b.

Barbiturates:
CNS DEPRESSANTS - Prolong GABA activity
Must Know Terms - Increase duration of Cl channel opening
Addiction - Have GABA-mimetic activity at high doses
- State of response to a drug whereby drug taker - Do not act through BZ receptors
feels compelled to use the drug, and suffers - Have own binding sites on GABAA complex
anxiety when separated from it - Also inhibit complex I of electron transport
Anesthesia chain (NADH coenzyme Q reductase)
- Loss of consciousness associated with an
absence of response to pain
Anxiolytic Sedative-Hypnotics
- Drug that reduces anxiety; a sedative Sedatives
Dependence - Drugs that have an inhibitory effect on the CNS
- State of response to a drug whereby removal of - They reduce:
the drug evokes unpleasant, and possibly life- o Nervousness
threatening symptoms; often the opposite of o Excitability
the drug’s effects o Irritability
Hypnosis - Without causing sleep
- Induction of sleep
REM sleep Hypnotics
- Phase of sleep associated with rapid eye - Calm or soothe the CNS to the point that they
movements; most dreaming takes place during cause sleep
this stage
Sedation Sedative-Hypnotics
- Reduction of anxiety - Effects are dose-dependent:
Tolerance o Low doses? Calm or soothe the CNS
- Reduction in drug effect requiring an increase in o High doses? + sleep
dosage to maintain the same response
a. Barbiturates
Principles regarding Sedatives and hypnotics - First introduced in 1903
SEDATIVE-HYPNOTICS - Standard agents for insomnia and sedation
- chemically heterogenous class of drugs which - Habit-forming
produce dose-dependent CNS depressant - Only a handful are used today due to safety and
effects efficacy of Benzodiazepines
- Ranges from sedation, to anesthesia, to - Have four (4) categories according to duration
respiratory depression, and death of action:
- Major subgroup is the benzodiazepines o Ultrashort:
- Other subgroups are still in use  Thiamylal
 Barbiturates  Thiopental
 Miscellaneous agents (carbamates, o Short:
alcohols, and cyclic ethers)  Pentobarbital
- Mechanisms:  Secobarbital
 Activation of: o Intermediate:
o GABAA  inc. Cl influx  Aprobarbital
o GABAB  inc. K influx  Butabarbital
 Both result in hyperpolarization o Long:
 Phenobarbital
a. Benzodiazepines: - Narrow therapeutic index
- Potentiate GABA - Range of the dosage is very limited/small
- Increase frequency of Cl channel opening - Even a small increment above the dosage is
- Act through BZ receptors (part of GABAA rapidly toxic
complex) - Mechanism of Action:
 BZ1 mediates sedation o Potentiate GABA (gamma-aminobutyric
 BZ2 mediates anti-anxiety and acid)
impairment of cognitive functions - Site of Action:
o Brainstem (reticular formation)
o Cerebral cortex
 - Drug Effects: - Mechanism of Action:
o Low doses? Sedative o Depress CNS activity
o High doses? Hypnotic (also lowers RR) o Affect hypothalamic, thalamic, and
notorious enzyme inducers limbic systems of the brain
- Therapeutic Uses: - Drug Effects:
o Hypnotics o Calming effect on the CNS
o Sedatives o Useful in controlling agitation and
o Anticonvulsants anxiety
o Surgical Procedures - Therapeutic Uses:
- Side Effects: o Sedation, sleep induction
o CNS? Drowsiness, vertigo, lethargy, o Skeletal muscle relaxation, anxiety
mental depression, coma relief
o Respiratory? Respiratory depression, o Treatment of alcohol withdrawal
apnea, bronchospasms, cough o Agitation, depression, epilepsy
o GI? Nausea, vomiting, diarrhea o Balanced anesthesia
o Others? Agranulocytosis, vasodilation, - Side Effects:
Steven-Johnson syndrome, o Mild and infrequent (HA, drowsiness,
Hypotension dizziness, vertigo, lethargy, paradoxical
- Toxicology: excitement nervousness], “hangover
o Overdose leads to respiratory effect”)
depression  respiratory arrest
o Therapeutic : - Nursing Implications:
 anesthesia induction o Before beginning therapy, perform a
 uncontrollable seizures thorough history regarding allergies,
(phenobarbital coma) use of other medications, health
- Drug Interactions: history, and medical history.
o Additive with ETOH, antihistamines, o Obtain baseline vital signs and I & O,
narcotics, benzodiazepines, including supine and erect BPs.
tranquilizers o Assess for potential disorders or
o Inhibited metabolism with MAOIs conditions that may be
(prolong its effects) contraindications, and for potential
o Increased metabolism? Reduces drug interactions.
anticoagulant response (clots form) o Patients should be instructed to avoid
alcohol and other CNS depressants.
b. Benzodiazepines o Check with physician before taking any
- Most commonly prescribed of the drug classes other medications, including OTC
- Favorable side effects medications.
- Better efficacy and safety o It may take 2 to 3 weeks to notice
- Classified as either: improved sleep when taking
o Sedative-Hypnotic barbiturates.
o Anxiolytic (relieves anxiety) o Abruptly stopping these medications,
- Sedative-Hypnotic: especially barbiturates, may cause
o Long acting: Flurazepam (Dalmane) rebound insomnia.
Quazepam (Doral) o Safety is important (keep side rails up,
o Short acting: Estazolam (Prosom) do not allow smoking, assist patient
Temazepam (Restoril) with ambulation [especially the
Triazolam (Halcion) elderly], keep call light within reach)
- Anxiolytics: o Monitor for side effects
o Alprazolam (Xanax) o Monitor for therapeutic effects
o Chloridiazepoxide (Librium)  Increased ability to sleep at
o Diazepam (Valium) night
o Lorazepam (Ativan)  Fewer awakenings
o Midazolam (Versed)  Shorter sleep induction time
o ***Note: Zolpidem (Ambien) and  Few side effects, such as
Zaleplon (Sonata) are non-BZ agents hangover effects
