Psychiatry-Pharmacology (USMLE)

Drug of choice for management of chronic generalized anxiety disorder

antidepressants

velaxafine and SSRIs preferred over TCAs

What drugs can be used for acute treatment of generalized anxiety disorder or as adjuncts during initiation of antidepressant therapy?
benzodiazepines
Name a second-line agent for generalized anxiety disorder.

buspirone

alternative agents: hydroxyzine and pregabalin

Drug of choice for panic disorder
SSRIs
List 2 adverse effects of alprazolam that do not make it an ideal choice for treatment of panic disorder.

rebound anxiety between doses

withdrawal syndromes, including seizures

Drug of choice for social anxiety disorder
SSRIs
List 3/5 FDA-approved drugs for the treatment of obsessive-compulsive disorder.

clomipramine

fluoxetine

fluvoxamine

paroxetine

sertraline

benzodiazepines or antipsychotic drugs can be added for highly anxious patients

Drug of choice for PTSD
SSRIs
List 2 SSRIs approved for the ACUTE treatment of PTSD. Which is indicated for long-term management as well?

sertraline: long-term management as well

paroxetine

Drug of choice for performance anxiety
propranolol and other beta-blockers
What amino acid precursor gives rise to dopamine?

tyrosine

must be transported across the blood-brain barrier into the dopamine neuron

What transporter allows for tyrosine uptake in the presynaptic neuron?

system L

Na+-independent manner

What is the rate-limiting enzyme in dopamine synthesis?

tyrosine hydroxylase

tetrahydrobiopterin cofactor required

What enzyme converts DOPA to dopamine?

DOPA decarboxylase

so rapid that DOPA levels in brain negligible

How do D1 and D2 receptors affect adenylyl cyclase activity?

D1: ↑ adenylyl cyclase

D2: ↓ adenylyl cyclase, ↑ K+ conductance, ↓ Ca2+ conductance

How do dopaminergic neurons from the substantia nigra affect GABAergic output from the striatum?
How do dopaminergic neurons from the substantia nigra affect GABAergic output from the striatum?
normally inhibit the GABAergic output
Destruction of neurons of which dopamine pathway cause Parkinson’s disease?

nigrostriatal

70% of neurons destroyed at time symptoms first appear

In regards to dopaminergic and cholinergic neurons, what is the strategy of treatment for Parkinson’s disease?

restore dopamine in basal ganglia

antagonize excitatory effect of cholinergic neurons

What enzyme converts levodopa to dopamine?
DOPA decarboxylase (in CNS)
Why does levodopa cause nausea, vomiting, cardiac arrhythmias, and hypotension?
much of the drug is decarboxylated to dopamine in the periphery
Name a DOPA decarboxylase inhibitor.
Name a DOPA decarboxylase inhibitor.

carbidopa

does not cross the blood-brain barrier

What drug contains carbidopa and levodopa in fixed proportions?
sinemet
How does food intake affect the appearance of levodopa in the plasma?
delays appearance of levodopa in plasma
METABOLISM OF LEVODOPA
METABOLISM OF LEVODOPA
Why does responsiveness to levodopa eventually decrease in Parkinson’s disease patients?
disappearance of dopaminergic nigrostriatal neurons
What vitamin is contraindicated with levodopa?

vitamin B6

increases peripheral metabolism of levodopa

What emergency can occur with concomitant administration of nonspecific MAO inhibitors and levodopa?
hypertensive crisis
Why are antipsychotics contraindicated in Parkinson’s disease?
may produce a parkinsonian syndrome
Why is levodopa contraindicated in angle-closure glaucoma?

Name an ergo dopamine agonist.

Which dopamine receptor subtype is acted upon by this drug?

bromocriptine

D2 receptor

used alongside levodopa

Bromocriptine adverse effects (3/5)
Bromocriptine adverse effects (3/5)
Name 2 nonergot dopamine agonists used in younger patients.

pramipexole

ropinirole

What nonergot dopamine agonist was available in a transdermal formulation?

rotigotine

recalled due to formation of rotigone crystals

What nonergot dopamine agonist is used for rescue therapy for treatment of “off” episodes of akinisia in patients on dopaminergic therapy?

apomorphine

pretreatment with antiemetic trimethobenzamide

Apomorphine adverse effects (3/6)

QT prolongation

dyskinesias

drowsiness

sweating

hypotension

bruising at the injection site

Name 2 MAOIs that selectively and IRREVERSIBLY inhibit MAO-B.
deprenyl (selegiline)
mainly used as adjunct to levodopa; allows dose of levodopa to be reducedrasagiline

Inhibition of DOPA decarboxylase by carbidopa increases what peripheral metabolite?
Inhibition of DOPA decarboxylase by carbidopa increases what peripheral metabolite?
3-o-methylDOPA
What COMT inhibitor is associated with fulminating hepatic necrosis?
tolcapone
Name 2 COMT inhibitors.

