pharmacology

define ligand

define ligand

any molecule that binds to a receptor

define endogenous ligand

ligand (naturally in body) normally produced by the body that binds a receptor (neurotransmitters)

define exogenous ligand

ligand introduced into the body (drugs)

Define agonist

ligand that activates receptors

Define antagonist

ligand that has no effect on its own but blocks binding of exogenous ligand (neurotransmitter receptor blocker)

-competes w/ endogenous ligand

Define non-competitive ligand

binds to site other than endogenous ligand binding site & modulates receptor activity (non-competitive inotropic neurotransmitter receptor blocker)

-have agonist or antagonist properties

Define affinity

The strength of attraction between drug and receptor at any drug concentration concentration or firmness w/ which drug binds to receptor

Define efficacy

(intrinsic activity) is the ability of a drug to illicit a pharmacological response (physiological) when interaction occurs w/ a receptor (relationship between response & occupancy of receptor)

define binding affinity

"strength" of binding between ligand and receptor

A higher concentration for a low or high affinity drug/ligand?

LOW affinity drug/ligand

A lower concentration for a low or high affinity drug/ligand?

HIGH affinity drug/ligand

if high & low affinity are both at equal concentration...?

higher affinity drug binds to more receptors than low affinity

Kd (Affinity constant)

Dissociation constant. On graph it is the ligand concentration at which 1/2 receptors bound

low Kd = ___ affinity & why?

high affinity cuz need less concentration of ligand

high Kd = ______ affinity & why?

low affinity cuz need higher concentration to reach 100% binding

Define efficacy simpler def

max effect a drug can produce regardless of dose; ability of drug-bound receptor to produce a full response

EC50 stands for?

Concentration of the drug required to produces 50% of maximal effect; measures efficacy

a full agonist has a _____ efficacy & produces _____

response while occupying a relatively low proportion of receptors

a full agonist has a high efficacy & produces a full response while occupying a relatively low proportion of receptors

a ____ agonist has ___ efficacy then a ____ agonist

a partial agonist has lower efficacy than a full agonist

explain selectivity of a drug

-common for some drugs to bind to many receptor types or bind to several members of same neurotransmitter receptor class

-less common for drugs to selectivity bind to 1 or 2 receptors

Why are relative affinities of a drug at diff receptors exploited?

to adjust the dose down so only highest affinity receptors are bound & activated ("targeted") minimize side effects

Evaluate dose response curves.

linear segment starts low, increases then levels off as it approaches max value (sigmoidal relationship) between dose & effect

- w/in limits increasing dose=increase desired effect

ED 50 (effective dose)

the dose where drug shows 50% of max effectiveness

therapeutic index

distance between LD50 & ED50 \n (lethal dose & effective dose)

LD 50 (lethal dose)

dose of drug at which is lethal (death) in 50% of subjects

wide therapeutic index means?

the safer the drug (over the counter drugs)

narrow therapeutic index means?

overdose is easier (needs higher regulation)

TD50 (toxic dose)

dose where drug causes some toxicity (harm) in 50% of subjects

Define psychoactive drugs

exogenous ligand that in small amounts alters experiences, emotion, mood, attention...

-natural or synthetic

-agonist, antagonist, or non-competitive ligand

Define tolerance

decrease in effect of drug after repeated use; over time need higher dose to get same effect

define metabolic tolerance

body gets better at eliminating drug

define functional tolerance

targeted receptors adapt

functional tolerance: antagonist

neurons may express MORE receptors if drug is an antagonist

functional tolerance: agonist

neurons may express LESS receptors if drug is an agonist

define physical dependence

stop using drugs leads to physical withdrawal symptoms

define psychological dependence

stop using drugs leads to psychological withdrawal symptoms; anxiety, distress

Define withdrawal

actual symptoms after stop using drug; specific symptoms depend on drug

ex: fatigue after stop using caffeine

define addiction

chronic relapsing disorder characterized by compulsive drug seeking behavior

-physical dependence, tolerance, & sensitization do not equal addiction

rate of absorption for injections: highest to lowest

1. intravenous (IV); fastest

2. intraperitoneal (IP)