which share the same characteristics as  Improved sense of well-being
hypnotic agents because of improved sleep
Atypical sedative-hypnotics Summary
a. Buspirone - Sedative-hypnotic-anxiolytic drugs include
- Selective anxiolytic with minimal CNS benzodiazepines, barbiturates, and alcohols
depressant effects (does not affect driving skills) - S-H drugs ideally should reduce anxiety without
- No anticonvulsant or muscle relaxant properties affecting mental or motor function (but these
- Interacts with brain serotonin receptors as get affected depending on the dose)
partial agonist - Most S-H drugs facilitate GABA action by binding
- Specific mechanism of action for its anxiolytic to the GABAA receptor, which has one binding
effect is unknown site for barbiturates, and another for
- Minimal tolerance with chronic use benzodiazepines.
- Little rebound anxiety or withdrawal symptoms - Binding of drugs at these sites leads to increased
upon discontinuance Cl influx, potentiating the inhibitory transmitter
- Safe in pregnancy effects of GABA.
b. Ramelteon - Differences in action in the various S-H drugs
- Activates melatonin receptors (suprachiasmatic relate to the differences in binding sites used.
nuclei of the CNS) and decreases latency of Along with BZ1 (sedation) and BZ2 (anti-anxiety
sleep onset and impairment of cognition)
- Minimal rebound insomnia or withdrawal - Benzodiazepines are used to treat anxiety states
symptoms and sleep disorders.
- No direct effect on GABA-ergic - Dose-dependent CNS depression may occur but
neurotranmission in the CNS can be reversed by Flumazenil.
- Minimal abuse liability (not a controlled - Chronic use can lead to tolerance and
substance) dependence with rebound effects upon
c. Tasimelteon withdrawal.
- Similar to Ramelteon - Phenobarbital is used to treat seizures.
- Similar melatonin receptor agonist Thiopental is used as an IV anesthetic.
- Recently approved Barbiturates induce deep CNS depression at
high doses and there is no antidote.
Orexin Antagonists - Tolerance, dependence, and severe withdrawal
a. Orexin symptoms are associated with chronic
- Peptide found in the hypothalamus barbiturate use.
- Involved in wakefulness - Zolpidem and Zaleplon are non-benzodiazepines
b. Suvorexant that bind to BZ1 receptors which make them
- Recently approved antagonist at orexin more specific hypnotics.
receptors
- Has hypnotic properties ***END***
 SYMPATHOMIMETICS & SYMPATHOLYTICS - Primary response:
o Smooth muscle relaxation (bronchial,
Must Know Terms: gastrointestinal, and uterine smooth
muscle relaxation)
Anorexiant o Glycogenolysis
- Drug that decreases appetite o Cardiac stimulation
Catecholamine
- Dihydroxyphenlethylamine derivative readily Dopaminergic Receptors
metabolized by catechol-o-methyltransferase - Additional adrenergic receptor stimulated by
Decongestant dopamine
- Alpha agonist drug that reduces conjunctival, - Primary response: dilation (increased blood
nasal, or oropharyngeal mucosal vasodilation by flow)
constricting blood vessels in the submucosal o Renal
tissue o Mesenteric
Mydriatic o Coronary and Cerebral
- Drug that causes dilation of the pupil; opposite _____________________________________
of miotic
Selective alpha or beta adrenoceptor agonist Sympathomimetics
- Drugs that have greater effects on alpha or beta
adrenoceptors; none are absolutely specific Catecholamines:
Sympathomimetic - Produce a sympathomimetic response
- Drug that mimics stimulation of the sympathetic - Endogenous (epinephrine, norepinephrine,
autonomic nervous system dopamine)
Reuptake Inhibitor - Synthetic (isoproterenol, dobutamine,
- Drug that increases activity of transmitters in phenylephrine)
the synapse by inhibiting their reuptake into the - Classification:
presynaptic nerve ending o Spectrum of Action
_____________________________________  Alpha, beta, or dopamine
receptors (further into
Receptors subgroups)
- Sympathomimetics  Prototypes:
o Mimic the effects of norepinephrine epinephrine (alpha & beta
(NE) and epinephrine (EPI) agonist)
o Located throughout the body phenylephrine (alpha agonist)
isoproterenol (beta agonist)
Receptors for sympathetic neurotransmitters  little effect on dopamine
- Alpha adrenergic receptors  norepinephrine receptors
- Beta adrenergic receptors  epinephrine  Dopamine (given as a drug
itself) also activates
Alpha Adrenergic Receptors  beta receptors
- Divided into alpha1 and alpha2 receptors (moderate doses)
(based on their locations on nerves)  alpha receptors
o Alpha1  postsynaptic effector cells (higher doses)
(cell, muscle, organ that nerves o Mode of Action
stimulate)  Direct activation (binds
o Alpha2 presynaptic nerve terminals directly to the receptor and
(control release of neurotransmitters) causes a physiologic response)
- Predominant response:  Indirect activation (increase
o Vasoconstriction concentration of the
o CNS stimulation endogenous catecholamine
transmitter in the synapse)
Beta Adrenergic Receptors  Cause release of
- Divided based on their locations: stored
o Beta1 adrenergic receptors  heart catecholamines
(primarily) (amphetamines and
o Beta2 smooth muscles of bronchioles, tyramine)
arterioles, and adrenergic receprots
visceral organs
  Inhibit reuptake of c. Dopaminergic agents
catecholamines - Depend on the dose (mixed activation of
(cocaine and TCA) receptors)
 Increase stores of
catecholamine; Clinical Uses:
potentiates indirect a. Anorexiant
acting agents (MAO - Adjuncts to diet in the short-term management
inhibitors) of obesity
Pharmacokinetics - Drugs: benzphetamine
- Relatively inactive by oral route; must be given phentermine
parentally (Epinephrine, Norepinephrine, dextroamphetamine
Dopamine) dexedrine