entacapone

tolcapone

Amantadine antiparkinsonian MOA

increases synthesis, release or reuptake of dopamine from the surviving neurons

less efficacious than levodopa and tolerance develops more readily, but fewer side effects

Amantadine systemic adverse effects (3/4)

restlessness

agitation

confusion

peripheral edema

What adverse effect is associated with high doses of amantadine?
acute toxic psychosis
What dermatologic adverse effect is associated with amantadine?
livedo reticularis
Drug of choice for Parkinson's disease
Drug of choice for Parkinson’s disease
levodopa + carbidopa
Are sedative-hypnotics with linear or non-linear dose-response relationships dangerous?
Are sedative-hypnotics with linear or non-linear dose-response relationships dangerous?

linear dose-response curve

increase in dose above that needed for hypnosis may lead to a state of general anesthesia

higher doses, they may depress respiratory and vasomotor centers in the medulla, leading to coma and death

What drugs are the most widely used anxiolytic drugs?
benzodiazepines
To what receptors do benzodiazepines bind?

GABAA receptors

chloride channels

List the subunits that make up the pentameric structure of the GABA<sub>A</sub> receptor.
List the subunits that make up the pentameric structure of the GABAA receptor.

alpha-2-beta-2-gamma

binding sites located between adjacent alpha and beta subunits

Between which 2 subunits of the GABA<sub>A</sub> receptor does benzodiazepine bind?
Between which 2 subunits of the GABAA receptor does benzodiazepine bind?

alpha subunit

gamma subunit

increased in frequency of channel opening events

Which 2 benzodiazepine receptor subtypes are found in the CNS?

BZ1

BZ2

How does benzodiazepine affect the EC50 for the GABA-induced Cl- influx?
How does benzodiazepine affect the EC50 for the GABA-induced Cl- influx?
decreases EC50
Name a benzodiazepine receptor antagonist.
flumazenil
List 3/5 actions of benzodiazepines.

reduction of anxiety

sedative and hypnotic actions

anticonvulsant

muscle relaxant

anesthesia

List 2 long-acting benzodiazepines.

diazepam

flurazepam

1-3 days

List 3 intermediate-acting benzodiazepines.

alprazolam

lorazepam

temazepam

10-20 hours

List 2 short-acting benzodiazepines.

oxazepam

triazolam

3-8 hours

List 3 benzodiazepines that are conjugated directly and not metabolized by the CYP450 system.
List 3 benzodiazepines that are conjugated directly and not metabolized by the CYP450 system.

oxazepam

lorazepam

temazepam

List 2 active metabolites of flurazepam that result from oxidation by liver enzymes.
List 2 active metabolites of flurazepam that result from oxidation by liver enzymes.

hydroxyethyl-flurazepam

desalkyl-flurazepamx

half-life: 30-100 hours

What benzodiazepine prodrug is decarboxylated to desmethyldiazepam in gastric juice?
What benzodiazepine prodrug is decarboxylated to desmethyldiazepam in gastric juice?
clorazepate
What benzodiazepine is useful in the treatment of skeletal muscle spasms and in treating spasticity from degenerative disorders like multiple sclerosis and cerebral palsy?
diazepam
Which benzodiazepine is used for some types of epileptic seizures?
clonazepam
List 2 benzodiazepines used in status epilepticus.

lorazepam

diazepam

List 2 benzodiazepines used in the management of withdrawal from ethanol.

diazepam

oxazepam

List a long-acting, intermediate-acting, and short-acting benzodiazepine used for sleep disorders.

flurazepam

temazepam

triazolam

What are the 2 most common side effects of benzodiazepines?

drowsiness

confusion

ataxia, cognitive impairment

Benzodiazepines withdrawal symptoms (3/6)

confusion

anxiety

agitation

restlessness

insomnia

tension

Benzodiazepine overdose Rx
flumazenil
What receptors are associated with barbiturates?

GABAA receptors

different binding site than that of benzodiazepines

increase the duration of the GABA-gated chloride channel openings

How do barbiturates affect CYP450 enzymes?
induce CYP450 enzymes
Barbiturate used for anesthesia

thiopental

ultra short-acting

Barbiturate used as an anticonvulsant

phenobarbital

long-term management of tonic-clonic seizures, status epilepticus and eclampsia

What nondepressant barbiturate can be used to treat hyperbilirubinemia and kernicterus in neonates?
N-phenylbarbital
How do barbiturates affect porphyrin synthesis?
increase porphyrin synthesis
What emergency situation can arise with rapid IV injection of barbiturates?
cardiovascular collapse
Which benzodiazepine receptor subtype is associated with non-benzodiazepine benzodiazepeine receptor agonists?
BZ1 subtype
List 2 non-benzodiazepine benzodiazepine receptor agonists that are indicated for the short-term treatment of insomnia?
zolpidem
difficulties with sleep initiationzaleplon
rapid onset and very short duration of action

