What is physical dependence?
State of adaption that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction ,decreasing blood level of the drug, and/or administration of an antagonist
What is tolerance?
State of adaption in which exposure to a drug induces changes that result in a diminution of one or more of the drugs effects over time
Physical dependence and tolerance are normal responses that often occur with the persistent use of certain medications. While dependence will invariably occur with chronic exposure, only a fraction of subjects will become addicted. What are the mechanisms for addiction?
Mesolimbic dopamine system is the prime target of addictive drugs
- -this system originates in the ventral tegmental area and projects to the nucleus accumbens, the amygdala and the prefrontal cortex
- -all addictive drugs activate the mesolimbic dopamine system.
Lets go through the drugs of abuse. First up are the CNS depressants. First up in this category is ethanol. What are some features?
–influences several cellular functions (GABAa receptors, Kir3/GIRK channels, adenosine reuptake, glycine receptor, NMDA receptors and 5-HT3 receptors)
What is withdrawal syndrome in regards to alcohol?
6-12 hours after cessation of heavy drinking
–tremor, nausea, vomiting ,excessive sweating, agitation and anxiety and sometimes hallucinations
Seizures can occur 24-48 hours later
48-72 hours later an alcohol withdrawal delirium becomes apparent
What is the treatment of alcohol withdrawal?
Meds are cross tolerant with alcohol
–diazepam and chloridazepoxide are long acting agents that have been shown to be excellent in treating alcohol withdrawal and because of the long half life of these drugs, withdrawal is smoother, and rebound withdrawal symptoms are less likely to occur
Lorazepam and Oxazepam: are intermediate short acting drugs and are preferable in the elderly and those with liver failure
Tx of alcoholism is Disulfiram, Naltrexone and Acamprosate. What are features of these drugs?
- Disulfiram: inhibitor of aldehyde dehydrogenase
- -aversion to drinking, if drinking does occur, acetaldehyde accumulates and headache and hypotension happens.
- Naltrexone: opioid receptor antagonist. reduces craving for alcohol
- Acamprosate: NMDA receptor antagonist, prevents relapse to alcohol drinking
- Topiramate (NOT FDA approved): facilitates GABA function and antagonizes glutamate receptors and may decrease mesocorticolimbic dopamine release after alcohol and reduce cravings
The second CNS depressant drug of abuse are the Benzodiazepines. What are some features?
Used for tx of anxiety disorders and insomnia
–physical dependence and addiction
–include tremors, anxiety, perceptual disturbances, dysphoria, psychosis and seizures
–dose needs to be gradually reduced
–long acting has less severe withdrawal syndrome
The third CNS depressant drug of abuse are the barbiturates. what are some features?
Use has declined greatly due to increased safety and efficacy of newer medications.
Next category of drugs of abuse are the psychostimulants, first up are the methylxanthines. What are these drugs and what is the MOA?
Caffeine and the related methylxanthines theophylline and theobromine
–block adenosine receptors that are expressed presynaptically on many neurons, including adrenergic neurons. Antagonism of the receptors by caffeine disinhibits NE release and thus acts as a stimulant.
–adenosine is a natural promoter of sleep and drowsiness. so caffeine blocks this.
What are the methylxanthines action on CNS, CV and GI?
–decrease in fatigue and increased mental alertness as a result of stimulating the cortex
–1.5 grams of caffeine produces anxiety and tremors
–positive inotropic and chronotropic effects on the heart
–mild diuretic actions
–stimulate secretion of HCl from the gastric mucosa
–if peptic ulcer avoid
What are the pharmacokinetics, uses, AE, tolerance of methylxanthines?
–cross the placenta to the fetus and is secreted into the mother’s milk
–metabolized in liver
–theophylline: chronic asthma
–caffeine + ergotamine is used for migraine (adds to the vasoconstrictive effects)
–insomnia, anxiety and agitation
–lethal dose is 10g of caffeine, which induces cardiac arrhythmias
–withdrawal: feelings of fatigue and sedation
The next psychostimulant is cocaine, what is the MOA and actions?
–inhibits dopamine, NE and 5-HT reuptake therefore prolonging and potentiates CNS and peripheral actions of these monoamines
–prolonged dopamine produces the intense euphoria that cocaine initially causes
–craving comes from the depletion of dopamine
–CNS: stimulation of cortex and brainstem (behavioral changes)
–sympathetic nervous system: increased NE adrenergic stimulation, thus producing tachy, and HTN
What are the PK, withdrawal and treatment of cocaine addiction?
–rapid onset, potential for overdosage and dependence is greatest with IV injection and freebase smoking
–dysphoria, depression, sleepiness, fatigue, cocaine, craving and bradycardia
–generally mild so no treatment
Tx of addiction:
–antidepressants and dopamine agonists but there is no clear treatment
The last psychostimulant drug of abuse is Amphetamines. What is the MOA and actions?
Methamphetamne and Methylphenidate
–increased release of catecholamine neurotransmitters, including dopamine.
–inhibitors of MAO and direct catecholaminergic agonists in the brain
–behavioral effects similar to cocaine
-CNS: stimulates entire cerebrospinal axis, cortex, brainstem and medulla
–Sympathetic Nervous System: acts on adrenergic system, indirectly, stimulating receptors through NE release
What are the PK, Uses, AE, and Tolerance for Amphetamines?
–drugs administered IV and smoking
–euphoria lasts 4 to 6 hours
-Attention deficit syndrome and Narcolepsy
–CNS: insomnia, weakness, confusion, panic states
–CV: palpitations, arrhythmias, HTN.