3. intramuscular (IM)

4. subcutaneous (SQ); slowest

rate of absorption for injections depends on?

density of capillaries/blood flow

1. intravenous (IV); fastest

inject into vein

2. intraperitoneal (IP)

inject into abdominal cavity

3. intramuscular (IM)

inject into muscle

4. subcutaneous (SQ); slowest

inject under skin

Routes of administration of drugs: inhalation

1. gases

2. smokes

3. solids

inhalation: gases

lungs - a lot of surface area exposed to air and capillaries

inhalation: smokes

different from gas because includes vapor and ash particles, but absorbed similarly

inhalation: solids

inhaled through nose; not as efficient as lungs

Routes of administration of drugs: slower routes

1. oral (ingested)

2. transdermal

slower routes: oral (ingested)

absorbed mostly through intestines, then through capillaries

slower routes: transdermal

not readily absorbed through epidermis (skin)

Typical Antipsychotics effectiveness

1st generation/typical in 1950s \n decrease positive effects of schizophrenia (hallucinations, delusions) \n -ex: chlorpromazine, haloperidol

Typical Antipsychotics side effects

- dry mouth \n -hypotension \n -dystonia (involuntary muscle contraction) \n -tardive dyskinesia (repetitive movement) \n -Parkinsonism \n -weight gain

Typical Antipsychotics mechanism

antagonist. (block) D2 receptors (inhibitory dopamine)

atypical antipsychotics

2nd gen/1980s \n (ex: olanzapine & risperidone)

atypical antipsychotics effectiveness

decrease positive (hallucinations) & negative symptoms in schizophrenia (delusions, catatonia)

atypical antipsychotics side effects

hypotension, diabetes, weight gain

atypical antipsychotics mechanism

antagonist on 5-HT2 (serotonin), D1 (excitatory dopamine), D2, and α1 (norepinephrine) receptors

antidepressants

used to treat affective (mood) disorders

Antidepressants: SSRIs & SNRIs

-selective serotonin reuptake inhibitors & serotonin & norepinephrine reuptake inhibitors \n \n block reuptake of 5-HT &/or NE (norepinephrine); antagonist at SERT & NET (transporters) \n increase serotonin activity

antidepressants: MAOIs

monoamine oxidase inhibitors \n -block monoamine (enzyme) from breaking down/degradation of DA, NE, & 5-HT

antidepressants: TCA's

Tricyclic Antidepressants \n -block reuptake of NE & 5-HT

Anxiolytics (Benzodiazepines) \n -depressants

ex: xanax, valium, Ativan

Anxiolytics: Benzodiazepines effectiveness \n -depressants

anxiety & panic

Anxiolytics: Benzodiazepines side effects

-depressants

tolerance, cross tolerance, interaction w/ alcohol, high abuse potential

Anxiolytics: Benzodiazepines mechanism

-depressants

bind to non-NT site on GABAa receptors, enhance Cl- currents triggered by GABA \n \n -non competitive agonist, increase GABA signaling

Alcohol side effect \n -depressants

-addiction \n -tolerance \n -physical dependence

alcohol mechanism

agonist (activates) GABA receptors (also, DA, opioid, & NMDA receptors

Some structural effects of alcoholism are...

reversible since studies show improvements in MRI scans after one month of no alcohol

Opioid side effects

\n AKA opiate \n -euphoria \n -tolerance \n -physical dependence \n -cross tolerance \n -respiratory depression \n -constipation \n -high abuse potential

Opioid mainly acts on...

reward areas of the brain (nucleus accumbens)

endogenous opioids in brain?

endorphins, enkephalins, dynorphins

Heroin \n -opioids

-structurally similar to morphine (convert to morphine in brain) \n -produces euphoria, highly addictive