What non-benzodiazepine benzodiazepeine receptor agonist decreases sleep latency and improves sleep maintenance?

eszopiclone

active enatiomer of zopiclone

Name a 5-HT1A partial agonist indicated for management of anxiety disorders.
Name a 5-HT1A partial agonist indicated for management of anxiety disorders.
buspirone
List 3/5 advantages of 5-HT1A partial agonists over other sedative-hypnotics.
List 3/5 advantages of 5-HT1A partial agonists over other sedative-hypnotics.
Name a melatonin receptor agonist indicated for the treatment of insomnia characterized by difficulty with sleep onset.

ramelteon

agonist at MT1 and MT2 melatonin receptors

Which antihistamine is approved for symptomatic relief of anxiety?

hydroxyzine

diphenhydramine and doxylamine effective in treating MILD types of insomnia

What beta-blocker is widely used to control performance anxiety?
propranolol
What alpha-blocker is used to modify autonomic expression of anxiety?
clonidine
Positive psychotic symptoms are believed to be linked to overactivity of _____ neurons in the _____ dopamine pathway.
Positive psychotic symptoms are believed to be linked to overactivity of dopamine neurons in the mesolimbic dopamine pathway.
Which dopamine receptors are blocked by antipsychotic drugs?
D2 receptors
List the 4 well-defined dopamine pathways in the brain.
List the 4 well-defined dopamine pathways in the brain.

mesolimbic pathway

nigrostriatal pathway

mesocortical pathway

tuberoinfundibular pathway

Blockade of D2 receptors in which dopamine pathway is believed to mediate the antipsychotic effects of antipsychotic drugs?
mesolimbic pathway
Describe the projection associated with the mesolimbic pathway.

brainstem to limbic areas

important role in emotional behaviors

Describe the projection associated with the nigrostriatal pathway.

substantia nigra to basal ganglia

controls motor movements

Which dopamine pathway is part of the extrapyramidal nervous system?
nigrostriatal pathway
Describe the projection associated with the mesocortical pathway.
brainstem to the limbic cortex
Negative symptoms seen in psychosis may be due to deficit of dopamine in which pathway?
mesocortical pathway
Describe the projection associated with the tuberoinfundibular pathway.

hypothalamus

anterior pituitary

Dopamine released from the neurons in the tuberoinfundibular pathway inhibits secretion of which hormone?

prolactin

may cause galactorrhea

Name 5 classical antipsychotic drugs. Which 3 are high-potency drugs? Which 2 are low-potency drugs?

Name 5 classical antipsychotic drugs.

Which 3 are high-potency drugs?

Which 2 are low-potency drugs?

fluphenazine

haloperidol

thiothixene

more likely to produce extrapyramidal reactions
—–
chlorpromazine

thioridazine

more likely to produce sedation and postural hypotension

Name 4/7 atypical antipsychotic drugs.

clozapine

risperidone

olanzapine

quetiapine

ziprasidone

aripiprazole

paliperidone

What makes atypical antipsychotic drugs
What makes atypical antipsychotic drugs “atypical?”
higher affinities for other receptors than for the D2 receptor

Typical vs. Atypical Antipsychotics

exert part of their action by blocking 5-HT receptors

more likely to cause extrapyramidal reactions

less likely to cause tardive dyskinesia

less likely to cause increases in prolactin

more effective at treating negative symptoms

less effective in refractory populations

exert part of their action by blocking 5-Ht receptors: *atypical*

more likely to cause extrapyramidal reactions: *typical*

less likely to cause tardive dyskinesia: *atypical*

less likely to cause increases in prolactin: *atypical*

more effective at treating negative symptoms: *atypical*

less effective in refractory populations: *typical*

How do antipsychotic drugs affect intellectual function and motor coordination?

do not depress intellectual function

minimal motor incoordination

List 2 antipsychotics that do not have antiemetic effects.

aripiprazole

thioridazine

antiemetic effects mediated by blockade of D2 receptors of the chemoreceptor trigger zone of the medulla

List 3 CYP450 enzymes that metabolize antipsychotic drugs.

1A2

2D6

3A4

do not interfere with the metabolism of other drugs

What drug is contraindicated in patients with extrapyramidal reactions due to antipsychotics?
levodopa
List 2 antimuscarinic drugs that can be used to treat Parkinsonism.

benztropine

trihexyphenidyl

addition of diphenydramine OR amantadine

List 2 drugs most commonly used to manage akathisia caused by antipsychotic medications.

clonazepam

propranolol

Name the most important unwanted effect of antipsychotics that may be due to dopamine receptor upregulation.
tardive dyskinesia
Which antipsychotic is recommended for patients with tardive dyskinesia who require antipsychotics?
Which antipsychotic is recommended for patients with tardive dyskinesia who require antipsychotics?
clozapine
A patient using antipsychotic medication presents with muscle rigidity, fever, altered mental status, stupor, unstable blood pressure, and myoglobinemia.

