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Microsoft word - antidepressant pharmacology 2012

Antidepressant Pharmacology – An Overview
Figure 1.
Source: NEJM 2005;353:1819-34

Figure 2.

Sue Corrigan, BScPharm, ACPR, Pharm D
Clinical Pharmacy Specialist, SMH December 2011

Figure 3: Antidepressant Pharmacology pictures:
NOTE: CYP enzymes noted are those inhibited by the Source: Stephen Stahl - Essential Psychopharmacology Sue Corrigan, BScPharm, ACPR, Pharm D Clinical Pharmacy Specialist, SMH December 2011 Table 1. Antidepressant Mechanism of Action
Re-uptake Inhibition
Receptor Blockade
Potent CYP enzyme
Alpha1 2D6 2C19
SSRIs Fluoxetine
Sertraline +++ - Amitriptyline +++ ++ NaSSA Mirtazapine

serotonin reuptake inhibition; NRI= norepinephrine reuptake inhibition; DRI= dopamine reuptake inhibition
Drug Class: SSRI= selective serotonin reuptake inhibitor; TCA= tricyclic antidepressant; NDRI= norepinephine
dopamine reuptake inhibitor; SNRI= serotonin norepinephrine reuptake inhibitor; NaSSA= noradrenergic and specific
serotonergic antidepressant
(+) to (++++) = increasing potency; (-) = weak effect; blank = no effect

J Clin Psych 2003;64[suppl 13]:5-12 Mayo Clin Proc 2001;76:511-27 Clinical Handbook of Psychotropic Drugs 2004, 14th Ed.
Figure 4. Action of Mirtazapine:
blocks pre-synaptic alpha-2 receptors on NE and 5-HT neurons which
"takes the brakes off" and enhances the release of NE and 5-HT. NE then activates alpha-1 receptors on 5-HT neuron to enhance release of 5-HT. Sue Corrigan, BScPharm, ACPR, Pharm D Clinical Pharmacy Specialist, SMH December 2011 Table 2. Clinical Effects of Neurotransmitter Reuptake Blockade

Receptor action Therapeutic Effects

Possible Side Effects
Norepinephrine Antidepressant effects
Insomnia, anorexia Augmentation of pressor effects of sympathomimetic amines Serotonin
Antidepressant effects GI disturbances (nausea, vomiting, diarrhea, Reuptake
Antianxiety effects wt loss early on; wt gain later in tx) Inhibition
Anti-OCD effects Sexual dysfunction May see increase in anxiety (early on or with fast dose titration) Dopamine
Antidepressant effects Aggravation of psychosis Reuptake
Enhanced motivation Inhibition
Enhanced cognition Antiparkinsonian Mitigation against prolactin elevation Psychomotor activation Muscarinic
(Potentiate drugs with anticholinergic Dry mouth, Blurred vision, Constipation, Urinary properties eg. Diphenhydramine, TCAs, blockade
oxybutynin, H2-blockers) Sinus tachycardia, QRS changes Memory disturbances Worsen narrow-angle glaucoma (Potentiates antihypertensives with Postural hypotension, dizziness, reflex tachycardia receptor
alpha-blocking properties eg. Prazosin, blockade
terazosin, labetalol) H1 (Histamine) (Potentiates effects of other CNS drugs)
Sedation, drowsiness blockade
Postural hypotension Weight gain
Other Side Effects:
SSRIs in general:
nausea, anxiety, tremor, insomnia, sweating, dry mouth, headache, dizziness,
diarrhea, constipation, sexual dysfunction (> 30%), SIADH (hyponatremia)
Fluoxetine: most anorexic and stimulating of SSRIs, weight loss; very long half-life (1 week!)
Fluvoxamine: most nauseating, constipating and sedating SSRI, many drug interactions
Paroxetine: most anticholinergic of SSRIs, increased sexual dysfunction; higher incidence of
discontinuation reactions, increased weight gain Sertraline: most diarrhea and male sexual dysfunction
Citalopram: fewest drug interactions
Escitalopram: less sedation, sweating and sexual dysfunction than citalopram (is the active portion of
the citalopram molecule)
TCAs in general: tachycardia, hypotension, dizziness, sedation, weight gain, sexual dysfunction,
sweating, tremor, ECG abnormalities, seizures, fatal in overdose, dry mouth, constipation
Venlafaxine: higher incidence of nausea/vomiting than with SSRIs; agitation, tremor, sweating,
headache, as dose increases can cause hypertension; higher incidence of discontinuation reactions; less weight gain than with SSRIs, few drug interactions; sweating, headache, moderate incidence of sexual dysfunction (10-30%) Note: at doses of less than 150 mg/day behaves mainly like an SSRI; beyond 150-225 mg/day you get increased NE effects Sue Corrigan, BScPharm, ACPR, Pharm D Clinical Pharmacy Specialist, SMH December 2011 Duloxetine: less effect on BP compared to Venlafaxine; otherwise similar to Venlafaxine

Mirtazapine: dry mouth, sedation, edema, arthralgias, increased appetite, high incidence of weight
gain, less sexual dysfunction than SSRIs/SNRIs

Bupropion: risk of seizures (0.4%/400 mg/d) – caution in those with seizure history; agitation,
insomnia, tremor, sweating, decreased appetite, GI upset, little-no weight gain, less sexual dysfunction than SSRIs/SNRIs, vivid dreams (esp people using for smoking cessation), psychosis

