Drugs

Drugs

1. Administration

   • Oral
     • easy and convenient
     • barriers
       • absorbed through lining in stomach or intestine (may be destroyed by enzymes in g-tract)
         • must next enter the bloodstream (drug must be soluble in water - blood dilutes the drug)
   • Inhaled
   • absorbed
   • injected
     • bloodstream
     • muscle
     • brain
       • must be hydrophilic
       • fewest barriers
   • Barriers
     • Blood Brain Barrier
       • prevents most substances from entering brain via bloodstream
       • What is it made of?
         • endothilial cells
           • in capillaries, not tightly join. BBB cells form tight junctions so most things cannot pass
         • astrocytes
           • end feet help knit junctions closed; provide support
       • Access
         • small, uncharged molecules (O2, CO2)
         • larger, charged molecules must be actively transported
       • BBB Free Brain Areas
         • Area Postrema
           • allows toxic substances in the blood to trigger vomiting response
         • Pituitary Gland
           • source of many hormones; need to interact w bloodstream to direct other hormones
         • Pineal Gland
           • hormones reach it to modulate day-night sequence
     • cell membranes
     • capillary walls
     • the placenta

2. Eliminating Drugs

   • catabolized
     • i.e. broken down in kidneys, liver, or intestines
     • enyme (cytosome P450)
   • excreted
   • Unable to be removed?
     • build up in body and become toxic (e.g. metal mercury)

3. Drug Action

   • Types
     • Agonist
       • enhances function of synapse
     • Antagonist
       • blocks/decreases function of synapse
   • At Synapse
     • can be effected at synthesis, storage, release, receptor interaction, inactivation, reuptake, or degradation

4. Tolerance

   • Metabolic Tolerance
     • increase in number of enzymes used to break down substance; broken down faster
   • Cellular Tolerance
     • activities of brain adjust to substance; synapses do not response as highly to drug
   • Learned Tolerance
     • people learn to cope with being intoxicated

5. Sensitization

   • occasional drug-taker may experience increased responsiveness
   • a drug may be taken for a number of weeks before effects show

6. Psychoactive drugs

   • substance that acts to alter mood, though or behaviour; manage neuropsychological illness
   • Classification
     • 1. Antianxiety Agents and Sedative Hypnosis
       • Barbituates and Alcohol
         • sedative hypnotic
         • produces sedation and sleep; can also produce anesthesia, coma, death
         • alcohol acts to inhibit glutamate release
       • Benzodiazepines
         • Minor tranquilizers
         • antianxiety agents
           • drugs that reduce anxiety (i.e. valium, xanex)
           • often used for temporary purposes (coping with death, etc.)
       • Tolerance
         • characteristic of sedative hypnotics; larger dose required to maintain initial effect
         • Cross-tolerance
           • response to novel drug (e.g. benzo) is reduced bc of tolerance to a related drug (e.g. alch)
           • means 2 drugs effect common NS target (i.e. barb and benzo effect similar inhib nt GABA)
       • GABA(a) Receptor
         • activation produces an influx of chloride ions which hyper polarizes neurone (IPSP)
         • 3 binding sites
           • GABA Binding Site
           • Sedative-Hypnotic Binding Site
             • directly influences CL- influx; increases binding of GABA; maximizes time the pore is open
           • Antianxiety Binding Site
             • increases the frequency the ion pore opens in response to GABA
           • Big IPSP when both drug channels open - none of the neurons fire when too much CL- enters
     • 2. Antipsychotic Agents
       • First Gen. Antipsychotics
         • Chlorpromazine and halopenidol
         • Blocks D(2) dopamine receptor
         • produce symptoms reminiscent of parkinsons
       • Second Gen. Antipsychotics
         • Clozapine
         • weakly block D2 dopamine receptors; also block serotonin 5-HT2 receptors
         • less parkinsonian side effects
       • Schizophrenia
         • antipsychotics have improved functioning of schizophrenia patients
         • psychosis
           • characterized by hallucinations and delusions, common in schizophrenia
         • Dopamine Hypothesis
           • symptoms due to excess dopamine
           • antipsychotics block D2 receptor
           • Amphetamine promotes release of dopamine; schiz symptoms
         • drug models
           • LSD
             • promotes hallucinations; serotonin agonist
     • 3. Antidepressants and Mood Stabilizers
       • Major Depression
         • mood disorder
         • worthlessness, sleeping disturbances, slowing of behaviour, thought of suicide
         • 2X as common in W
         • inadequate nutrition (folic acid, B vitamins), stress, changes in neural functioning, damage to neurons
       • Antidepressants
         • Monoamine Oxidase (MAO) Inhibitors
           • block the enzyme MAO from degrading nts dopamine, serotonin, NA
           • not very specific
         • Tricyclic Antidepressants
           • first gen.
           • blocks serotonin reuptake transporter proteins
         • 2nd Gen. Antidepressants
           • similar to 1st gen.; more selective on serotonin reuptake transporter proteins
           • Selective Serotonin Reuptake Inhibitors (SSRI)
             • block reuptake of serotonin into the presynaptic terminal
             • Prozac
       • Mood Stabilizers
         • Used to treat bipolar disorder
           • periods of depression alternating w normal and intense excitation
         • mute the intensity of one pole of disorder, making other less likely to occur
         • mechanisms not well understood
           • e.g. Lithium may stim. neuronal repair
     • 4. Opioid Anagesics
       • Opioid
         • compound that binds to a group of brain receptors also sensitive to morphine
         • Opium
           • synthesized into codeine and morphine
         • Endorphins
           • peptides in body that produce opioid-like effects
           • associated with feelings of pain and pleasure
           • causes release of DA by blocking inhibitory nt release
           • receptors found in many regions of CNS
           • 3 classes
             • endomorphins (binds to mu receptor)
             • enkephalins (binds to kappa receptor)
             • dyorphins (binds to delta receptor)
           • natural (opium) and synthetic (heroine, methadone) opioids mimic endorphins
       • Nalorphine and Naloxone
         • drugs that act as agonists at opioid receptors
         • competitive inhibitors
         • can block action of morphine
     • 5. Psychotopics
       • Behavioural Stimulants
         • increase motor behaviour, elevate mood and alertness
         • rapid administration usually = addiction
         • Amphetamine
           • blocks dopamine reuptake transporter, more dopamine in synaptic cleft; stimulates release of DA from presyn membrane
           • used to treat ADHD, asthma, weight loss aid
           • methamphetamine (meth, speed) is a derivative
         • Cocaine
           • obtained from coca plant
           • blocks dopamine reuptake
           • powder is sniffed; vaporizes at low temp. & inhaled
           • derivates novacaine used as local anesthetic
         • Psychedelic Drugs
           • Acetylcholine Psychedelics
             • atropine (blocks); nicotine (facilitates) transmission at achetylcholine synapses
           • Anandamine Psychedelics
             • nt plays a role in enhancing forgetting; prevents brain's memory system from being overwhelmed
             • THC is an active ingredient in mj - agonist receptor for anandamide
           • Glutamate Psychedelics
             • Phencyclidine (PCP), ketamine produces hallucinations and out of body experiences; part of their action is to block glutamate NMDA receptors
           • Norepinephrine Psychedelics
             • induce a sense of boundlessness and visual hallucinations
             • mescaline
           • Serotonin Psychedelics
             • LSD, ecstacy
             • stimulate serotonin receptors and block the activity of other serotonergic neurone through receptors
       • General Stimulants
         • drugs that cause general increase in metabolic activity of cells
         • inhibits enzyme that normally reaks row the 2nd msgr cAMP
         • increase in cAMP leads to an increase in glucose production in cells; makes it more available = higher rates of cellular activity