neuroleptic malignant syndrome

dantrolene or bromocriptine may be helpful

List 2 antipsychotics that are commonly associated with seizures.

chlorpromazine

clozapine

List 2 consequences of alpha-1 receptor blockade by antipsychotics.

orthostatic hypotension

impaired ejaculation

Which antipsychotic can cause agranulocytosis in 1-2% of patients?

clozapine

regular blood cell counts are mandatory

How do antipsychotics affect prolactin secretion?
How do antipsychotics affect prolactin secretion?
increase in prolactin secretion
Which 2 antipsychotics can cause weight gain?

clozapine

olanzapine

Which antipsychotic is least likely to cause weight gain?
ziprasidone
Which antipsychotic causes a high incidence of QTc- and T-wave changes and may (rarely) produce ventricular arrhythmias and sudden death?

thioridazine

ziprasidone also can prolong QT

Which antipsychotic causes deposits in the cornea and lens?
chlorpromazine
Which antipsychotic causes retinal deposits?
thioridazine
List 3/5 psychiatric indications for antipsychotics.

schizophrenia

bipolar disorder (atypical)

Tourette’s syndrome

Huntington’s disease

Alzheimer’s dementia (control of disturbed behavior)

List 2 non-psychiatric indications for antipsychotics.

nausea

vomiting

What antipsychotic is used in combination with fentanyl in neurolept-anesthesia?
droperidol
Which antipsychotic is category B?

clozapine

others are category C

Name 4 MAOIs.

isocarboxazid

phenelzine

tranylcypromine

selegiline

MAOIs adverse effects (3/6)

drowsiness

orthostatic hypotension

blurred vision

dry mouth

dysuria

constipation

Overstimulation of which 2 receptors are associated with serotonin syndrome?

5-HT1A

5-HT2

hyperthermia, muscle rigidity, myoclonus caused by any drug that increases serotonin

What monoamine compound can cause drug interactions with MAOIs?
What monoamine compound can cause drug interactions with MAOIs?
tyramine
OTC cold preparations that contain _____ and _____ are contraindicated in patients taking MAO inhibitors.
OTC cold preparations that contain pseudoephedrine and phenylpropanolamine are contraindicated in patients taking MAO inhibitors.
Name 3/5 tricyclic antidepressants (TCAs).
Name 3/5 tricyclic antidepressants (TCAs).

amitriptyline

clomipramine

desipramine

imipramine

nortriptyline

What 2 transporters are blocked by TCAs (major MOA)?

serotonin transporter (SERT)

norepinephrine transporter (NERT)

increased monoamine concentration in the cleft

Name a TCA that has very little affinity for NET, but potently binds SERT.
clomipramine
Name 2 TCAs that are more selective for NET than for SERT.

desipramine

nortriptyline

List 4 additional receptors blocked by TCAs.

alpha-adrenergic receptors

muscarinic receptors

histamine receptors

5-HT receptors

Blockade of which receptors by TCAs can cause the following adverse effects:

blurred vision

xerostomia

uirinary retention

constipation

aggravation of narrow-angle glaucoma

muscarinic receptors
The mechanism by which TCAs cause arrhythmias is similar to that of which antiarrhythmic drug?
quinidine
What is the most serious adverse effect of TCAs associated with the elderly (2)?

orthostatic hypotension

reflex tachycardia

blockade of alpha-1-adrenoceptors

Blockade of which receptors by TCAs causes sedation and weight gain?
H1 blockade
Describe the sexual adverse effects of TCAs with highly serotonergic effects.
What lethal complications are associated with TCA overdose?

arrhythmias

treatment includes cardiac monitoring, airway support and gastric lavage; sodium bicarbonate useful in reversing conduction block

Name 3/6 SSRIs.
Name 3/6 SSRIs.

citalopram

escitalopram

fluoxetine

fluvoxamine

paroxetine

sertraline

Drug of choice for depression
SSRIs
List 3/4 adverse effects associated with TCAs that are not seen with SSRI use.

orthostatic hypotension

sedation

dry mouth

blurred vision

little blocking activity at muscarinic, alpha-adrenergic, and histamine H1 receptors

List 4/7 uses for SSRIs other than depression.

obsessive-compulsive disorder

PD

GAD

PTSD

seasonal affective disorder

PMDD

bulimia

List 3 gastrointestinal adverse effects of SSRIs.

nausea

GI upset

diarrhea

Which 2 SSRIs inhibit CYP2D6?

fluoxetine

paroxetine

Which SSRI inhibits CYP1A2, CYP2C19, and CYP3A4
fluvoxamine
List 3 SSRIs that have low potential for drug interactions.

citalopram

escitalopram

sertraline

Name 2 SNRIs.
Name 2 SNRIs.

