Unit 05L abused drugs

Question 1

what is an abused substance and the main classes

Answer 1

• any substance that is administered repeatedly ina amteern and amount that interferes with health or daily functioning
• main calsses are:sedatives, opioids, stimulants, hallucinogens and cannabinoids

*most addictive are those that increase dopamine levels in the limbi system

Question 2

describe tolerance

Answer 2

• tolerance and dependence
• tolerance is reduced drug effect resulting from repeated use - higher dose requried for same effect
• can also have behavioural tolerance: changes in someones actions compensate for the drug effect
• functional tolerance: due to changes in drug receptor/targer (increased or decreased receptor numbers) and/or metabolic toelrance changes in the expression of enymes that inc drug emtbaolism

Question 3

describe dependance

Answer 3

• known as drug addiction
• compulsive need to use deugs in order to function normally
• physiological changes such as drug seeking behaviour (addiction) and physiological changes like withdrawal symptoms - which result from discontinued use and produce symptoms often opporite of intiaial effects

Question 4

what is the mesolimbic dopamine pathway

Answer 4

• final common substrate for the rewarding action of drugs
• all drugs of abuse activate teh mesolimbic dopamine pathway
• comprised of ventral tegmental area (VTA) dopamine neurons that project to the nucleus accumbens (NAc)
• different inter neurons interact with VTA neurons and NAc neurons to modulate mesolimbic neurotransmission

Question 5

how does nicotine interact with mesolimbic dopamine apthway

Answer 5

• interacts with excitatory nicotinic cholinergic receptors located on VTA dopamine neuron cell bodies to enhance dopamine release in the nucelus accumbens

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Question 6

how does cocaine interact with mesolimbic dopamine pathway

Answer 6

• acts predominantly at the dopamine nerve terminal to inhibit reuptake of dopamine via the dopamine transporter (DAT)
• increases synpatic levels of dopamine that can impinge on NAc

*cocaine dec reuptake of norepinephrine, dopaminea and serotonin

Question 7

how does amphetamine interact with mesolimbic dopamine pathway

Answer 7

• acts at dopamine nerve terminal to faciliate release of dopamine containing vesicble and possible enhance reverse transport of dopamine though DAT (not shown in pic)

*INC release of norepinephrine, inc release of dopamine, inc release of serotonin

Question 8

what do Cannabinoids and opiods do to GABA

Answer 8

• decrease GABA release from local inhibitory interneurons in VTA
• results in disinhibition of dopamine neuron activity and increased dopaminergic neurotransmission
• cannabinoids and opioids can also cat within the NAc

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Question 9

CNS deperssents in mesolimbin dopamine pathway

Answer 9

• Alcohol and other CNS depressants act on NMDA receptors (NMDA-R) to reduce glutamatergic neurotransmission in the NAc.

The effects of alcohol on dopaminergic neurons in the VTA appear to be both excitatory and inhibitory, and are the subject of active investigation (not shown).

Question 10

what is the therapeutic approach to treat drug abuse?

Answer 10

• multistep approach
• first goal = treat acute overdose and any smyptoms with antagonists

second = manage withdrawal symptoms - administer drugs to supress acute withdrawal followed by gradual reduction in dose

last = long term rehabillitation to avoid drug relapse

Question 11

describe sedative abuse

Answer 11

• sedative abuse often bc individual seeking an escape or they are used in patterns of alternating sedatives and sitmulants
• often used as date rape drugs
• dependence and symptoms with withdrawal of mroe common from chronic use of athanol and barbiturates then benzodiazepines

Question 12

symptoms of sedative withdrawl

Answer 12

tremors, irritability, anxiety, hypertension, nausea, vomiting, sweating, and perceptual distortion

Question 13

what is clonidine prescribed for

Answer 13

help with autonomic symptoms of withdrawal and low-dose benzodiazepines can be used to treat ethanol withdrawal

*MOA of clonidine described in autonomic and cardiovasuclar pharmacology sections

Question 14

describe tolerance with sedative drugs

Answer 14

tolerance can develop to the sedative effect of drugs but not to the respiratory depressant effect

• metabolic tolerance to ethanol can occur - microsomal ethanol oxidizing system (MEOS) of ethanol metabolism is induced in chronic alcoholism, therefore alcoholics may have an enhanced rate of ethanol metabolism.

Question 15

decribe opioids

Answer 15

• ex: morphine, heroin and fentanyl - derived from the opium poppy
• those that abuse opiods are seeking initial rush followed by euphoria, tranquility and sleepiness

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Question 16

MOA of opioids

Answer 16

• involves an opioid receptor (such as mu) which is G-protein linked.

At the presynaptic membrane, opioids cause a decrease in Ca+2 which decrease the release of the neurotransmitters GABA and glutamate.

Opioids also cause an increase in K+ efflux and the inhibition of postsynaptic neurons.

