3. Depression
ā¢ Most antidepressants are approved for
both acute and long-term treatment of
major depression.
ā¢ Acute episodes of major depressive
disorder (MDD) tend to last about 6-14
months untreated, but at least 20% of
episodes last 2 years or longer.
ā¢ The goal of acute treatment of MDD is
remission of all symptoms.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
4. Depression
ā¢ Antidepressants may not achieve their maximum
benefit for 1-2 months or longer.
ā¢ It is not unusual for a trial of therapy to last 8-12
weeks at therapeutic doses.
ā¢ The antidepressants are successful in achieving
remission in about 30-40% of patients within a
single trial of 8-12 weeks.
ā¢ If an inadequate response is obtained, therapy is
often switched to another agent or augmented by
addition of another drug.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
5. Depression
ā¢ Bupropion or mirtazapine might be added to an
SSRI or SNRI to augment antidepressant benefit if
monotherapy is unsuccessful.
ā¢ 70-80% percent of patients are able to achieve
remission with sequenced augmentation or
switching strategies.
ā¢ Once an adequate response is achieved,
continuation therapy is recommended for a
minimum of 6-12 months to reduce the
substantial risk of relapse.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
6. Depression
ā¢ 85% of patients who have a single episode of
MDD will have at least one recurrence in a
lifetime.
ā¢ Many patients have multiple recurrences.
ā¢ These recurrences may progress to more
serious, chronic and treatment-resistant
episodes.
ā¢ It is not unusual for patients to require
maintenance treatment to prevent
recurrences.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
7. Depression
ā¢ It is commonly recommended that patients be
considered for long-term maintenance treatment
if they have had two or more serious MDD
episodes in the previous 5 years or 3 or more
serious episodes in a lifetime.
ā¢ Patients with bipolar depression may not benefit
much from antidepressants even when added to
mood stabilizers.
ā¢ Antidepressants are sometimes associated with
switches into mania or more rapid cycling.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
8. Depression
ā¢ Psychotherapeutic interventions (cognitive
behavior therapy) appear to be as effective
as antidepressant treatment for mild to
moderate forms of depression.
ā¢ Psychotherapy is often combined with
antidepressant treatment.
ā¢ The combination is more effective than
either strategy alone.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
9. Anxiety disorders
A number of SSRIs and SNRIs have been
approved for all the major anxiety disorders:
ā¢ PTSD (post-traumatic stress disorder)
ā¢ OCD (obsessive compulsive disorder)
ā¢ social anxiety disorder (SAD)
ā¢ GAD (generalised anxiety disorder)
ā¢ panic disorder
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
10. Anxiety disorders
ā¢ Panic disorder is characterized by
recurrent episodes of brief
overwhelming anxiety, which often
occur without precipitant.
ā¢ Patients may begin to fear having an
attack or they avoid situations in
which they might have an attack.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
11. Anxiety disorders
GAD is characterized by
a chronic, free-floating
anxiety and undue
worry that tends to be
chronic in nature.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
12. Anxiety disorders
ā¢ The benzodiazepines provide much more
rapid relief of both generalised anxiety and
panic than do any of the antidepressants.
ā¢ The antidepressants are more effective in
the long-term treatment of these anxiety
disorders.
ā¢ Antidepressants do not carry the risks of
dependence and tolerance that may occur
with benzodiazepines.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
13. Anxiety disorders
ā¢ OCD is characterized by repetitive anxiety-
provoking thoughts (obsessions) or repetitive
behaviors aimed at reducing anxiety
(compulsions).
ā¢ Clomipramine and several of the SSRIs are
approved for the treatment of OCD.
ā¢ These drugs are moderately effective.
ā¢ Behavior therapy is usually combined with the
antidepressant for additional benefits.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
14. Anxiety disorders
ā¢ Social anxiety disorder: patient experiences
severe anxiety in social interactions.
ā¢ This anxiety may limit patientsĀ“ ability to
function adequately in their jobs or
interpersonal relationships.
ā¢ Several SSRIs and venlafaxine are approved
for the treatment of social anxiety.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
15. Anxiety disorders
ā¢ PTSD is manifested when a traumatic or life-
threatening event results in intrusive anxiety-
provoking thoughts or imagery, hypervigilance,
nightmares and avoidance of situations that
remind the patient of the trauma.