venlafaxine

duloxetine

lack blockade of H1, muscarinic and alpha-1 receptors

Which SNRI is a potent inhibitor of 5-HT uptake that inhibits norepinephrine uptake at higher doses?
venlafaxine
Which SNRI has weak inhibition of dopamine reuptake?
venlafaxine
Do SNRIs or SSRIs have fewer CYP450 interactions?
SNRIs
Name a norepinephrine and dopamine reuptake inhibitor (NDRI).

buproprion

not associated with sexual dysfunction problems which occur with SSRIs because it lacks the serotonergic component

What disorder is associated with SSRI and NDRI overdose?
seizures
Name 2 5-HT2 antagonists/reuptake inhibitors (SARIs).
Name 2 5-HT2 antagonists/reuptake inhibitors (SARIs).

nefazodone

trazodone

*combine 5-HT reuptake blockade with 5-HT2 antagonism

Stimulation of which 5-HT receptors in the raphe nuclei can help treat depression?

5-HT1A

Stimulation of 5-HT2 receptors in the forebrain may cause agitation or anxiety, while stimulation of 5-HT2 receptors in the spinal cord may cause sexual dysfunction.

Name a noradrenergic and specific serotonergic antidepressant (NASSA).
Name a noradrenergic and specific serotonergic antidepressant (NASSA).
mirtazapine

NASSAs are antagonists of central presynaptic _____ receptors. They enhance the release of _____ and _____.

Additionally, these drugs are antagonists at _____ and _____ receptors.

Finally, _____ is a potent H1 antagonist, which is associated with sedation and weight gain.

NASSAs are antagonists of central presynaptic alpha-2 receptors. They enhance the release of norepinephrine and 5-HT.

Additionally, these drugs are antagonists at 5-HT2 and 5-HT3 receptors.

Finally, mirtazapine is a potent H1 antagonist, which is associated with sedation and weight gain.

Drug of choice for anxiety disorders
SSRIs
Drug of choice for neuropathic pain
Drug of choice for neuropathic pain
TCAs
Are SSRIs useful for treating anorexia or bulimia?
bulimia
SSRI of choice for treatment of bulimia
fluoxetine
Which antidepressants are beneficial to women with premenstrual dysphoric disorder? Which 2 specific drugs are indicated for this disorder?

SSRIs

fluoxetine, sertraline

Which antidepressant is as effective as nicotine patches in smoking cessation therapy?
buproprion
Which antidepressants can be used for enuresis?

TCAs

not commonly used because of adverse effects

What
What “theory” is the most widely accepted explanation for the actions of lithium in treating bipolar disorder?
inositol depletion theory
How does lithium block the regeneration of inositol?
How does lithium block the regeneration of inositol?

inhibition of inositol polyphosphatase and monophosphatase

Free inositol is essential for the synthesis of PIP2, therefore lithium blocks the phosphatidylinositol signaling cascade in the brain

List the 2 mechanisms of inositol synthesis in CNS neurons.

regeneration from IP3

de novo synthesis from glucose 6-phosphate

both inhibited by lithium, which leads to inhibition of central adrenergic, muscarinic, and serotonergic neurotransmission

What type of antagonism is associated with lithium use?

uncompetitive antagonism

only neurons with active receptors will be affected by lithium

Lithium adverse effects (3/4)

tremor

sedation

ataxia

aphasia

Lithium contraindications (2)
pregnancy: category D
increased incidence of congenital cardiac anomaliesnursing mothers

ALTERNATIVES TO LITHIUM
ALTERNATIVES TO LITHIUM
List 2 types of indirect-acting adrenergic agonists.

releasing agents

uptake inhibitors

List 3 releasing agents (indirect-acting adrenergic agonist).

amphetamine

methylphenydate

tyramine

Tyramine mechanism

causes norepinephrine release from presynaptic terminals

– potentiates effects of NE produced endogenously

List 2 ways by which amphetamines increase blood pressure.

increases blood pressure by alpha-agonist action on vasculature

increases blood pressure by beta-stimulatory effects on heart

– has central stimulatory action

Name a structural analogue of amphetamine widely used to treat ADHD in children.
methylphenidate
Releasing agent (indirect-acting adrenergic agonist) found in fermented food such as ripe cheese and Chianti wine
Releasing agent (indirect-acting adrenergic agonist) found in fermented food such as ripe cheese and Chianti wine
tyramine
Tyramine drug interaction

tyramine is normally oxidized by MAO

patients taking MAO inhibitors can manifest serious vasopressor episodes

Ephedrine actions on blood pressure and respiratory system

increases systolic and diastolic blood pressures

bronchodilation

Ephedrine mechanism and uses (2)
stimulates alpha and beta receptors and releases NE from nerve endings
– poor substrate for COMT and MAO since it is not a catecholamine
– excellent absorption orally and penetrates the CNSsometimes used prophylactically in chronic treatment of asthma to prevent attacks

mild stimulation of CNS: increases alertness, decreases fatigue and prevents sleep