Antidepressants and Suicidality

• Suicide is the 9th leading cause of death in Canada 2nd leading cause in people aged 15-34 yrs 3rd leading cause in people aged 35-44 yrs • Risk factors include depression and other mental illnesses; alcohol and substance abuse • In the US – the ratio of suicide attempts to completed suicides: General population: 25 attempts : 1 suicide 100-200 attempts : 1 suicide Ages 65 and older: 4 attempts : 1 suicide Ref: and summer 2009 newsletter
Figure 5:
Ref: Nutt DJ. J of Psychopharmacology 2003;17: 355-64 Sue Corrigan, BScPharm, ACPR, Pharm D Clinical Pharmacy Specialist, SMH December 2011 Consider risk of untreated depression: • Cohort study in Washington and Idaho state looking at claim records from an HMO of over 100,000 pts over 10 yrs showed an increased risk of suicide attempts in the 1 month PRIOR to starting a prescription for antidepressants compared to the few months post.
Figure 6:
Ref: Simon GE, Savarino J. Am J Psych 2007;164:1029-34. FDA 2006 meta-analysis of trials for increased risk of suicide – ** Fluoxetine and Sertraline had a DECREASED risk of "suicidal ideation or worse" as an
** all other SSRIs, Venlafaxafine, Bupropion, Mirtazapine, Duloxetine had NS results ** Sertraline had a DECREASED risk of "suicide preparation or worse" as an outcome ** Paroxetine had an INCREASED risk of "suicide preparation or worse" Ref: Stone M et al. BMJ 2009;339:b2880 online (print p.431-4); Barbui C et al. EBMH 2008;11:34-36.

Antidepressants and Cardiac disease:

Sertraline has been found to be safe for use in depression post MI. Citalopram has been found to be safe for use in depression with CAD.

Sue Corrigan, BScPharm, ACPR, Pharm D
Clinical Pharmacy Specialist, SMH December 2011 Serotonin Syndrome:
Mild cases may present with tremor, sweating and diarrhea. Severe life-threatening cases may have delirium/agitation, neuromuscular rigidity and hyperthermia.
Figure 7:
Figure 8:
Ref: Bower EW and Shannon M. NEJM 2005;352:1112-20. Sue Corrigan, BScPharm, ACPR, Pharm D Clinical Pharmacy Specialist, SMH December 2011
Discontinuation Reactions with Antidepressants:

Occurs in approximately 20% of pts after abrupt discontinuation of an antidepressant medication that was taken for at least 6 wks. Symptoms typically appear within 3 days of stopping the agent.
FINISH – Mnemonic to recognize Discontinuation Syndrome:
F lu-like symptoms (fatigue, lethargy, malaise, muscle aches, diarrhea)
I nsomnia
N ausea
I mbalance (gait instability, dizziness, lightheadedness, vertigo)
S ensory disturbances (paresthesias, "electric shock" sensations, visual disturbances)
H yperarousal (anxiety, agitation)
Symptoms are usually mild and self-limiting – lasting 1-2 weeks. If intolerable – they will be extinguished with the resumption of the antidepressant agent. Can occur with SSRIs (except NOT with fluoxetine), TCAs, MAOIs, Venlafaxine, Duloxetine, Mirtazapine Higher risk with agents with a shorter half-life: Paroxetine, Venlafaxine, Duloxetine
Management – use a slower tapering course, if not possible switch to Fluoxetine
Ref: Warner CH et al. Am Fam Phys 2006;74:449-56.
Common Antidepressant Doses – See RxFiles table or Clinical Handbook of Psychotropic Drugs

General Comments regarding Drug Interactions
• Carbamazapine is a strong inducer of CYP P450 enzymes and it lowers the levels of most SSRI's, Trazodone, Mirtazapine, and Venlafaxine • SSRIs affect platelet aggregation and can therefore increase the antiplatelet effects of drugs like aspirin, clopidogrel, prasugrel; because of this action there is an increased risk of GI bleeds. This is very important when given in combination with NSAIDs (risk of GI bleeds higher than with either SSRI or NSAID alone). • MAOIs will increase the effects of all other antidepressants and combinations are considered contraindicated. Can lead to serotonin syndrome and hypertensive emergencies. ƒ Note: Linezolid (antibiotic) has weak MAOI properties and can cause serotonin syndrome; macrolides (clarithromycin) can also increase levels of SSRIs • Tramadol has weak SSRI properties and there are case reports of serotonin syndrome when given in combination with SSRI's. • Cigarette smoking can decrease the levels of Mirtazapine and Duloxetine through induction of • Antiretrovirals (ex. Ritonavir) may be potent enzyme inducers and could lower levels of certain antidepressants. • Triptans (migraine medications, eg. Sumatriptan, Rizatriptan) can lead to serotonin syndrome • Paroxetine inhibits CYP 2D6 – can lower metabolism of Risperidone; Tramadol to its active
Useful Readings:

Mann JJ. Medical management of depression. NEJM 2005;353:1819-34 Belmaker RH and Agam G. Major depressive disorder. NEJM 2008;358-55-68 Stahl SS. Selecting an antidepressant by using mechanism of action to enhance efficacy and avoid side effects. J Clin Psych 1998;59(suppl 18):23-29. Sue Corrigan, BScPharm, ACPR, Pharm D Clinical Pharmacy Specialist, SMH December 2011


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