Question 17

what are the additional risks associated with recreational opioid heroin

Answer 17

• effects of heroin last 3-5 hours so need several doses a day to prevent withdrawl
• many formulations of heroin which vary in potenccy and their risk of overdose - heroin is often overlapped with fentanyl and cocaine use

*Overdosing on opioids is very dangerous because it can cause respiratory depression which can lead to coma or even death

Question 18

routs of administrion for heroin

Answer 18

• smoking, injected subcutaneous (skin popping) and injected (mainlining)
• increased risk of spreading diseases with shared needles

Question 19

how is acute opioid toxicity managed

Answer 19

• use of opioid receptor antagonists like naloxone
• opioid antagonists are competitive antagonists that bind to the opioid receptors with higher affinity than agonsists but do not activate the receptors which prevent the body from responding to opiates

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Question 20

how can opioid detoxification be accomplished

Answer 20

• with methadone
• oral longer acting opioid receptor agonist and clonidine which helps with autonomic symptoms of withdrawal

Question 21

describe the mechanism of action of μ-opioid receptor agonists in the spinal cord

Answer 21

in the spinal chord

**inhibits central relaying of nociceptive stimuli, dec repsonse to incoming action potential and excitatory neurotransmission

• opioids bind to opioid receptors in pre synpatic neuron to close clacium channel,s less release of excitatory neurotransmitters like glutamate

*leads to less excitation of the secondary neuron, hyperpolarization and dec in action potential frequency

• also bind to opioid mu receptors in membrane of cell body (dendriates of secondary neruon) to open potasium channels - leads to hyperpolization and dec in action potential freq

*less pain signals sent to the brain

Question 22

describe the role of opioids in the brain reward pathway

Answer 22

A. GABAergic neurons tonically inhibit the dopaminergic neurons that arise in the ventral tegmental area and are responsible for reward

• these GABAergic neurons can be inhibited by endogenous enkephalins which locally modualte the release of neurotrasnmitter at the GABAergic nerve terminal

B. administration of exogenous opioids results in decreased GABA release and disinhibition of the dopaminergic reward neurons - increased releaed of dopamine in cucleus accumbens signals a strong reward

Question 23

decribe Stimulants

Answer 23

• include cocaine, amphetamines and MDMA (Molly/ecstasy)
• main routes of administation are inhalation, IV and oral
• MOA amphetamines and MDMA = increase in release of norepinephrine, dopamine and serotonin.

MOA of cocaine = decrease in reuptake of norepinephrine, dopamine and serotonin.

Question 24

decribe tolerance/dependents of stimulants

Answer 24

Tolerance and dependence develops following the chronic use of stimulants.

The desired effects of stimulants are increased alertness and euphoria

Question 25

adverse effects of stimulants

Answer 25

psychosis, delusions and excess sympathomimetic activity.

Cocaine overdose can cause intracranial hemorrhage, stroke, seizure, arrhythmias, heart attack, hyperthermia, coma or death.

Amphetamines are less commonly associated with fatality

ecstasy can cause hyperthermia, serotonin syndrome, seizures and neuronal damage.

Question 26

what are gallucinogens

Answer 26

• do not amplify familiar states of mind like stimnulants and opioids - instead incude experiences that are different from those of ordinary consciousness
• MOA psychedelic hallucinogens such as lysergic acid diethylamide (LSD), mescaline and psilocybin is not entirely clear but it is known that it involves serotonin.
• psychedelic hallucinogens are agonists at several 5-HT receptors (most are agonsists or partial agonsists of the 5-HT2A receptor)

Question 27

what is phenyclidine

Answer 27

PCP - hallucinogen called angel dust

• functions as an NMDA receptor antagonist

Question 28

tolerance, dependance and adverse effects of hallucinogens

Answer 28

Tolerance develops following abuse of hallucinogens but physiological dependence is rare.

The desired effect of taking this substance is visual illusions and perceptual distortion.

Adverse effects include panic reactions and psychosis, and LSD has also been shown to cause strong uterine contractions. Like some other drugs of abuse, overdose of PCP can be fatal.

Question 29

what are cannabinoids

Answer 29

• class of chemical compounds that activate the cannabinoid receptors and decrease neurotransmitter release in the brain
  ex: marijuana and hashish - contain active component Δ-9-tetrahydrocannabinol (THC).
• main route of administration is inhalation

tolerance as well as mild physiological dependence can occur with continued frequent use.

Question 30

what are the two subtypes of cannabinoid receptor

Answer 30

CB1 - mainly expressed in the brain (CNS)

CB2 - expressed in the immune system and hematopoietic cells (periphery).

belong to the G-protein linked family and inhibit GABA or glutamate release.

Question 31

MOA of cannabinoids

Answer 31

• normally in brain stimualtion of NMDA receptor increases Ca²⁺ which increases synthesis of endogenous cannabinoid neurotransmitter anandamide in the brain
• in dopamine pathway, another endogenous cannabinoid, 2-arachidonoylglycerol (2-AG) is produced
• Anandamide and 2-AG binds to presynaptic CB1 receptors and decreases glutamate or GABA release.

*THC mimics the action of endogenous cannabinoids and activates the CB1 receptor.

Question 32

initial and secondary effects of cannabinoids

Answer 32

initial = euphoria, laughter and altered sense of time

secondary = relaxation, introspection and sleepiness

• Impaired cognition, perception, reaction time, learning and memory can also result, and cannabis use can cause paranoia, anxiety and hallucinations.

chronic sue of inhaled cannabinoids can cause bronchitis and lung cancer

Question 33

what are the excitatroy neurotransmitters? what are the inhibitory ones?

Answer 33

Excitatory neurotransmitters include glutamate and acetylcholine

inhibitory neurotransmitters include GABA and dopamine.

*Norepinephrine and serotonin are examples of mixed neurotransmitters that can have excitatory or inhibitory effects depending on the receptor subtype they activate.