Mechanism of Action b. Anaphylaxis

a. Alpha receptor effects
- Mediated by the trimeric coupling protein G4.
- G4 activation  release of inositol 
phospholipase C activation  1,4,5-
triphosphate (IP3) and diacylglycerol (DAG) from
membrane lipids calcium released by IP3;
enzymes activated by DAG
- Note: alpha2 receptors activation results in
inhibition of adenylyl cyclase via coupling
protein G
b. Beta receptor effects
- all beta receptors stimulate adenylyl cyclase via
coupling protein G3  increase in cyclic
adenosine monophosphate (cAMP) in the cell
c. Dopamine receptor effects
- Activate adenylyl cyclase via Gs  increase
cAMP in neurons and vascular smooth muscle
- Note: D2 receptors are more important in the
brain but may play possible roles in presynaptic
receptors in the peripheral nerves
- Epinephrine (drug of choice for immediate
treatment of anaphylactic shock [hypotension,
bronchospasm, and angioedema])
- Antihistamines and corticosteroids are also used
but not as effective as epinephrine
c. CNS
- Amphetamine (narcolepsy, and weight
reduction)
- Methylphenidate (ADHD)
- Often abused for purposes of deferring sleep
and mood-elevating, euphoria-producing effect
(cocaine)
d. Eye
- Phenylephrine and tetrahydrozoline (reduce
conjunctival itching and congestion  from
allergy and irritation)
- Phenylephrine (mydriatic)
- Apraclonidine and brimonidine (glaucoma)

Effects e. Bronchi
a. Alpha adrenergic agents - Drugs of choice for acute asthmatic
- Vasoconstriction of blood vessels bronchoconstriction
- Relaxation of GI smooth muscles - Drugs: albuterol
- Contraction of the uterus and bladder metaproterenol
- Male ejaculation terbutaline
- Decreased insulin release
- Contraction of the ciliary muscles of the eye f. Cardiovascular
(dilated pupils) - Heart failure
- Septic and cardiogenic shock (norepinephrine)
b. Beta adrenergic agents
- Bronchodilation g. Genitourinary
- uterine relaxation - Ritodrine and terbutaline (beta2 agonists) are
- Glycogenolysis (liver) used to suppress labor
- Beta adrenergic agents (B1)  cardiac o Cardiac stimulant effect may be
stimulation (myocardium, AV and SA nodes) hazardous to the mother and child
o Increased: - Ephedrine may be used for children (enuresis)
 Force of contraction (positive and elderly (urinary incontinence)
inotropic effect)
 Heart rate (positive Toxicity
chronotropic effect) - Little toxicity to the CNS because of their limited
 Conduction through AV node ability to penetrate into the brain
(positive dromotropic effect) - Effects are more evident in the periphery
 Effects
Adrenoceptor blockers 1. Non-selective blockers:
- Most important are on the cardiovascular
Adrenergic Blockers system (reduction in vascular tone  decrease
- Bind to adrenergic receptors but inhibit or block in arterial and venous pressures)
stimulation of the sympathetic nervous system - No significant direct cardiac effects
- Have opposite effect of adrenergic agents - Cause baroreceptor-mediated tachycardia (due
- Adrenergic antagonists or sympatholytics to drop in mean arterial pressure)
Sympatholytics - May be exaggerated
- Inhibit or lyse sympathetic neurotransmitters - Alpha2 receptors in the heart (which reduce the
(norepinephrine and epinephrine) net release of norepinephrine) are also blocked
- Classified as either: 2. Selective alpha blockers
o α1 and α2 receptor blockers - Because they block alpha1 receptors more
o β1 and β2 receptor blockers effectively than alpha2 receptors, induce less
- Other classifications depend on reversibility and reflex tachycardia (than non-selectives)
duration of action - Useful in relaxing smooth muscles in the
prostate
ALPHA BLOCKERS
Classifications: Clinical Uses
A. Phenoxybenzamine 1. Non-selective alpha blockers
- Irreversible, long-acting - Limited clinical applications
- Prototype alpha blocker - Pre-surgical management of
- Slightly alpha1 selective pheochromocytoma (may have severe
B. Phentolamine hypertension and reduced blood volume 
- Reversible, short-acting must be corrected prior to surgery)
- Competitive antagonist o Phenoxybenzamine (preparatory
- Does not distinguish between alpha1 and alpha2 phase)
receptors o Phentolamine (occasionally used
C. Prazosin during surgery)
- Reversible - For reversal of accidental local infiltration of
- Highly selective alpha1 blocker alpha agonists (epinephrine) may cause severe
- Similar drugs: Doxazosin tissue ischemia and necrosis (uses
Terazosin phentolamine)
Tamsulosin - Substance abuse/overdose (amphetamines,
D. Yohimbine cocaine, or phenylpropanolamine) may be
- Alpha2 selective blocker reversed
- Used primarily in research applications - Raynaud’s phenomenon (sometimes responds)
- Similar drug: Rauwolscine but efficacy is not well-documented
- Erectile dysfunction: Phentolamine, Yohimbine
2. Selective alpha blockers
Pharmacokinetics - Hypertension (prazosin, doxazosin, and
- Active through oral and parenteral route terazosin)
- Phentolamine (rarely given orally) - Prevent urinary distention in benign prostatic
hyperplasia (+ tamsulosin, and silodosin)
Mechanism of Action
- Phenoxybenzamine covalently binds to the Toxicity
alpha receptor - Orthostatic hypotension
- Irreversible blockade - Reflex tachycardia (non-selective alpha blockers)
- All the rest are competitive antagonists
- Effects can be counteracted by increased BETA BLOCKERS
concentrations of agonists Classification
Note: important in the treatment of - All are competitive antagonists
pheochromocytoma (massive release of - Prototype drug is propanolol
catecholamines may overcome - Subgroups:
reversible blockade) o Receptor selectivity
o Partial agonist activity
o Local anesthetic action
o Lipid-solubility
Subgroups:
1. Receptor Selectivity
Beta1 selective
- Advantageous in treating asthma patients
(functioning B2 receptors are necessary to
prevent bronchospasm)
- Drugs: Acebutolol
Atenolol
Esmolol
Metoprolol
- Non-selective Nadolol
Propanolol
Timolol
- Note: except for those starting with
“c” and “l”, all blockers starting
with letters from “a” to “m” are
beta1 selective
- Carvedilol and Labetalol have combined alpha
and beta-blocking activity