ā¢ SSRIs are considered first-line treatment for PTSD
and can benefit a number of symptoms including
anxious thoughts and hypervigilance.
ā¢ Psychotherapeutic interventions!
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
16. Pain disorders
ā¢ Antidepressants possess analgesic properties
independent of their mood effects.
ā¢ TCAs are used in the treatment of neuropathic
and other pain conditions.
ā¢ Medications that possess both norepinephrine
and 5-HT reuptake blocking properties are often
useful in treating pain disorders.
ā¢ Ascending corticospinal monoamine pathways are
important in the endogenous analgesic system.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
17. Pain disorders
ā¢ Chronic pain conditions are commonly
associated with major depression.
ā¢ Duloxetine is approved for the
treatment of chronic joint and muscle
pain.
ā¢ Milnacipran has been approved for the
treatment of fibromyalgia.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
18. Premenstrual dysphoric disorder
5% of women in the child-bearing years will have
prominent mood and physical symptoms during the
late luteal phase of almost every cycle:
ā¢ anxiety
ā¢ depressed mood
ā¢ irritability
ā¢ insomnia
ā¢ fatigue
ā¢ other physical symptoms
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
19. Premenstrual dysphoric disorder
ā¢ Fluoxetine and sertraline are approved for
this indication.
ā¢ Treating for 2 weeks out of the month in
the luteal phase may be as effective as
continuous treatment.
ā¢ The rapid effects of SSRIs in PMDD may be
associated with rapid increases in
pregnenolone levels.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
20. Smoking cessation
ā¢ Bupropion is approved for the smoking cessation.
ā¢ This drug may mimic nicotineĀ“s effects on
dopamine and norepinephrine.
ā¢ Bupropion may antagonize nicotinic receptors.
ā¢ Nicotine is also known to have antidepressant
effects in some people: bupropion may substitute
for this effect.
ā¢ Nortriptyline may also be helpful in smoking
cessation.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
21. Eating disorders
Bulimia
ā¢ Bulimia nervosa is
characterized by episodic
intake of large amounts of
food (binges) followed by
ritualistic purging through
emesis, the use of laxatives
or other methods.
ā¢ Hypokalemia!
Anorexia nervosa
ā¢ Anorexia is a disorder in which
reduced food intake results in
a loss of weight of 15% or
more of ideal body weight.
ā¢ The person has a morbid fear
of gaining weight and a highly
distorted body image.
ā¢ It is often chronic.
ā¢ It may be fatal in 10% of cases.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
22. Eating disorders
ā¢ Antidepressants appear to be helpful in the
treatment of bulimia, but not anorexia.
ā¢ Fluoxetine and other antidepressants have
shown benefit in reducing the binge-purge
cycle.
ā¢ The primary treatment for anorexia is
refeeding, family therapy and cognitive
behavioral therapy.
ā¢ Bupropion may have some benefits in treating
obesity.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
23. Other uses
ā¢ Enuresis in children is sometimes treated with
TCAs.
ā¢ Duloxetine is approved for the treatment of
urinary stress incontinence.
ā¢ SSRIs may be helpful for treating vasomotor
symptoms in perimenopause.
ā¢ SSRIs delay orgasm in some patients: treatment of
premature ejaculation.
ā¢ Bupropion: treatment of sexual adverse effects of
SSRIs.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
25. Choice of an antidepressant for the treatment
of depression:
ā¢ cost
ā¢ availability
ā¢ adverse effects
ā¢ potential drug interactions
ā¢ patientĀ“s history of response
ā¢ age
ā¢ gender
ā¢ medical status
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
26. !!!
ā¢ Older patients are particularly sensitive to
the anticholinergic effects of the TCAs.
ā¢ The CYP3A4-inhibitor SSRI fluvoxamine may
interact with many other medications that
an older patient may require.
ā¢ Female patients may respond to and
tolerate serotonergic better than
noradrenergic or TCA antidepressants.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
27. !!!
ā¢ Patients with narrow-angle
glaucoma may have an
exacerbation with noradrenergic
antidepressants.
ā¢ Bupriopion and other
antidepressants lower the seizure
threshold in epilepsy patients.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
28. MDD
ā¢ SSRIs are the most commonly prescribed first-line
agents in the treatment of both MDD and anxiety
disorders.
