Psychopharmacology exam 3 study guide

Goal of Psychoactive drugs

get into the bloodstream so drug molecules can get into the brain

Pharmacokinetics

Drug movement of the body

• pharma- drugs

• kinetics- movement

  • route of administration

  • absorption

  • distribution

  • depot binding

  • metabolism

  • excretion

Pharmacodynamics

how it interacts with body and changes its behavior

• nomenclature

  • agonist/ antagonist

  • direct/indirect

• drug action vs drug effects

• therapeutic/ side effects

• dose- response relationship

• chronic effects

  • tolerance

Routes of administration

• oral administration (PO)

• Intravenous (IV)

• Intramuscular(IM)

• Subcutaneous(SC)

• intracranial Ventricular (ICV)

• Epidural

• inhalation

• rectal administration

• Intraperitoneal (IP)

• topical

Oral Administration (PO)

• most common type, economical and easy to employ, relatively safe, least efficient way to get drugs into the bloodstream, produces slow change in behavior, takes time, gavage another way to say PO for research animals, goes through metabolism pretty quickly going through the liver.

Intravenous (IV)

• directly into the bloodstream, rapid, first to use in an emergency situation since it can get to the brain fastest, once it’s in bloodstream can not get it out,

Intramuscular (IM)

• administered into muscle, once in muscle slowly pass into blood vessels, faster than PO and slower than IV.

Subcutaneous (SC)

• package to be put in between skin and muscle so package can dissolve slowly and we get drug for a long period of time.

Intracranial Ventricular (ICV)

• directly administered to the brain, rarely ever used

Epidural

• drug administer into the spinal fluid(CSF) often used during child birth, effects mostly lower body not upperbody

Inhalation

• inhale dust or smoke particles of the drug into the lungs, 2nd fastest to get drugs, absorbed via capillaries in lungs

Rectal Administration

• administered to the anus that will melt slowly over time and goes into the blood vessels, Melting=longer delivery

Intraperitoneal(IP)

• injection into the cavity of the stomach that surrounds the organs

• research animals

topical

• applied to skin or mucosa membrane EX: (nasal, eye, oral cavity, skin)

Absorption

Movement of drug from site of admin into blood circulation

1. Lipid- Solubility

2. Transport across membranes

3. Ionization

Lipid Solubility

• does it dissolve in fat, have to dissolve in fat, needs to be lipid not water, the more lipid easier to pass through cells and into the bloodstream

• partition coefficient

• only fatty molecules pass through

transport across the membrane

• phospholipid bilayer

• moves from high→low concentration (concentration gradient)

• passive diffusion

  • lipid soluble molecules pass through the cell bilayer

Ionization

• dissociation of a molecule into component ions

• pKa- drug characteristic how acidic or basic is the drug

• We want as much non ionization as possible so it can stay as the drug and not break down into its base components.

• Same into same = non-ionization

• pH-the solution you put drugs into

  • ex: stomach blood intestines etc

Distribution

• BBB- blood-brain barrier, brain surrounded by brain capillaries, lipid soluble

• some areas with little/no BBB

  • area postrema- near medulla determines if there’s too much toxin in the blood and if there is it’ll trigger vomit reflux (Excretion)

  • median eminence- hypothalamus(hormones endocrine system)

Depot Binding

A process where drugs binds or attaches to inactive site

• blood plasma

  • attachment here increases molecule size

  • cannot cross BBB

  • may attach to this

• fat tissue

  • drug attaches to fat tissue

  • 2nd phase effect- drug detaches/ circulates through blood causing 2nd effect/ weaker

Metabolism

• AKA biotransformation

• liver- all blood goes through the liver, produces enzymes(put things together or tear apart) in liver they tear stuff apart

• 1st order kinetics

  • amount of drug removed from blood is exponential at 50%

  • half-life

Metabolism: The liver

• utilizes microsomal enzymes

• cytochrome p450(CYP450) [family of enzymes]

  • oxidize most psychoactive compounds

    • responsible for breaking down drugs

• genetic differences - bigger liver= more enzymes, smaller liver= less enzymes

Excretion

• #1 method ? urine

• The kidney

  • filters- blood goes in dirty then comes out clean

  • 120-150 quarts of blood daily

  • 1-2 quarts of urine

  • nephron- big filter

    • small filtering units

-Some drugs can be excreted through breast milk, others through breath,sweat, and poop

Drug action

AKA: mechanism of action (pharmacodynamics)
• Molecular & cellular changes produced by drug when it binds
to target site

drug effects

Changes in physiological or psychological functioning as a result of drug action.