2. Partial Agonist Activity

Intrinsic sympathomimetic activity
- Advantageous in treating patients with asthma
- In theory, less likely to cause bronchospasm
- Drugs: Pindolol
Acebutolol

3. Local Anesthetic Activity

Membrane-stabilizing activity
- Disadvantage when beta blockers are used on
the eye (decreases protective reflexes 
increases risk of ulceration)
- Timolol (only one with absent local anesthetic
effects, and used in glaucoma)

Effects and Clinical Uses

Remarkably broad:
- Eye (open angle glaucoma)
- Heart(hypertension, angina, arrhythmia)
o maybe heart failure  labetalol,
carvedilol, and metoprolol
- combined alpha and beta 
Pheochromocytoma blocker agents (when
producing norepinephrine and epinephrine)
- Propanolol Infantile hemangioma

Toxicity
- Bradycardia
- AV blockade
- Heart failure

***END***
 CHOLINERGICS AND CHOLINERGIC BLOCKERS o Pupils (constriction, and reduced
CHOLINERGICS intraocular pressure)
- Drugs that stimulate the parasympathetic o Salivary and sweat glands
nervous system (opposes the SNS) - Cardiovascular
- Also known as: cholinergic agonists o Decreased heart rate
parasympathomimetics o Vasodilation
- Mimics the effects of Acetylcholine (Ach) - Respiratory
Cholinergic Receptors o Bronchial constriction
- Two (2) types, determined by: o Narrowed airways
o Location Drug Effects
o Action (once stimulated) Dose-dependent:
- Nicotinic and Muscarinic receptors - Recommended (muscarinic receptors)
= Desired effects
Nicotinic Receptors - High doses (nicotinic receptors)
- Found in the ganglia of both PSNS and SNS = Undesirable effects
- Named because it can be stimulated by the
alkaloid “nicotine” Clinical Uses
Muscarinic Receptors Direct-acting agents:
- Named because it can be stimulated by the - Reduce intraocular pressure (topical application)
alkaloid “muscarine” - Useful for glaucoma and intraocular surgery
- Located postsynaptically: o Drugs: acetylcholine
o Smooth muscle carbachol
o Cardiac muscle pilocarpine
o Glands of parasympathetic fibers - Bladder and GI tract:
o Effector organs of cholinergic o increases tone and motility
sympathetic fibers o relaxes their sphincters (allows to
empty)
Mechanism of Action o useful for postsurgical atony
- Direct-acting (agonist) o Drug: Bethanechol
o Binds to cholinergic receptors (causes
stimulation) Indirect-acting Agents:
- Indirect-acting - Cause skeletal muscle contractions
o Inhibits the enzyme, “cholinesterase” - Useful for diagnosis and treatment of
o Result: more acetylcholine is available myasthenia gravis
at the receptors - Used to reverse neuromuscular blocking agents
o Reversible and anticholinergic poisoning (antidote)
 Binds cholinesterase for only o Drugs: physostigmine
minutes to hours Pyridostigmine
o Irreversible - Treatment of mild to moderate Alzheimer’s
 Forms a permanent covalent disease
bond o Drug: Donepezil (Aricept)
 Body needs to synthesize new - Helps increase or maintain memory and learning
cholinesterase to use it abilities

Drug Effects Toxicity

- As seen when the PSNS is stimulated Muscarinic Toxicity
- Rest and digest - CNS stimulation
- SLUDGE: - Miosis (and spasm of accommodation)
Salivation - Bronchoconstriction
Lacrimation - Excessive GI and GU smooth muscle activity
Urinary Incontinence - Increased secretory activity (sweat glands,
Diarrhea lacrimal glands, GI tract)
Gastrointestinal cramps - Vasodilation
Emesis
- Stimulation: Nicotinic Toxicity
o Intestines and bladder (gastric - Ganglionic stimulation
secretions, motility, and urinary - Fasciculations (and eventual paralysis)
frequency)
 - Stimulation (convulsions) followed by Toxicity
depression “Dry as a bone, hot as a pistol, red as a beet, mad as a
- Strongly addictive (even in small doses) hatter.”
_____________________________________ Treatment is symptomatic:

CHOLINERGIC BLOCKERS Hyperthermia (cooling blankets or

- Drugs that block or inhibit the actions of evaporative cooling)
acetylcholine (ACh) in the PSNS
Severe tachycardia (low doses of
Mechanism of Action physostigmine)
Competitive antagonists
- Competes with ACh (for the same receptor site)
- Block Ach at the muscarinic receptors in the
PSNS ***END***
- Once bound to these receptors, nerve
transmission is inhibited

Result: ACh is unable to bind to receptor

site (and unable to cause its
cholinergic effects)
Effects
Cardiovascular:
Small doses: decrease heart rate
Large doses: increase heart rate
CNS
Small doses: decrease muscle rigidity & tremors
Large doses: drowsiness, disorientation, and
hallucinations
Genitourinary
Relaxed detrusor muscle
Increased constriction of internal sphincter
Result: urinary retention
Glandular
Decreased bronchial secretions, salivation, sweating
Respiratory
Decreased bronchial secretions
Dilated bronchial airways