ā¢ SNRIs, bupropion and mirtazapine are also
reasonable first-line agents for the treatment of
MDD.
ā¢ Bupropion, mirtazapine and nefazodone are the
antidepressants with the least association with
sexual side effects.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
29. Bupropion Mirtazapin
ā¢ The primary indication
for bupropion is major
depression, including
seasonal (winter)
depression.
ā¢ Off-label uses of
bupropion include the
treatment of attention
deficit hyperkinetic
disorder (ADHD).
ā¢ The primary indication
for mirtazapine is
major depression.
ā¢ It has strong
antihistamine
properties so it is
occasionaly used as a
hypnotic and as an
adjunctive treatment
to more activating
antidepressants.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
30. TCA, MAOI
ā¢ The TCAs and MAOIs are now
relegated to second or third line
treatment for MDD.
ā¢ Both TCAs and MAOIs are potentially
lethal in overdose, require titration to
achieve a therapeutic dose, have
serious drug interactions and have
many troublesome adverse effects.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
31. Other
ā¢ TCAs and SNRIs are useful in the
treatment of pain conditions.
ā¢ SSRIs and the highly serotonergic TCA-
clomipramine are effective in the
treatment of OCD.
ā¢ Bupropion and nortriptyline are useful
in the treatment of smoking cessation.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
39. Dosing
ā¢ Patients with MDD, who show little or no
benefit after at least 4 weeks of treatment,
may benefit from a higher dose.
ā¢ The dose is generally titrated to the
maximum dosage recommended or to the
highest dosage tolerated.
ā¢ Some patients may benefit from doses
lower than the usual minimum
recommended therapeutic dose.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
40. Dosing
ā¢ TCAs and MAOIs typically require titration to a
therapeutic dosage over several weeks.
ā¢ Dosing of the TCAs may be guided by monitoring
TCA serum levels.
ā¢ Some anxiety disorders may require higher doses
of antidepressants than are used in the treatment
of MDD.
ā¢ Patients with OCD often require maximum or
somewhat higher than maximum recommended
MDD doses.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
41. Dosing
ā¢ In the treatment of pain disorders, modest
doses of TCAs are often sufficient.
ā¢ Imipramine 25-50 mg/day might be
beneficial in the treatment of pain
associated with a neuropathy.
ā¢ SNRIs are usually prescribed in pain
disorders at the same doses used in the
treatment of depression.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
43. Adverse effects
All antidepressants are associated with the
risk of increased suicidality in patients
under the age 25.
Use of antidepressants is associated with
suicidal ideation and gestures, but not
completed suicides, in up to 4% of patients
under 25 years (clinical trials).
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
44. SSRIs
ā¢ SSRIs enhance serotonergic tone, not just in the
brain, but throughout the body.
ā¢ Increased serotonergic activity in the gut is
commonly associated with nausea,
gastrointestinal upset, diarrhea and other GI
symptoms.
ā¢ GI adverse effects usually emerge early in the
course of treatment and tend to improve after the
first week.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
45. SSRIs
ā¢ Increasing serotonergic tone at the level of the
spinal cord and above is associated with
diminished sexual function and interest.
ā¢ At least 30-40% of patients treated with SSRIs
report loss of libido, delayed orgasm or
diminished arousal.
ā¢ The sexual effects often persist as long as the
patient remains on the antidepressant, but may
diminish with time.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
46. SSRIs
ā¢ Other serotonergic side effects are headaches,
insomnia or hypersomnia.
ā¢ Some patients gain weight while taking SSRIs,
particularly paroxetine.
ā¢ Sudden discontinuation of short half-life SSRIs
(paroxetine, sertraline) is associated with a
discontinuation syndrome: dizziness,
paresthesias.
ā¢ These symptoms beginn 1 or 2 days after stopping
the drug and persist for 1 week or longer.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
47. SSRIs
FDA teratogen classification C
category!
Paroxetine is D category: cardiac
septal defects in first trimester
exposures.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
48. SNRIs
ā¢ SNRIs have many of the serotonergic adverse effects
associated with SSRIs.
ā¢ These agent may also have noradrenergic effects:
increased blood pressure and heart rate, CNS
activation (insomnia, anxiety, agitation).
ā¢ A dose-related increase in blood pressure is more
common with the immediate-release form of
venlafaxine, as well as cardiac toxicity.