Heroin mechanism \n -opioids

-(agonist) acts on μ-opioid receptors in VTA (ventral tegmental area) & nucleus accumbens, parts of mesocorticolimbic DA pathway involved in reward/reinforcement \n \n -activates μ-opioid receptors hyperpolarizes (Cl- in) GABAergic neurons & inhibits GABA release onto DA neurons=increase DA in VTA (inhibits inhibition)

Nalaxone

opioid antagonist that rapidly reverses overdose

Cannabinoids: cannabis effectiveness

therapeutic uses: anxiety, pain (chronic>acute), chemotherapy side effects, glaucoma, epilepsy, MS (multiple sclerosis), spasticity

Cannabinoids: cannabis side effects

feelings of relaxation, hunger, sometimes paranoia

Cannabinoids: cannabis mechanism

agonist at CB1 & CB2 cannabinoid receptors (GPCRs)

stimulants: nicotine side effects

increase alertness, heart rate, blood pressure, digestion

stimulants: nicotine

mildly neuroprotective in Parkinson's, Alzheimer's, MCI (mild cognitive impairment)

stimulants: nicotine mechanism

agonist at nicotinic acetylcholine receptor (AChRs) in CNS & autonomic ganglia (higher bind affinity AChR>ACh) \n \n -activates DA in VTA (reward)

stimulants: Caffeine side effects

increase blood pressure, tolerance, physical dependence

stimulants: caffeine mechanism

\n adenosine receptor (AR) antagonist on pre-synaptic terminals \n \n -adenosine=drowsy \n -activated AR inhibit monoamine & ACh (acetylcholine)

Stimulant: Amphetamines

increase alertness, motivation, endurance, euphoria \n -longterm lead to schizoid behavior

Stimulant: Amphetamines side effects

increased blood pressure, tolerance, physical dependence

Stimulant: Amphetamines mechanism

Increase DA & NE, levels at the synapse (by acting w/in axon terminals) and decreasing reuptake \n \n -DAT reverse transport send NT out instead of back

Stimulants: Cocaine

creates euphoric state, increases endurance

Stimulants: Cocaine side effects

long term use lead to psychosis, neurodegeneration, altered brain activity

Stimulants: cocaine mechanism

-DAT (transporter) antagonist \n -blocks monoamine NT reuptake (especially DA)

Empathogen: MDMA

promising treatment for PTSD

Empathogen: MDMA side effects

-social, empathic, visual, euphoric (pos) \n -neurotoxic to thermoregulatory systems (risk of hyperthermia; neg)

Empathogen: MDMA mechanism

-agonist at 5-HT2a receptors, 5-HT1B & SERT (transporter) \n -inc release of DA, NE, 5-HT, oxytocin

psychedelics: LSD (lysergic acid diethylamide) side effect

-distorts visual perception, induces feeling of creativity \n -may cause long term changes in mood/personality

psychedelics: LSD mechanism

agonist at 5-HT2a receptor which is highly expressed in visual cortex

Dissociative: PCP and Ketamine

developed as anesthetics in 1960s \n -used in vet clinics & children in hospitals

Dissociative: PCP and ketamine side effects

produce dreamlike state, detachment from reality, separation between consciousness & sensory inputs

Dissociative: PCP (phencyclidine; aka angel dust)mechanism

antagonist of NMDA receptor-type glutamate receptors, inhibits DA reuptake \n \n -induces depersonalization, schizoid behaviors, hallucinations, aggressions

Dissociative: Ketamine (Special K) mechanism

competitive antagonist of NMDA receptor-type glutamate receptors, inhibits DA reuptake \n \n -medical use: anesthetic, pain killer, rapid long-lasting antidepressant (one dose lasts for weeks)

Reward circuitry:dopamine

-DA=key NT affected by addictive drugs \n -DA released from VTA neurons into nucleus accumbens

Reward circuitry:

drugs like stimulants, opioids, etc directly or indirectly activate mesocorticolimbic neural circuit that mediates reward & pleasure