Clinical Uses
CNS:
Decreases muscle rigidity and tremors (Parkinson’s
disease, and extrapyramidal reactions)
Respiratory:
Asthma and bronchospasms (exercise-induced)
Chronic bronchitis
COPD
Cardiovascular disorders:
Sinus node dysfunction
Symptomatic 2nd degree heart block
Sinus bradycardia with hemodynamic compromise
(advanced life support)
Gastrointestinal:
Peptic ulcer disease
Irritable bowel disease
GI hypersecretory states
Poisoning
Parathion (can be given atropine as antidote)
 PSYCHOTHERAPEUTICS Schizophrenia
Psychotherapeutics - Symptoms may be ameliorated:
- Therapy of emotional and mental disorders o Thought disorder
Normal human emotions: o Emotional withdrawal
o Grief o Hallucinations
o Anxiety o Delusions
o Depression Unfortunately:
- Ability to cope can range from depression or o Protracted therapy is needed (many
anxiety, to constant emotional distress years)
- To the point of interfering with the ability to o Result in severe toxicity
function or normal daily living - Positive symptoms:
- When this happens, treatments with these o Hallucinations
medications is a possible option o Delusions
o Confusion and disorganized speech
Psychotherapeutics o Movement disorders
Three (3) main emotional and mental disorders: - Negative symptoms:
Psychoses, Affective disorders, Anxiety o Lack of pleasure
o Lack of speech
Psychosis o Flat affect/voice
- Major emotional disorder that impairs mental o Withdrawal
function o Struggles with ADLs
- Individual cannot participate in everyday life o No follow-through
- Hallmark? Loss of contact with reality
Bipolar Affective Disorder
Affective Disorders - Mainstay drug is Lithium
- Major emotional disorder that impairs mental - Use of other drugs are increasing
function o Antipsychotic agents
- Individual cannot participate in everyday life o Antiseizure drugs
- Mania _________________________________________
o Abnormally pronounced emotions
- Depression ANTIPSYCHOTICS
o Abnormally reduced emotions
- Bipolar affective disorder Classification of Antipsychotics
o Exhibits both mania and depression - Can be divided into:
o Typical (first generation)
Antipsychotics o Atypical (second generation)
- Drugs used to treat schizophrenia are also
effective in the treatment of other psychoses First Generation Antipsychotics
and agitated states Three (3) major clinical subgroups:
- Affinity:
older  D2 receptors A. Phenothiazines:
newer  5HT2 receptors a. Chlorpromazine
b. Thioridazine
Schizophrenia c. Fluphenazine
- Clinical syndrome of variable but profoundly B. Thioxanthenes:
disruptive, psychopathology that involves a. Thiothixene
cognition, emotion, perception, and other C. Butyrophenones
aspects of behavior. a. Haloperidol
- Usually begins before 25 years old (lasts
throughout life) Second Generation Antipsychotics
- Affects persons of all social classes - Varied heterocyclic structures but effective in
- Both patients and families suffer from poor care schizophrenia:
and ostracism (due to ignorance about the o Clozapine
disorder) o Loxapine
- Often discussed as a single disease entity o Olanzapine
- May comprise a group of disorders with *Aripiprazole: third generation  dopamine partial
heterogenous etiologies. agonist
- Not cured by drug therapy
Pharmacokinetics
- Well-absorbed orally
- Readily enter into the CNS and most other
tissues (lipid solubility)
- Have long plasma half-lives (permits once a day
dosing)
- Parenteral forms are available for some agents
(for rapid initiation of therapy and depot
treatment):
o Fluphenazine
o Haloperidol
Mechanism of Action
A. Dopamine Synthesis
- Proposes that schizophrenia is due to an excess
of dopaminergic activity (in specific neuronal
tracts of the brain)
- Basis:
o Many antipsychotic drugs block
dopamine receptors (D2)
o Dopamine agonist drugs
(amphetamines, and levodopa)
exacerbate schizophrenia
o Increased density of dopamine
receptors observed in untreated
schizophrenics
- not fully satisfactory:
o Antipsychotic medications are only
partially effective in most patients
o Other effective drugs have higher
affinity for other receptors (than D2)
o Phencyclidine (PCP) causes psychotic
syndrome without any effect on
dopamine receptors [dissociative
anesthetic]
B. Dopamine Receptors
- There are five (5) different receptors for
dopamine
o D2 is found in the caudate putamen,
nucleus accumbens, cerebral cortex,
and hypothalamus
- Negatively coupled to adenylyl cyclase
- Efficacy of older drugs (neuroleptics) correlates
with their affinity for D2 receptors
- Problem  D2 blockade also correlates with
extrapyramidal dysfunction
C. Other Receptors
- Most of newer antipsychotics have higher
affinities for other receptors (than D2) or have
no affinity at all for D2
- For example:
o Affinity for D4 and 5HT2A only
(Clozapine)
o High affinity for 5HT2A but may interact
with D2 and other receptors
(Olanzapine, Quetiapine, and
Risperidone)
o Antagonist at D2, 5HT2A, and 5HT1D;
agonist at 5HT1A receptor (Ziprasidone)
o Partial agonist at D2 and 5HT1A;
strong antagonist at 5HT2A receptors
(Aripiprazole)
- Receptor binding characteristics of the newer
drugs led to another NT as a suspect:
o Serotonin synthesis
- Most atypical drugs cause less EPS than
standard drugs
- All antipsychotics block H1 receptors up to
some degree (except Haloperidol)
- Major effect that correlates with therapeutic
benefit  dopamine receptor blockade (older
antipsychotics)
D. Dopaminergic pathways:
- Mesocortical-mesolimbic pathway (mentation
and mood)
- Chemoreceptor trigger zone (emesis)
- Nigrostriatal tract (extrapyramidal function)