3 factors of pharmacodynamics

• receptor

• ligand

• agonist vs antagonist

Direct

• Acts directly on post synaptic receptor

• binds directly on receptor to activate

• direct agonist or antagonist

Indirect

• can influence system

• but can increase or decrease NT- receptor activity

• indirect agonist or antagonist

Curare

• direct antagonist

• mechanism of action : blocks nicotinic responses

Reserpine

• indirect antagonist

• Mechanism of action: block vesicular Monoamine Transporter (VMAT)

  • Reduces monoamine storage and amount of monoamine release

Levadopa (l-dopa)

• Indirect Agonist

• Mechanism of action : Acts as dopamine precursor dopa

• increases DA synthesis

• this increases the amount of DA in synapse

Therapeutic effect

• drug-target interaction produces the desired behavioral effect

Side effect

• all other physiological or behavioral changes

Dose-Response relationship

• degree of effect response and doses given

Dose-Responsive Curves

• S-shape

• threshold dose- smallest dose of drug capable of producing an effect

• ED 100 - effective dose, maximum response occurs 100% charge

• ED50 - effective dose, 50%effective dose

• Potency- less drug that produce some effect, difference in quantity that produces same behavior in drugs

Therapeutic index

• Ed50- safe, 50% of pop show desried effect

• TD50- not safe, toxic dose, 50% of pop show specific toxic effect

• Therapeutic index(TI)= TD50/ED50

Chronic Effects

• needing more drugs is not tolerance its a sign of tolerance

• not all behavioral effects show tolerance

Tolerance

• A reduced response as a result of repeated drug use

• 3 types: Metabolic, Pharmacodynamic, Behavioral

Cross tolerance

• diminished effect of a second drug due to tolerance of initial drug

• alcohol & barbiturates- tolerance of one drug can result to a tolerance of another drug

Metabolic (in Liver)

• enzyme induction

• When you take substance liver produces enzymes to destroy drug

• if you do it everyday liver will produce so much more enzymes to reduce effect aka tolerance

Tolerance (pharmacodynamic)

• changes in nerve cell function due to chronic drug use

• down regulation = less receptors- receptors will remove receptors

• up regulation = more receptors- drug block receptor, body up amount of receptors to combat that to reach homeostasis

Behavioral tolerance

• classical conditioning

• 3 p’s become conditioned stimuli

• NYC heroin Overdose

Historical Highlights

• OTC products

• Vin Mariani- wine with coke and not the drink

• 1874 Bayer laboratories

  • synthesized heroin

  • cough suppressant- really addicting cough syrup

Pure food/ drug act (1906)

regulated labeling of patent medicines and created the FDA

harrison act (1914)

regulated dispensing and use of opioid drug/ cocaine

18th constitutional amendment (prohibition) 1920

Banned alcohol sales except for medicinal use (repealed in 1933)

Marijuana Tax act (1937)

banned nonmedical use of cannabis (over- turned by US supreme court in 1969)

controlled Substance act (1970)

Established schedule of controlled substance/ created the DEA

ex: schedules 1,2,3,4,5 (most to least )

Schedule I (1)

• substance that have no accepted medical use in the US / have high abuse potential

• ex: Heroin, LSD, mescaline, marijuana, THC, MDMA

Schedule II (2)

• Substances that have a high abuse potential with severe psychic or physical dependence liability

• Ex: Opium, morphine, codeine, meperidine(Demerol), cocaine, amphetamine, methylphenidate (Ritalin), pentobarbital, phencyclidine(PCP)

Schedule III(3)

• substance that have an abuse potential less than those in schedules I/II, including compounds containing limited quantities of certain narcotics and nonnarcotic drugs

• ex: Paregoric, barbiturates other than those listed in another schedule

Schedule IV(4)

• substances that have an abuse potential less than those in schedule III

• ex: Phenobarbital, chloral hydrate, diazepam (Valium), alprazolam (Xanax)

Schedule V(5)

• Substances that have an abuse potential less than those in schedule IV; consisting of preparations containing limited amounts of certain narcotic drugs generally for antitussive (cough suppressant) and antidiarrheal purposes

Addiction

• Early views emphasized physical dependence

• Focus on withdrawal symptoms during abstinence

• More recent approaches emphasize:

• 1. Cravings

• 2. Drug use followed by abstinence

• 3. Chronic, relapsing disorder

Progression of Drug use

• Sendsen & LeMoal, 2011

• Pathological drug use is a cyclical pattern of three components

• 1. Periods of preoccupation with drugs and anticipation of upcoming use.

• 2. Periods of drug intoxication.

• 3. Periods following drug use characterized by withdrawal symptoms and negative affect (negative mood states).