ā¢ Duloxetine rarely causes hepatic toxicity in patients
with a history of liver damage.
ā¢ Discontinuation syndrome!
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
49. TCAs
ā¢ Anticholinergic effects are the most common:
dry mouth, constipation, urinary retention,
blurred vision and confusion.
ā¢ These effects are more common with tertiary
amine TCAs (amitriptyline, imipramine) than
with the secondary amine TCAs (desipramine,
nortriptyline).
ā¢ Potent Ī±-blocking property: orthostatic
hypotension.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
50. TCAs
H1 antagonism: weight gain and sedation.
Class 1A antiarrhythmic agents: arrhythmogenic at
higher doses.
Sexual effects, particularly with highly serotonergic
TCAs (clomipramine).
Prominent discontinuation syndrome: cholinergic
rebound and flulike symptoms.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
51. 5-HT2 antagonists
ā¢ The most common adverse effects are sedation
and gastrointestinal disturbances.
ā¢ Sedative effects, particularly with trazodone, can
be very prononuced.
ā¢ The GI effects are dose-related.
ā¢ Sexual effects are uncommon with nefazodone or
trazodone treatment.
ā¢ Trazodone may rarely be associated with inducing
priapism.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
52. 5-HT2 antagonists
ā¢ Nefazodone and trazodone are Ī±-blocking
agents: dose-related orthostatic
hypotension.
ā¢ Nefazodone has been associated with
hepatotoxicity: rare fatalities and cases of
fulminant hepatic failure requiring
transplantation (1/250000 to 1/300000
patient-years of nefazodone treatment).
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
53. Tetracyclics, unicyclics
Amoxapine is sometimes associated with
parkinsonian syndrome (D2-blocking action).
Mirtazapine has significant sedative effect.
Maprotiline has a moderately high affinity
for NET and may cause TCA-like adverse
effects and seizures (rarely).
Bupropion is occasionally associated with
agitation, insomnia and anorexia.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
54. MAOIs
ā¢ Most common adverse effects are orthostatic
hypotension and weight gain.
ā¢ The irreversible nonselective MAOIs are
associated with the highest rates of sexual
effects of all the antidepressants.
ā¢ Anorgasmia!
ā¢ The amphetamine-like properties of some
MAOIs contributes to activation, insomnia nad
restlessness.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
55. MAOIs
ā¢ Phenelzine tends to be more sedating than
selegiline and tranylcypromine.
ā¢ Confusion: higher doses of MAOIs.
ā¢ MAOIs may cause dangerous interactions with
certain foods and serotonergic drugs: MAOIs block
metabolism of tyramine and similar ingested
amines.
ā¢ Sudden discontinuation syndrome: delirium-like
presentation with psychosis, excitement and
confusion.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
56. Overdose
ā¢ Suicide attempts are a common and unfortunate
consequence of major depression.
ā¢ The lifetime risk of completing suicide in patients
previously hospitalized with MDD is up to 15%.
ā¢ Overdose, especially with TCAs, can induce lethal
arrhythmias: ventricular tachycardia, fibrillation.
ā¢ TCAs overdose can also cause blood pressure
changes and anticholinergic effects: altered
mental status and seizures.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
57. Overdose
ā¢ A 1500 mg dose of imipramine or
amitriptyline is enough to be lethal in many
patients.
ā¢ Toddlers toxicity: 100 mg!
ā¢ Treatment: cardiac monitoring, airway
support, gastric lavage.
ā¢ Sodium bicarbonate to uncouple the TCA
from cardiac sodium channels!
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
58. Overdose
ā¢ Overdose with MAOIs: autonomic
instability, hyperadrenergic
symptoms, psychotic symptoms,
confusion, delirium, fever and
seizures.
ā¢ Management: cardiac monitoring,
vital signs support and lavage.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
59. Overdose
ā¢ Fatalities with SSRIs overdose alone are extremely
uncommon.
ā¢ Venlafaxine (SNRI) has been associated with some
cardiac toxicity in overdose.
ā¢ Bupropion overdose: seizures.
ā¢ Mirtazapine overdose: sedation, disorientation and
tachycardia.
ā¢ Fatal overdose: newer antidepressants with other
antidepressant, including alcohol.
ā¢ Treatment: emptying of gastric contents, vital sign
support, initial intervention.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
61. SSRIs
ā¢ The most common are PHARMACOKINETIC
interactions.