- Tuberoinfundibular pathway (prolactin release)
**Note: all antipsychotic agents block both α1 and histamine
H1 receptors (to some extent)
Clinical Uses for Antipsychotics
A. Treatment for Schizophrenia
- Reduce some positive symptoms (hyperactivity,
hallucinations, delusions, and bizarre ideations)
- Can facilitate functioning in both in-patient and
out-patient environments
- May take several weeks to develop beneficial
effects
- Older drugs are used more (due to cheaper
cost), but have little to no effect on negative
symptoms
- Newer drugs reportedly improve negative
symptoms (emotional blunting, social
withdrawal, and lack of motivation)
- Some patients respond more with specific drugs
- Clozapine is effective for patients who are
resistant to other antipsychotics
B. Other Psychiatric & Neurologic Conditions
- 2nd generation antipsychotics are often used
with lithium (initial treatment of mania)
- Several are approved for treatment of acute
mania (aripiprazole and olanzapine) 
maintenance treatment of bipolar disorder
- Also for:
o Schizoaffective disorders (psychotic
symptoms)
o Gilles de la Tourette syndrome
(Molindone)
o Overdose of CNS stimulants
 o Alzheimer’s and Parkinsonism (2nd
generation)
C. Non-Psychiatric Indications
- Anti-emetics
o Most phenothiazines (especially
prochlorperazine  sole indication)
o Except thioridazine
- Antipruritics and sedatives (H1 receptor
blockade)
Toxicity
Reversible neurologic effects
- Dose-dependent EPS dysfunction (parkinson-
like syndrome)
o Commonly occurs with haloperidol (but
also fluphenazine, and trifluoperazine)
- Others (akathisia and dystonia)
o diphenhydramine
Tardive dyskinesia
- Choreoathetoid movements of muscles of the
lips and buccal cavity (may be irreversible)
- Tend to develop after several years (but appear
as early as 6 months)
- No effective drug treatment
Neuroleptic malignant syndrome
- Patients too sensitive to extrapyramidal effects
may develop this (muscle rigidity, impairment of
sweating, hyperpyrexia, and autonomic
instability)
- Treatment  Dantrolene, Diazepam, and
Diphenhydramine
Miscellaneous
- Thioridazine:low dose  visual impairments
(retinal deposits)
high doseventricular
arrhythmias
- Clozapine: low dose agranulocytosis (1-2%)
high dose  seizures
_______________________________________________
BIPOLAR DRUGS
Principle to remember for Lithium effectiveness:
- Manic phase
- Acute-phase illness
- Prevention of recurrent and depressive episodes
Pharmacokinetics
- Absorbed completely from the gut
- Cleared by the kidneys at 1/5th the rate of
creatinine
- Half-life is 20 hours
- Can increase lithium in the blood:
o Dehydration
o Thiazides
o ACE inhibitors
o Loop diuretics
- Increases renal clearance:
o Caffeine
o Theophylline
Mechanism of Action
- Not well-defined
- Inhibits several enzymes involved in the
recycling of neuronal membrane
phosphoinositides
- Depletes source of 2nd messengers (which is
important in amine transmission)
Clinical Use
- Treatment for bipolar disorder:
- Lithium carbonate (main drug)
o Reduces manic behavior, as well as
frequency and magnitude of mood
swings (maintenance therapy)
o Antipsychotic agents (and maybe
benzodiazepines) may be used at start
of therapy because of their faster onset
(Olanzapine and Quetiapine 
monotherapy for mania)
o Protective against suicide and self-
harm (with antidepressants)
- Valproic acid and carbamazepine (equally
effective)
Toxicity
- Adverse neurologic effects:
o Tremors
o Sedation
o Ataxia
o Aphasia
- Possible thyroid enlargement (but no
hyperthyroidism)
- In pregnancy, may increase incidence of
Ebstein’s anomaly (cardiac abnormality)
- Teratogenic risk is low (but low APGAR scores)
- Lithium should be withheld 24-48 hours prior to
delivery (and contraindicated for nursing
mothers)
Other Drugs for BPD
- Manic phase (olanzapine and quetiapine 
monotherapy)
- Valproic acid (anti-mania  USA)
o Often as first choice (and for those who
fail to respond to lithium)
- Carbamazepine and lamotrigine (anti-seizure
drugs) for: Acute mania and Prophylaxis (during
depressive phase)
***END***
 ENDOCRINE DRUGS Effects of Thyroid Hormone
Must Know Terms Organ-level effects:
Cretinism - Normal growth and development of systems
Irreversible mental retardation and dwarfism (nervous, skeletal, and reproductive)
(caused by congenital hypothyroidism) - Control of metabolism for fats, carbohydrates,
Myxedema proteins, and vitamins
Severe hypothyroidism
Goiter Clinical Uses
Enlargement of the thyroid gland Thyroid hormone therapy:
Grave’s disease - Form of choice  Levothyroxine
Autoimmune disorder resulting in hyperthyroidism - Faster onset, but more expensive
during early phase (hypothyroidism in later phases Liothyronine
 upon destruction of the gland)
Thyroglobulin Toxicity
Protein synthesized in the TG; residues are used to Thyrotoxicosis  be careful with patients who are:
synthesize thyroid hormones - Older (with cardiovascular disease)
Thyroid-stimulating hormone (TSH) - Long-standing myxedema (higher sensitivity to
Anterior PG hormone that regulates TG growth, the stimulatory effects)
uptake of iodine, and synthesis of thyroid hormone o Give lower doses
Thyroid storm
Severe thyrotoxicosis ANTI-THYROID DRUGS
Thyrotoxicosis A. Thioamides
Medical syndrome caused by excessive thyroid - Inhibit thyroid hormone synthesis by blocking
hormone peroxidase-catalyzed enzyme reactions
Thyroxine-binding globulin (TBG) - Examples:
Protein produced by the liver that transports thyroid o Propylthiouracil (PTU)
hormone in the blood  Preferred for pregnant patient