GI: anorexia, nausea, vomiting
–marked tolerance, and an abstinence syndrome can occur with withdrawal. Increased appetite, sleepiness, exhaustion and mental depression.
Next drug for abuse is Nicotine. What is the MOA and actions of nicotine?
–selective full agonist of the nicotine receptor
–when nicotine excites neurons, dopamine is released in then nucleus accumbens and the prefrontal cortex, thus fulfilling the dopamine requirement of addictive drugs
–low dose: ganglionic stimulation by depolarization
–high dose: ganglionic blockade
–CNS: crosses the BBB; appetite suppressant
–Peripheral effects: sympathetics in the heart and blood pressure but parasympathetic in the GI
What are the PK and withdrawal syndrome associated with nicotine?
1 to 2 mg of nicotine per cigarette that smoker takes in
Lethal dose of nicotine is 60mg
–mild and involves irritability and sleeplessness.
What is treatment for nicotine addiction?
Nicotine Replacement Therapy: transdermal patch, gum, nasal spray, vapor inhaler or by lozenge for buccal absorption
Sustained Release Bupropion: atypical antidepressant
Varenicline: partial agonist at neuronal nicotinic acetylcholine receptors in the CNS
–tends to attenuate the rewarding effects of nicotine if a person relapses and uses tobacco
Next drugs for abuse are the Opioids, what drugs does this include?
Heroin Morphine Codeine Oxycodone among health professionals: meperidine and fentanyl
What is the tolerance, dependence and withdrawal of these substances.
Addiction: provides behavioral disruptions
Withdrawal is unpleasant but not life threatening (flu like symptoms)
All opioids induce strong tolerance and dependence
What is the treatment of opioid withdrawal?
- Detoxification using Opioid Agonists
- -Methadone – long acting opioid that produces a smoother withdrawal
- -Buprenorphine – long acting partial mu agonist and kappa receptor antagonist – produces minimal withdrawal symptoms
- Detoxification using Adrenergic Agonists
- -Clonidine and Lofexidine: presynaptic alpha 2 agonists, which inhibit noradrenergic storm and are able to attenuate symptoms.
- Detoxification using Opioid Antagonists
- -Naltrexone: antagonists with a high affinity for the mu opioid receptor
The next drug for abuse is Marijuana. What is the MOA?
Delta-Tetrahydrocannabinol (Delta THC): produces most of the characteristic pharmacological effects
–CB1 receptor for cannabinoid: found in brain and mediates the psychological effects of THC
–CB2 receptor for cannabinoid: present mainly on immune cells
G protein receptors that inhibit adenylyl cyclase, opening of potassium channels and closing of calcium channels
What are the actions, tolerance, dependence and uses of marijuana?
Euphoria followed by drowsiness and relaxation
–affects short term memory and mental activity
AE: increased HR, decreased BP and reddening of conjunctiva
Tolerance and Dependence:
–develop with continued use
–therapeutic THC is called Dronabinol and is approved for anorexia associated with weight loss in AIDS and n/v associated with chemo patients
Next set of drugs of abuse are the psychedelic agents. Which include what?
LSD Mescaline Psilocybin Phencyclidine MDMA
First up for the psychedelic agents is LSD. what are some features and MOA?
LSD like drugs include: Mescaline and Psilocybin and are found in nature and these drugs have three major neurotransmitters: NE, dopamine and Serotonin
–agonist effects at subtypes of 5-HT2 receptors in the CNS
What are the symptoms, tolerance and dependence and withdrawal and AE of LSD and its related drugs?
–somatic symptoms: mydriasis, hypertension, tachy or increased body temp
– psychomimetic symptoms
Tolerance, Physical Dependence and Withdrawal:
–tolerance develops to the behavioral effects of LSD after 3 to 4 daily doses
–no withdrawal or addiction
—bad trips with severe agitation: use diazepam
Next up for the psychedelic agents is Phencyclidine (PCP). What are some features?
Ketamine (is an analog for PCP)
PCP is a classic dissociative anesthetic
–acts in the CNS producing both stimulation and depression.
–reuptake inhibition of NE and dopamine
–exerts some cholinergic and anticholinergic effects and some other actions at nicotinic and opioid receptors
–dissociative properties due to NMDA receptor antagonists ( produce behavioral effects in schizophrenia)
What are the clinical manifestations of PCP?
Violent or Bizarre Behavior Psychosis Nystagmus: vertical and horizontal (has it while awake) Tachy HTN Diaphoresis Miosis -no antidote for PCP but can use benzos for sedation
The last psychedelic agent is MDMA (Ecstasy) what are some features?
Foster feelings of empathy and intimacy without impairing intellectual capacities
Release of biogenic amines by reversing the action of their transporters.
Affinity for the serotonin transporter and therefore most strongly increases the concentration of serotonin in the synaptic cleft.
Acute effects include tachy, muscle aches, agitation, hyperthermia and seizures
Withdrawal is marked by a mood offset: depression
Produces degeneration of serotonergic neurons
The next drugs of abuse are the inhalants, which include NO, volatile organic solvents, and organic nitrites. What are some features of these drugs?
NO: euphoria and analgesia and LOC. Taken as 35% N20 mixed with O2
Volatile Organic Solvents: gasoline, pain thinner, lighter fluid or glue. Sense of exhilaration and light headedness. Implicated in cancer, cardiotoxicity, neuropathies and hepatotoxicity
Organic Nitrites: Amyl Nitrite: dilation of smooth muscle and used for tx of angina. Used to enhance erection and are not addictive
Finally the last drugs of abuse are anabolic steroids, what are they used for?
Used to increase muscle size and definition by body builders
–coabused with other growth enhancers such as human growth hormone