Pseudoephedrine uses
available over the counter as a component of many decongestant mixtures
Phenoxybenzamine mechanism and uses (2)

irreversible non-selective alpha antagonist

prior to surgical removal of pheochromocytoma

chronic management of inoperable tumors

– non-selective alpha antagonists usually not successful for hypertension

How does blockade of alpha1-adrenergic receptors affect sympathetic tone of blood vessels and peripheral vascular resistance?
reduces sympathetic tone of blood vessels and decreases PVR
Phentolamine mechanism and uses (4)
reversible non-selective alpha antagonist
—–
short term control of hypertensiondiagnosis of pheochromocytoma by phentolamine blocking test

hypertensive crisis associated with stimulant drug overdose (cocaine)

hypertensive crisis due to sudden withdrawal of sympatholytic anti-hypertensive drugs, e.g. clonidine

The systemic blood pressure decreases in response to epinephrine given with pretreatment of phenoxybenzamine. What is this phenomenon called?
The systemic blood pressure decreases in response to epinephrine given with pretreatment of phenoxybenzamine. What is this phenomenon called?

epinephrine reversal

– the vasoconstrictive alpha1 action of epinephrine is blocked, but the vasodilation caused by activation of beta2-receptors is not

Alpha1-selective adrenergic blockers use
treatment of hypertension
Alpha1-blockers CV effects
lower arterial blood pressure by relaxing both arterial and venous smooth muscle
Why must the first dose of alpha1-blockers be 1/3 or 1/4 of the normal dose?
the first dose produces an exaggerated hypotensive response that can result in syncope
Are alpha1-blockers the drugs of choice for hypertension?
no
Drug class of choice for benign prostatic hyperplasia symptom relief

alpha1-blockers

– relaxes smooth muscle in the bladder neck, prostate capsule and prostatic urethra, improving urinary flow

Terazosin mechanism and use (2)

alpha1-blocker with longer half-life than prazosin

– used for hypertension and BPH

Doxazosin mechanism and use (2)

alpha1-blocker with longer half-life

– used for hypertension and BPH

Tamsulosin mechanism and use

alpha1-blocker

– used for BPH

– little effect on bp, so less likely to cause orthostatic hypotension

Yohimbine mechanism and use

alpha2-selective adrenergic blocker

– used in the past to treat erectile dysfunction <– phosphodiesterase type 5 inhibitors have replaced it

Propranolol mechanism
non-selective beta-blocker
How do beta-blockers affect heart rate and myocardial contractility?

slow heart rate

decrease myocardial contractility

Why are non-selective beta-blockers contraindicated in patients with asthma?
blocking beta2 receptors in the lungs can precipitate a respiratory crisis in patients with COPD or asthma
How do non-selective beta-blockers affect glycogenolysis and glucagon secretion?
decreases both
Non-selective beta-blockers uses (3/9)
hypertension
– beta-blockers lower blood pressure in hypertension by decreasing COglaucoma
– diminish intraocular pressure

migraine
– effective prophylaxis
– mechanism may depend on blockade of catecholamine-induced vasodilation of brain vasculature

hyperthyroidism
– beta-blockers blunt sympathetic stimulation

angina pectoris
– decrease O2 requirement of heart muscle
– not for acute management

atrial fibrillation
– control ventricular rate

MI
– protective effect on the myocardium

performance anxiety
– preferred Rx

essential tremor
– most commonly used drugs for treatment

List 2 reasons that diabetics should be careful while taking non-selective beta-blockers.

non-selective beta-blockers may impair recovery from hypoglycemia in insulin-dependent diabetics

mask the tachycardia that is typically seen with hypoglycemia, denying the patient an important warning sign

List 2 ways in which non-selective beta-blockers adversely affect one’s serum lipid profile.

inhibit TAG breakdown in adipose tissue

reduce HDL, increase LDL, increase TAGs

– beta1-blockers improve serum lipid profile of dyslipidemic patients

Why is it important to not withdraw beta-blocker therapy abruptly?
up-regulation of beta-receptors due to long-term therapy can cause acute tachycardia, hypertension, and/or ischemia upon abrupt withdrawal
Nadolol mechanism and uses (2)

non-selective beta-blocker

– management of angina pectoris
– management of hypertension

Timolol mechanism and uses (3)

non-selective beta-blocker

– treatment of hypertension
– prophylaxis of migraine headache
– treatment of intraocular hypertension or open-angle glaucoma

What 2 patient populations (with specific disorders) benefit from beta1-selective adrenergic antagonists?

hypertensive patients with impaired pulmonary function

diabetic hypertensive patients who are receiving insulin or oral hypoglycemic agents

Atenolol mechanism and uses (3)

beta1-selective adrenergic antagonist

– management of hypertension
– long-term management of angina pectoris
– management of MI to reduce CV mortality

Metoprolol mechanism and uses (3)

beta1-selective adrenergic antagonist

– management of hypertension
– long-term management of angina pectoris
– management of MI to reduce CV mortality