(because it is less likely to
THYROID DRUGS cross placenta and also into
breastmilk)
Thyroid Hormones o Methimazole
Thyroid gland secretes two (2) types of hormones:  Preferred due to its once-a-
- Iodine-containing amino acids (thyroxine and day dosing
triiodothyronine) - Also inhibit peripheral conversion of T4 to T3
o Broad effects on: Growth, (PTU > Methimazole)
Development. - Onset (very slow)  3-4 weeks for full effect
- Peptide (calcitonin) - Because thioamides do not inhibit release of
o Sole effect: Calcium metabolism pre-formed thyroid hormone
- Adverse Effects:  reversible and rare
Mechanism of Action o Vasculitis
Triiodothyronine (T3) o Agranulocytosis
- 10x more potent than thryoxine (T4) o Hypoprothrombinemia
Thyroxine (T4) o Liver dysfunction
- Converted into T3 in the target cells, liver, and
kidneys B. Iodine Salts and Iodine
- Most of its effects are due to T3 - Inhibit iodination of tyrosine and thyroid
Both T3 and T4: hormone release
- Bind to intracellular receptors that control - Decrease size and vascularity of hyperplastic
expression of genes (responsible for many thyroid gland
metabolic processes) - Rapid onset of action (within 2-7 days) due to its
Focus on T3: ability to inhibit release and stop synthesis of
- Proteins synthesized (because of T3) depend on thyroid hormone
tissue involved - Problem? TG “escapes” block after a few
o NA/K ATPase, specific contractile weeks of treatment
proteins in smooth muscles and the - Clinical uses (limited to)
heart, enzymes in lipid metabolism, o Patients about to undergo surgical
and important developmental resection of a hyperactive thyroid
components in the brain o Thyroid storm
 - Usual forms:
o Lugol’s solution (iodine and potassium
iodide)
o Potassium iodide (saturated solution)
C. Radioactive Iodine
- Taken up readily and concentrated in the
thyroid gland
- Effect? large dose (permanent cure)
does not endanger other tissues
- Do not use in:
o Pregnant
o Nursing women
D. Anion Inhibitors
- Block uptake of iodide by the thyroid gland
through competitive inhibition of iodide
transporter
- Examples: Thiocyanate (SCN)
Perchlorate (ClO4)
- Unpredictable effectiveness
- May even cause aplastic anemia (rarely used
clinically)
E. Other Drugs
- Beta-blockers
o Controls tachycardia and other
abnormalities of severe thyrotoxicosis
o Inhibitis peripheral conversion of T4 to
T3 (Propanolol)
- Anti-arrhythmia
o Blocks peripheral conversion of T4 to
T3 (amiodarone)
o May cause hypothyroidism  give
thyroid hormone
o May cause hyperthyroidism either
through:
 Leakage of thyroid hormone
into the circulation (persons
with underlying thyroid
disease)  corticosteroids
 Iodine-induced mechanism in
those with multinodular goiter
- Contrast media:
o Ditrizoate (oral) and Iohexol (IV)
o Rapidly suppress conversion of T4 to T3
in the liver, kidney, and other
peripheral tissues
DRUGS FOR DIABETES MANAGEMENT
INSULIN
- Manufactured by bacterial recombinant DNA
technology
- Available forms provide four (4) rates of onset
and durations (rapid to long-acting)
- Synthesized as a prohormone (proinsulin)
o 86-amino acid single-chain polypeptide
o Cleavage results in a 2-chain 51-peptide
insulin molecule and a 31-amino acid
residual C-peptide
 Neither proinsulin nor the C-
peptide has any physiologic
actions
Goal of therapy:
- Control both basal and postprandial (after
meals) glucose levels
- Minimize risk of hypoglycemia
o Different forms are often combined to
achieve these goals
Effects:
- Important effects on almost every tissue in the
body
Liver (increases storage of glucose as
glycogen; decreases protein metabolism)
Skeletal muscle (stimulates glycogen
synthesis and protein synthesis)
Adipose tissue (facilitates storage of
triglycerides; reduces intracellular lipolysis)
Preparations:
Rapid-acting:
- Rapid onset, early peak in activity (permits
control of postprandial glucose levels)
- Given immediately before meals
- Preferred type for continuous subcutaneous
infusion devices
- Also used for emergency treatment of
uncomplicated DKA
 Insulin lispro
 Insulin aspart
 Insulin glulisine
- Main difference is in the primary amino acid
sequences which increase the speed of entry
into the cells; but no effect on insulin receptor
interaction
Short-acting:
- Regular insulin
- Given IV (especially in emergencies) or SQ
(ordinary maintenance regimens)
Short-acting:
- Was primary form of insulin control therapy
(prior to advent of rapid-acting preparations)
o Requires administration 1 hour before
meals
Intermediate-acting:
- Neutral protamine Hagedorn insulin (NPH
insulin)
 o Combination of regular insulin (short-
acting) and protamine (basic protein
used to reverse actions of heparin)
o Produces delayed onset and peak of
action
o Often combined with regular and rapid-
acting insulins
Long-acting:
- Modified forms of human insulin
- Provide peakless levels of basal insulin level
(lasting more than 20 hours)
- Helps control basal insulin (without producing
hypoglycemia)
 Insulin glargine
 Insulin detemir
Insulin Delivery Systems
- Standard route is subcutaneous (using
conventional disposable needles and syringes)
o Portable pen-sized injectors (may use
cartridges that are disposable)
- Continuous subcutaneous infusion devices
(avoid need for multiply daily injections)
o Provide flexibility in the patient’s daily
activities
o Dosing may be adjusted depending on
activities
Hazards of Insulin Use
- Most common complication is hypoglycemia
(excessive insulin effect/dosage)
- Prepare to give glucose as needed to prevent
brain damage
o Sugar/candy by mouth