ā¢ Paroxetine and fluoxetine are potent CYP2D6
inhibitors: administration with TCAs can lead to
dramatic and sometimes unpredictable elevations
in the tricyclic drug concentration.
ā¢ Fluvoxamine is CYP3A4 inhibitor: elevation of
level of diltiazem (bradycardia, hypotension).
ā¢ Citalopram and escitalopram are relatively free of
pharmacokinetic interactions.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
63. SNRIs
ā¢ Venlafaxine is a substrate of CYP2D6.
ā¢ Desvenlafaxine is a minor substrate for
CYP3A4.
ā¢ Duloxetine is a moderate inhibitor of
CYP2D6: elevation of TCA levels.
ā¢ SNRIs are contraindicated in
combination with MAOIs.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
64. TCAs
ā¢ Elevations of TCA levels may occur when
combined with CYP2D6 or from constitutional
factors (CYP2D6 polymorphism associated with
slow metabolism of TCAs and other 2D6
substances).
ā¢ Additive TCA anticholinergic or antihistamine
effects with benztropine, diphenhydramine and
similar agents.
ā¢ Antihypertensive drugs may exacerbate the
orthostatic hypotension induced by TCA.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
65. 5-HT2 antagonists
ā¢ Nefazodone is an inhibitor of the
CYP3A4 isoenzyme: elevation of
triazolam levels, simvastatin levelsā¦
ā¢ Trazodone is a substrate of CYP3A4:
ritonavir and ketoconazole (potent
inhibitors of CYP3A4) increase
trazodone levels.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
66. Tetracyclics, unicyclics
ā¢ Bupropion is metabolized primarily by
CYP2B6: cyclophosphamide may alter its
metabolism.
ā¢ Hydroxybupropion (bupropion metabolite)
is a moderate inhibitor of CYP2D6: increase
of desipramine levels.
ā¢ Bupriopion should be avoided in patients
taking MAOIs.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
67. Tetracyclics, unicyclics
ā¢ Mirtazapine is a substrate for several
CYP450 enzymes: 2D6, 3A4 and 1A2.
ā¢ Drugs that inhibit these isoenzymes
may raise mirtazapine levels.
ā¢ The sedating effects of mirtazapine
may be additive with those of CNS
depressants (alcohol,
benzodiazepines).
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
68. Tetracyclics, unicyclics
ā¢ Amoxapine and meprotiline are
CYP2D6 substrates: they should be
used with caution in combination with
inhibitors (fluoxetine).
ā¢ These drugs have anticholinergic and
antihistaminic properties: additive
effects with drugs of similar profile.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
69. MAOIs
ā¢ Pharmacodynamic interaction of MAOIs
with serotonergic agents (SSRIs, SNRIs,
most TCAs, analgesic agent meperidine)
may result in a life-threatening SEROTONIN
SYNDROME.
ā¢ The serotonin syndrome is probably caused
by overstimulation of 5-HT receptors in the
central gray nuclei and the medulla.
ā¢ Symptoms range from mild to lethal.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
71. MAOIs
Most serotonergic antidepressants should be
discontinued at least 2 weeks before starting an
MAOI.
Fluoxetine (long half-life) should be discontinued
for 4-5 weeks before and MAOI is initiated.
MAOI must be discontinued for at least 2 weeks
before starting a serotonergic agent.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
72. MAOIs
ā¢ MAOI combined with tyramine in the diet or with
sympathomimetic substrates of MAO is important
interaction.
ā¢ MAOI prevents the breakdown of tyramine in the gut:
high serum levels of tyramine enhance peripheral
noradrenergic effects, including raising blood
pressure dramatically.
ā¢ Patients on an MAOI, who ingest large amounts of
dietary tyramine, may experience malignant
hypertension leading to stroke or myocardial
infarction.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
73. MAOIs
ā¢ Patients taking MAOIs require a low-tyramine
diet.
ā¢ They should avoid AGED CHEESES, TAP BEER, SOY
PRODUCTS AND DRIED SAUSAGES.
ā¢ Similar sympathomimetics may also cause
significant hypertension when combined with
MAOIs.
ā¢ OTC drugs that contain psudoephedrine
(decongestants) and phenylpropanolamine are
contraindicated in patients taking MAOIs.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
74. Literature
ā¢ Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.