Esmolol mechanism and uses

ultra-short acting beta1-selective adrenergic antagonist (half-life = ~10 minutes)

– supraventricular arrhythmias
– arrhythmias associated with thyrotoxicosis
– perioperative hypertension
– myocardial ischemia in acutely ill patients

Labetalol mechanism and use

competitive antagonist at beta and alpha1 receptors

– management of hypertension

* substantially more potent as a beta-antagonist than as an alpha-antagonist

Carvedilol mechanism and uses (2)

competitive antagonist at beta- and alpha1-receptors

– used in hypertension and congestive heart failure

* substantially more potent as a beta-antagonist than as an alpha-antagonist

Pindolol mechanism and uses

partial beta-agonist

– antihypertensive in individuals with diminished cardiac reserve or a propensity to bradycardia

* not demonstrated in controlled trials, but may be important in individual patients

Alpha-methyltyrosine (metyrosine) mechanism and uses (2)

competitive inhibitor of tyrosine hydroxylase (inhibits NE synthesis)

– management of malignant pheochromocytoma
– preoperative preparation of patients for resection of pheochromocytoma

Reserpine mechanism and uses

irreversibly damages VMAT (vesicles cannot store NE and dopamine); MAO free to degrade NE in the cytoplasm

– gradual decrease in blood pressure and slowing of cardiac rate

Guanethidine mechanism and use

displaces NE from transmitter vesicles leading to depletion of NE

– antihypertensive (causes a gradual decrease in bp and heart rate)

* additionally, the drug inhibits release of NE <– primarily responsible for its antihypertensive action

Trazodone side effects (3)

priapism in men

sedation

postural hypotension

Excessive self-administration of any substance for nonmedical purposes
abuse
List 3 actions that can cause withdrawal syndromes.

abrupt cessation

rapid dose reduction

administration of an antagonist

What neurological system is the prime target of addictive drugs?
What neurological system is the prime target of addictive drugs?

mesolimbic dopamine system

all addictive drugs activate the mesolimbic dopamine system

CNS depressants (3)

ethanol

benzodiazepines

barbiturates

Receptors affected by ethanol (3/6)

GABA(A) receptors

Kir3/GIRK channels

adenosine reuptake

glycine receptors

NMDA receptors

5-HT3 receptors

Tremor, nausea, vomiting, sweating, agitation, anxiety

ethanol withdrawal

may be followed by hallucinations

Ethanol Withdrawal Syndrome

24-48 hours

48-72 hours

24-48 hours: generalized seizures

48-72 hours: delirium tremens

delirium tremens associated with 5-15% mortality

Alcohol withdrawal Rx (2)

diazepam

chlordiazepoxide

long half-life benzodiazepines → smoother withdrawal and rebound withdrawal symptoms less likely to occur

Alcohol withdrawal Rx in elderly and those with liver failure (2)

lorazepam

oxazepam

intermediate-acting drugs not as dependent on hepatic metabolism

Alcoholism Rx (3)

disulfiram

naltrexone

acamprosate

Enzyme inhibited by disulfiram

aldehyde dehydrogenase inhibitor

used to create aversion to drinking

Receptor antagonized by naltrexone

opioid receptor

reduces craving for alcohol

Receptor antagonized by acamprosate

NMDA receptor

prevents relapse

Name a GABA agonist that may reduce cravings for alcohol.

topiramate: antagonizes glutamate receptors

not FDA-approved

Benzodiazepines

physical dependence

addiction

physical dependence: yes

addiction: rare

Nausea, vomiting, tremor, incoordination, restlessness, blurred vision, sweating, anorexia
low-dose benzodiazepine withdrawal
Seizures, psychosis, depression

high-dose benzodiazepine withdrawal

includes symptoms of low-dose withdrawal

Low-dose benzodiazepine withdrawal Rx

diazepam

switched to a long-acting drug

Is low-dose or high-dose benzodiazepine withdrawal associated with illicit drug and/or alcohol use?
high-dose withdrawal
Psychostimulants (3)

methylxanthines

cocaine

amphetamines

Methylxanthines (3)

caffeine

theophylline

theobromine

Receptors blocked by methylxanthines

presynaptic adenosine receptors

blockade of adenosine receptors increases norepinephrine release

Caffeine amount

decrease in fatigue and increased mental alertness

anxiety and tremors

spinal cord stimulation

decrease in fatigue and increased mental alertness: 100-200 mg

anxiety and tremors: 1.5 g

spinal cord stimulation: 2-5 g

Methylxanthines actions

cardiac inotropy and chronotropy

gastric mucosa HCl secretion

positive inotropic and chronotropic effects on the heart

stimulates secretion of HCl
individuals with peptic ulcers should avoid

Methylxanthines high dose adverse effects (2)

emesis

convulsions

Lethal dose of caffeine
10 g (about 100 cups of coffee) → cardiac arrhythmias
Is caffeine listed in the category of addicting stimulants?