o Glucose (as D50 50mL) by IV
- Most vulnerable to hypoglycemia:
o Advanced renal disease (dialysis
patients)
o Extremes of ages (below 7 years old,
and elderly)
- Insulin-induced immunologic complication
o Formation of antibodies to insulin or
non-insulin protein contaminants (e.g.
protamine)
 Results in relative resistance
to the drug
o Uncommon (because of highly purified
human insulins)
NON-INSULIN ANTIDIABETIC DRUGS
Four (4) well-established groups:
Insulin Secretagogues
Biguanides
Thiazolidinediones
Alpha-Glucosidase Inhibitors
Novel agents:
Pramlintide
Exenatide
Sitagliptin
Canagliflozin
A. Insulin Secretagogues
Mechanism of Action:
- Stimulate release of endogenous insulin
(promotes closure of potassium cells in the
pancreatic beta-cell membranes)
o This depolarizes the cell and triggers
insulin release
- Not effective for those without functioning
pancreatic beta-cells
Three (3) Groups:
- Sulfonylureas (majority)
o 1st generation (tolbutamide,
chlorpropamide)
o 2nd generation (glyburide, glipizide,
glimepiride) more potent and used
more commonly
- Meglitinide (repaglinide)
- D-phenylalanine derivatives (nateglinide)
Both Meglitinide and D-phenulalanine
derivatives:
rapid onset with short duration of
action
useful before meals (postprandial
glucose)
Toxicities:
- Hypolycemia (high-potency agents)
o Glyburide and gliplizide
- Occasional rash or other allergic reactions
- Weight gain (common)
o Undesirable in patients with DM II
(mostly already overweight)
B. Biguanides
- Inhibit hepatic and renal gluconeogenesis
- Stimulates glucose uptake and glycolysis
(peripheral tissues)
- Slows absorption of glucose from GI tract
- Reduction of plasma glucagon levels
Metformin:
- Primary member of the biguanide group
- Reduces postprandial glucose and fasting blood
sugar levels
- Reduces endogenous insulin production through
increased insulin sensitivity
o Drug of choice in overweight patients
with DM II
o Reduces risk of DM in high-risk patients
o Restores fertility in anovulatory women
with PCOS and evidence of insulin
resistance
Adverse Effects:
- No hypoglycemia
 - GI distress (nausea, and diarrhea)
- Lactic acidosis (renal or liver disease, alcoholism, Activates receptors involved in both glycemic control
conditions which increase vulnerability to tissue and osteogenesis
anoxia and lactic acid production [chronic
cardiopulmonary dyfunction] NOVEL AGENTS:
A. Pramlintide
C. Thiazolidinediones - Injectable synthetic analogue of amylin
- Increase target tissue sensitivity to insulin - Effects:
- Increased glucose uptake in the muscles and o Suppresses glucagon release
adipose tissue o Slows gastric emptying
- Inhibits gluoneogenesis o Reduces appetite (through the CNS)
- Reduce both fasting and postprandial - Adverse Effects:
hyperglycemia o Hypoglycemia
- Used as monotherapy or in combination with o GI tract disturbances
other antidiabetic drugs B. Exenatide
o Reduces risk of DM II in high-risk - Glucagon-like peptide-1 (GLP-1)
patients o Member of the incretin family
Examples: o Released from endocrine cells in the
o Rosiglitazone epithelium of the bowel (in response to
o Pioglitazone food)
- Glucagon-like peptide-1 (GLP-1) Effects:
D. Alpha-Glucosidase Inhibitors o Augments glucose-stimulated insulin
- Carbohydrate analogues which act within the release from pancreatic beta cells
intestines to inhibit alpha-glucosidase o Retards gastric emptying
o Enzyme needed for conversion of o Inhibits glucagon secretion
complex starches, oligosaccharides, o Produces a feeling of satiety
and disaccharides to monosaccharides - Long-acting injectable peptide analog of GLP-1
(may now be transported out of the - Used in combination with metformin or a
intestinal lumen and into the sulfonylurea for DM II
bloodstream) - Adverse effects:
- Examples: o Nausea (initial therapy)
o Acarbose o Hypoglycemia (if combined with
o Miglitol sulfonylurea)
- Leads to reduced absorption of carbohydrates, o Acute pancreatitis (fatal and most
and results to decreased postprandial severe AE)
hyperglycemia C. Sitagliptin
- Do not have any effect on fasting blood sugar - Oral inhibitor of dipeptidyl peptidase-4 (DPP-4)
- Used as monotherapy or in combination with - Enzyme that degrades GLP-1 (and other
other antidiabetic drugs incretins)
- Taken just before meals - Approved for use as monotherapy or in
- Shown to prevent DM II in prediabetic patients combination (metformin or a thiazolidinedione)
- Toxicities: - Inhibits glucagon secretion and anorexic effect
o Flatulence - Adverse effects:
o Diarrhea o Headache
o Abdominal pain o Nasopharyngitis
***All due to increased fermentation o URTI
of unabsorbed carbohydrates by D. Canagliflozin
colonic microflora - Inhibits sodium-glucose transporter 2 (SGLT2)
o Hypoglycemia - Leads to glycosuria and lowers glucose levels in
 Patient should be given patients with DM II
glucose (D50W 50mL), and - Adverse effects:
NOT sucrose (may have o Increased incidence of genitourinary
delayed absorption) tract infections
Pramlintide o May lead to intravascular volume
Amylin: contraction  hypotension

37-amino acid hormone (produced by pancreatic DRUGS FOR HYPERGLYCEMIA

beta-cells)
A. Glucagon
Effects:
- Increases heart rate and force of contraction
- Increases hepatic glycogenolysis and
gluconeogenesis
- Relaxes smooth muscle (especially the gut)
Clinical Uses:
- Severe hypoglycemia (in diabetic)
o Requires intact hepatic glycogen stores
- May be most effective method of stimulating
depressed heart (increases cardiac AMP without
needing access to Beta-receptors)
- Given IV or IM

***END***