Connotation of “addiction”

• DSM V

• APA

• Substance use disorder

  • Individual has manifested a maladaptive pattern of substance use over at least a 12-month period

Dependence: Psychological vs Physiological

• Psychological

• Subjective pleasure- ( I like the way it makes me feel)

• Physiological

• Physiological/pharmacodynamic changes as a result of drug use

  • Cessation results in withdrawal symptoms

  • Not all abuse drugs produce both, some don’t produce either

Physical dependence: Withdrawal symptoms : conceptually

- withdraw symptoms are the opposite of drug effects

- not one cluster of symptoms that happen to everything

• Homeostasis- balance, body wants to restore balance/ get drugs out

• Drug increases/decreases physiology- different drugs effects physiology differently

• Body works to restore homeostasis

• Remove drug

• Body still working to offset drug fx

• Withdrawals

• Withdrawal symptoms are the body’s attempt to restore

homeostasis

• Opposite of the drug effects

Drug Use/ Behaviorism

• Drugs act as Positive Reinforcers

• Behaviors associated with drug use are reinforced

• Reinforcers vs Reward

• Reinforcers lead to conditioning of prior stimuli/behavior

• Reward: positive subjective experience (euphoria)

  • Or relaxation in the case of alcohol, tranquilizers, etc.

• Degree of reward influences strength of reinforcement

• Good reward= better reinforcement

• Bad reward= poor reinforcement

Factors in a drug’s abuse potiential

• Cost and availability

• Onset and magnitude of reinforcing effect

• Pharmacokinetics & pharmacodynamics

• Social consequences of use

• Stimulus-Response Characteristics

• pos. vs. neg. reinforcement/punishment properties

Discovery of the brain reward center

• Olds & Milner (1954)

• Self-stimulation via electrodes in rats

  • Medial forebrain bundle

  • self stimulation rates > 5,000/hr

• dopamine via mesolimbic path into nucleus accumbens

Risk Factors: Heritability & Enviroment

• THERE IS NOT ONE SINGULAR ADDICTION

GENE!!!!!

• Li et al., 2008

• Meta-analysis of genetic studies

• 1500 genetic interactions

• More on genes: next slide

• Psychosocial variables

• Swendsen et al., 2009

• Stress

• Comorbidity

• Familial & Sociocultural

• Windle & Davies, 1999

  • Familial influence

• Thombs, 1999

• 1. Social facilitation

• 2. Removal of role/responsibility

• 3. Group solidarity

• 4. Creation of sub-culture

Addiction : Reward Deficiency Syndrome

• In Nucleus Accumbens:

• DA#2 receptor (DA2R) plays role in reward/aversion

• Chromosome 11: alleles code for DA2R production

• Two alleles: A1 and A2

• If you get two copies of A1 allele results in 30% fewer DA2R in Nucleus Accumbens

• People with fewer DA2R experience less pleasure

• Deprivation of the reward system

• Reward Deficiency Syndrome (RDS)

• How can people increase DA activity?

Are there Vulnerability factors ? The role of DA

• Thanos et al., 2001

• Animals with lower DA2R receptors self-administered at higher rates

• Volkow et al., 2006a

• Clinical study of familial alcoholism

• Non-alcoholic family members had higher DA receptor levels

• Volkow et al, 2007b

• High vs Low DA2R groups rating euphoria of methylphenidate

• Low DA2R group reported greater euphoria

• Volkow et al., 2009

• Meta analysis of PET and fMRI

• Drug abusers = decreased DA release

• Zald et al., 2008 (Vanderbilt)

• Novelty-seekers vs controls

• High thrill seekers = lower DA2R’s(BC they have low levels of DA2R they seek out DA through drug abuse or seek out thrilling activities)

Long-Term Changes in PFC

• Normal role of frontal cortex

• Executive Functioning

  • Reasoning & planning

  • Organization & problem-solving

  • Mental flexibility

  • Regulation of emotion & motivation

  • Behavioral inhibition

Brain Imaging Studies

Comparing Healthy Controls vs SUD’s

-The part of the brain that tells you to not do drugs is impaired from using said drugs

• Hypofrontality

• Dorsolateral prefrontal cortex (DLPFC)

• Working memory, cognitive flexibility, planning, reasoning

• Anterior Cingulate Cortex (ACC)- Both a frontal cortex structure and in limbic system

• Drive and motivation

• Orbitofrontal Circuit (OFC)- right behind orbits of the eye

• Behavioral inhibition & Impulse control

Disruption of pathways from the frontal cortex

• Pre-Frontal cortex to Nucleus Accumbens

• Disruption of glutamate transmission

• Response inhibition & impulse control

• trouble governing emotions

Is Addiction a disease ?

• What is a disease?

• S E P T

• Symptoms

• Etiology

• Pathology

• Treatment

• Initial use is voluntary (with vulnerability)

• After repeated use

• Symptoms

• Craving, drug seeking, drug taking

• Etiology

• Stress, social influence, genetic vulnerability (altered DA & DA receptor levels)

• Pathology

• Alterations to frontal cortex structures responsible for motivation, behavioral

Models of addiction

• Self-administration

• Via cannula into nucleus accumbens

• Operant conditioning

• Break point

  • Amount of work required outweighs drug reward

• Conditioned Place Preference

• Classical Conditioning

• The occurrence of one stimuli signals that a second stimuli will occur