NO!

classified as schedule 2 drug by DEA

Reuptake inhibited by cocaine (3)
dopamine
prolongation of dopaminergic effects in brain’s limbic system produces intense euphorianorepinephrine

serotonin

Parts of the brain stimulated by cocaine (2)

cortex

brainstem

High doses of cocaine adverse effects (4)

tremors

convulsions

respiratory depression

vasomotor depression

Cocaine Actions

heart rate

blood pressure

pupils

peripheral vascular tone

tachycardia

hypertension

pupillary dilation

peripheral vasoconstriction

How does cocaine cause hyperthermia?
How does cocaine cause hyperthermia?
Dysphoria, depression, sleepiness, fatigue, bradycardia

cocaine withdrawal syndrome

treatment usually not required

Amphetamines (4)

amphetamine

methamphetamine

phenmetrazine

methylphenidate

Amphetamines actions (3)
increase release of catecholamines
similar to cocaine due to release of dopamineweak inhibitors of MAO

direct catecholaminergic agonists in the brain

High dose amphetamines adverse effects (2)

psychosis

convulsions

Amphetamine and methylphenidate uses (2)

attention deficit syndrome

narcolepsy

Increased appetite, sleepiness, exhaustion, mental depression

amphetamines withdrawal syndrome

antidepressants may be indicated

What part of the brain comprises of dopamine neurons with nicotinic receptors?

ventral tegmental area

nicotine action excites these neurons, releasing dopamine in the nucleus accumbens and prefrontal cortex

How does nicotine affect attention, learning, problem solving, and reaction time?
improves all
How does nicotine affect appetite?
appetite suppressant
List 2 complications of high doses of nicotine.

central respiratory paralysis

severe hypotension caused by medullary paralysis

Nicotine withdrawal syndrome (2)

irritability

sleeplessness

Nicotine addiction Rx (3)

nicotine replacement therapy

sustained-release buproprion
mechanism unclear

varenicline
partial agonist at nicotinic receptors in the CNS

Most commonly abused opioids (4)

heroin

morphine

codeine

oxycodone

Most commonly abused opioids among health professionals (2)

meperidine

fentanyl

Dysphoria, lacrimation, rhinorrhea, yawning
opioid withdrawal syndrome
Opioid detoxification Rx (2 opioids)

methadone

buprenorphine

long-acting opioids

Opioid detoxification Rx (2 adrenergic agonists)

clonidine

lofexidine

presynaptic alpha-2 agonists

many withdrawal symptoms due to noradrenergic storm that results from rebound firing due to tolerance to the effects of opioids on the ANS

What cannabinoid produces most of the effects of smoking marijuana?
delta-9-tetrahydrocannabinol
What type of receptor is associated with the 2 cannabinoid receptor subtypes (CB1 and CB2)?

G protein-linked receptors

inhibition of adenylyl cyclase opens potassium channels and closes calcium channels

CB1 receptor location

brain

mediate the psychological effects of THC

CB2 receptor location
immune cells
Name the 2 cannabinoid ligands.

anandamide

2-arachidonylglycerol

Marijuana adverse effects (3/4)
Marijuana adverse effects (3/4)

increased heart rate

decreased blood pressure

reddening of the conjunctiva

toxic psychosis at high doses

Dronabinol uses (2)

anorexia associated with weight loss in patients with AIDS

nausea and vomiting associated with cancer chemotherapy (second line)

Psychedelic agents (5)

LSD

mescaline

psilocybin

phencyclidine

MDMA

Drugs that affect thought, perception and mood without causing marked psychomotor stimulation or depression
psychedelic agents
List 2 LSD-like drugs.

mescaline

psilocybin

What receptors are acted upon by LSD?
5-HT2 receptors in the CNS
Does LSD cause addiction and/or a withdrawal syndrome?
no
LSD-induced agitation Rx
diazepam

What type of receptors are antagonized by phencyclidine?

What type of antagonist is phencyclidine?

NMDA subtype of glutamate receptor

noncompetitive

What 2 dissociative conditions are associated with phencyclidine use?

dissociative anesthesia

dissociative analgesia

Reuptake of what neurotransmitter is inhibited by high doses of phencyclidine?
dopamine
Drug that fosters feelings of empathy and intimacy without impairing intellectual capacities
MDMA (ecstasy)
What neurotransmitter is associated with MDMA use?
serotonin
What mood disorder is associated with MDMA use?
depression
Inhalant that produces euphoria and analgesia and then loss of consciousness
Inhalant that produces euphoria and analgesia and then loss of consciousness
nitrous oxide
Which group of inhalants is implicated in cancer, cardiotoxicity, neuropathies, and hepatotoxicity?
volatile organic solvents
List 2 organic nitrites used to enhance erection.

amyl nitrite

butyl nitrite

not addictive

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