa to predict absorption

• Morphine is a base with a pKa of 8
• Lining of intestine has a pH of about 3.5
• Nearly all molecules of morphine will be ionized
  in the intestine
• Morphine is slowly absorbed when given orally

59
(No Transcript)
60
Absorption of acids

• Aspirin has a pKa of 3.5.
• Aspirin is an acid (acetylsalicylic acid, ASA).
• 50 of molecules are not ionized in digestive
  system
• Aspirin is quickly absorbed when taken orally

61
Distribution

• Where drugs go in the body
• Lipid solubility
• Barriers
• Blood-brain

62
Blood-Brain Barrier
63
Placental Barrier
64
Transport mechanisms

• Passive
• Attaches to a carrier in the membrane which is
  lipid soluble
• Passes through the membrane by diffusion along
  the concentration gradient.

65
Transport mechanisms

• Active
• Pumps non lipid soluble molecules across membrane
• uses energy
• Can work against diffusion

66
Protein binding

• Blood contains large protein molecules that can
  bind to a drug molecule
• These protein molecules cannot leave the blood
• Drug is trapped in the blood till it is
  metaboilized.

67
Transdermal administration

• Salves, lotions and patches
• Epidermis cells are packed with keratin which
  blocks water soluble drugs and slows down
  absorption of lipid soluble drugs

68
Excretion and metabolism

• Liver and kidneys, the dynamic duo of drug
  elimination.

69
The kidneysmaintain correct balance of
electrolytes in body fluids
70
The nephron

• The nephron is the functional unit of the kidney.
  There are millions of nephrons.

71
kidneys

• The kidneys filter everything out of the blood
  and then reabsorb stuff the body needs.
• Uses transport mechanisms
• Lipid soluble molecules are reabsorbed
• Non lipid soluble molecules are eliminated in the
  urine

72
kidneys

• if the urine is acidic, bases will ionize and be
  excreted, if the urine is basic, acidic drugs
  will be excreted

73
The Liver

• Chemical factory that controls chemical reactions
• Chemical reactions are controlled by enzymes
• Makes molecules useful to the body
• Modifies chemicals harmful to the body
• Metabolism the restructuring of molecules
• Metabolite restructured molecules

74
enzymes

• An enzyme is a catalyst that controls a chemical
  reaction
• Name usually ends in ase, eg, alcohol
  dehydrogenase.

75
detoxification

• Restructured molecules are usually less
  physiologically active, but not always
• Restructured molecules are usually more likely to
  ionize and have less lipid solubility so the
  liver can eliminate them

76
First pass metabolism

• Some drugs are degraded by enzymes in the
  stomach, intestines, and liver before they
  circulate to the rest of the body.

77
Half-life

• Time taken to reduce blood level by ½
• Kidneys are more efficient when blood levers are
  high
• Causes an excretion curve that is nor a straight
  line

78
Half-lives of some drugs

• Cocaine 0.5-1.5 hr
• Nicotine 2 hr
• THC 20-30 hr
• Aspirin 3-4 hr
• Prozac 7-9 days
• Morphine 1.5-2 hr

79
Zero order kinetics

• Some drugs like alcohol do not have a half life
  because they are eliminated at the same rate no
  matter what their concentration
• This is because the enzyme that destroys alcohol
  works at the same rate no matter what the
  concentration

80
Zero order kinetics

• Alcohol has zero order kinetics
• Alcohol dehydrogenase works at a constant rate,
  10-12 mg/kg blood/hr

nicotine
alcohol
81
Factors that alter metabolism

• Stimulation of enzymes
• Depression of enzymes
• Age
• Species

82
Stimulation of enzymes

• Metabolism of alcohol
• Heavy drinkers have higher levels of alcohol
  dehydrogenase
• Causes metabolic tolerance

83
Stimulation of enzymes

• St. Johns Wort used as a natural
  antidepressant
• Stimulates cytochrome P4503A4
• Caused reduced blood levels of many drugs
  including cyclosporine, alprazolam and oral
  contraceptives

84
Depression of enzyme activity

• Enzyme activity can be suppressed by blocking
  their activity or giving another drug for them
  to metabolize
• Disulfiram blocks aldehyde dehydrogenase

85
Depression of enzyme activity

• Grapefruit juice can block cytochrome P4053A4
  which destroys many drugs in the intestine (first
  pass metabilism)
• Grapefruit juice will increase levels of
  busparone, lovostatin and sildenafil (Viagra)

86
Species differences

• Many species have different enzymes and different
  levels of enzymes.
• The same drug at the same dose may have different
  effect in different species

87
Age

• As organisms grow and as they age enzyme levels
  change and different enzymes are used causing
  different concentrations of the drug and
  different metabolites.
• Elderly people are often more sensitive to drugs
  because of reduced liver function

88
Time course for blood level of drugs

• A graph that plats the effect of a drug over time
  after administration.
• This is the time course for absorption (assuming
  no excretion) and the time course for excretion
  assuming instantaneous absorption
• The resultant is the combination of absorption
  and excretion functions.

89
Time course for blood level of drugs

• Different rates of absorption can cause quite
  different curves.
• Fast absorption causes high peak levels and short
  duration
• Slow absorption causes low peak levels and long
  effect

90
Therapeutic window

• Therapeutic drugs require that a blood level be
  maintained that is high enough to have a
  therapeutic effect (main effect), but not so high
  that there are toxic (side) effects.

91
Therapeutic window

• This is difficult to do with drugs that are
  rapidly absorbed.
• Rapidly absorbed drugs require small doses many
  times a day.
• For this reason many drugs have formulations that
  are released and absorbed slowly