Trace the Journey of a

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Trace the Journey of a Psychoactive Drug
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HOW DO DRUGS.
Get in the body ? Get in the brain? Get out ?
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Pharmacokineticsmovement of drugs within a
biological system

• Absorbed
• Distributed
• Metabolized
• Excreted

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To Get to Their Targets Drugs Must.
Drug
Extracellular fluid
Blood
Targets
(receptor on cell or go into cell)
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Ways to Enter Blood (routes of administration)

• Oral
• Inhalation
• Injection
• Other
• Transdermal
• Mucous membranes
• Implants/pumps

Route makes huge difference in drug
effects------ (whether or not it gets there, how
fast, and how much)
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Must go thru GI system first
ORAL ROUTE

• Factors which influence
• Concentration
• Lipid/water solubility
• Ionization (difficult to cross lipid membrane)
• Acidity (ionize in opposite pH)
• Contents/movement of GI

pH 1.2
pH2-6.6
pH7.4
1st -pass metabolism
Blood circulates around entire body 1/min
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Oral Route

• CONS
• Absorbed more slowly
• If drug insoluble, never enters circulation
• Absorption variable cuz GI environment constantly
  changing
• First-pass metabolism
• Some substances irritating
• Need patient cooperation

• PROs
• Safe
• Convenient
• Economical

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How do Drugs go from Bloodstream into Tissue?

• Capillaries
• Walls - cells packed tightly together
• Small pores allow small molecules to pass
• Most drug molecules small enough to pass
• Absorption rate influenced by vasularization
  (lots of blood flow rapid rate of entry into
  tissue)

pores
Nerve cells 40-50um from capillary
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Inhalation

• Absorption immediate because capillary walls of
  lungs exposed
• Speedy route lungs-heart-brain
• Volatile gases - diffuse in and out of blood
  (anesthetic, nitrous oxide)
• Smoking (marijuana, opium, cocaine) - smokeborne
  particles dissolve on membrane diffuse thru
  capillary walls, dont diffuse out of lungs

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

• PROs
• Rapid onset
• Once drug source removed, no additional drug
  enters body
• No 1st pass metabolism

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Injection

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

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IV

• PROs
• Fast (dispersed equally 1min)
• Dose readily controlled
• Blood levels remain steady
• CONS
• DANGEROUS! Drug cant be recalled!
• Contamination/infection
• Clogged blood vessel if drugs insoluble or comes
  out of solution

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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.
• IC - rarely used in humans, too risky

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Transdermal

• Thru the skin
• Must be lipid soluble
• Even, slow rate of absorption
• Nicotine patches
• Motion sickness patches
• Some compounds can poison thru the skin
  (malathion)

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Mucous Membranes

• Mouth, nose, eye, rectum, vagina
• Some drugs readily absorbed (cocaine,
  amphetamine), most are not.

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Factors Affecting Absorption Distribution

• Solubility
• lipid cross membranes, if not, H2O-filled pores
• ionization
• polar substances dissolve/ionize in water
• pH-acids ionize in alkaline visa versa
• Tissue Affinity
• -protein binding ( ex. Albumin)
• Membrane Barriers - capillary, cell, BBB,
  placental
• Membrane transport

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Heroin

• Alkaline
• If taken orally, hits stomach (pH 1.2)
  ionizes.
• Cant cross lipid membranes into blood

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Valium

• 99 binds w/ blood proteins
• Equilibrium is reached so as 1 thats unbound
  diffuses out of blood, bound molecules free
  themselves to maintain proportion
• Low steady level of drug

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Getting Drug into the Brain

• Drug cant change behavior until it gets to brain
• Brain wants to keep ionic substances and
  neurotransmitters from the rest of the body out
• Blood-Brain Barrier (BBB)

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BBB
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3 places w/ no BBB Incomplete until 1-2 yrs
Hypothalamus/
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HOW ARE DRUGS ELIMINATED?
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Most Drugs are Chemically Altered Before
Elimination
Metabolism - The process of restructuring
molecules
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THE LIVER

• Most important in metabolism of drugs
• Many enzymes which
• Deactivate drug molecules
• Ionize most molecules so easier to excrete via
  kidneys
• Enzymes can transform drugs by
• Oxidation (p-450)
• Reduction
• Hydrolysis
• conjugation

Ionized metabolites
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Elimination

• Skin, breath, feces, sweat, saliva - small
  amounts
• Some lipid soluble drugs are stored in fat for
  weeks

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KIDNEYS

• Most important filter
• Remove waste via the nephron (functional unit of
  the kidney) and sends to bladder
• Filters out everything, then reabsorbs what is
  needed.

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Dose-Response (D-R) Relationship

• Effectiveness of drug determined by a D-R curve
• Shows relationship between drug dose magnitude
  of effect

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D-R Curve Shows Drug Characteristics

• Potency - amount of drug to achieve a certain
  effect
• Efficacy - dose that produces maximum effect
• Slope - steep slope small changes cause big
  differences in response.

A drug may be less potent but have a higher
efficacy
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Efficacy Potency
Intensity of Effect
A
B
Dosage (mg/kg)
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Effective and Lethal Dosage

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

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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
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Drug Half-Life

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

By 6 half-lives, 98.4 of drug eliminated
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Combined Effects

• Co-administration of drugs combined effects
• Additive
• Synergistic (2 drugs bigger than expected
  effect)
• cummulative

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Steady State Concentrationsdue to Cummulative
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Individual Differences in Response to Drug
AGE
GENDER
Health
SIZE nutrition
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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

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Metabolic

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

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Cellular

• Neurons compensate for constant presence of drug
• Change receptor s
• Change release of neurotransmitter

Post
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Behavioral

• Learn ability to behave normally
• Conditioned tolerance
• Connected to environment, body starts
  compensating before drug administered addicted
  rats large dose of heroin in novel or usual
  environment.96 died in novel room, 32 in usual

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