7. Behaviour on Drugs

   • Disinhibition Theory
     • alcohol has selective depressant effect on cortex; region that controls judgements, which sparing subcortical structures; "too drunk to know better"
     • limit: behaviour depends on context (home or bar)
   • Alcohol Myopia (nearsightedness) Theory
     • under influence of alch, people respond to restricted set of immediate and prominent cues; ignore more remote cues and potential consequences
   • Addiction and Dependence
     • Substance Abuse
       • pattern of drug use which people rely heavily on a drug chronically and excessivly
     • Substance Dependence
       • addiction; physically dependent on a drug in addition to abusing it; tolerance of drug, increased doses
     • Withdrawal Symptoms
       • physical and psychological symptoms when drug use suddenly ends
       • muscle aches, cramps, anxiety, nausea, death
     • Psychomotor Activation
       • increase in behavioural and cog. activity at certain levels of consumption
     • Role of Dopamine
       • drugs that are abused increase mesolimbic dopamine activity
     • Why?
       • Dependency hypothesis
         • users initially experience pleasure but then endure withdrawal when it wears off; but... users are still drawn back after symptoms gone?
       • Incentive-Sensitization Theory
         • wanting (craving) and liking (pleasure) produced by diff parts of the brain
           • wanting: sensitized w repeated use, craving increases -- mesolimbic system
           • liking: tolerance develops w repeated use, pleasure decrease -- opioid neurons
     • Neural Basis
       • taking drug -frontal cortex; drug activates opioid systems related to pleasurable experience; wanting drugs - activity in dopaminergic system;
     • Genetics
       • 1 twin more likely to abuse alcohol if other does
       • adopted kids more likely to abuse alch if biological parents did
       • selective breeding of animals that consume large quantities of alch
     • Treatment
       • recognize addiction will likely be lifelong problem
       • treated in the same way medical problems are

8. Brain Damage

   • many substances can be neurotowxins
     • glutamate allows calcium into cell to activate 2nd msgr; can activate a "suicide gene to cause cell death
   • amphetamines
     • MDMA; hallucinogenic amphetamines that degenerate very fine serotinergic nerve terminals
   • cocaine
     • blocks cerebral blood flow and neuronal death
   • NOT associated w damage
     • LSD, marijuana, opiates

9. Hormones

   • can be used as drugs to treat or prevent disease; as replacement therapy; increase strength
   • Steroid Hormones
   • Peptide Hormones
     • 3 classes
       • Glucocorticoid Hormones
       • Gonadal Hormones
       • Homeostatic Hormones