e disorders
3/18/2016 7677• BONE REMODELING
– About 10% of the adult skeleton is replaced each
year
• Osteoclasts – osteoblasts
• TREATMENT OF OSTEOPOROSIS
• Nondrug strategies:
– adequate dietary intake:
• Ca2+ and vit D, exercise, and smoking
cessation.
– avoid drugs: e.g. glucocorticoids
3/18/2016
78ratide
3/18/2016 79• Pharmacologic therapy:
• Bisphosphonates
– Alendronate, ibandronate, risedronate, and
zoledronic acid:
• for prevention and treatment of:
–postmenopausal osteoporosis
• Mechanism of action
– decrease osteoclastic bone resorption:
• mainly through an increase in osteoclastic
apoptosis
3/18/2016
8081pproved for the prevention and treatment of osteoporosis: –in women intolerant to bisphosphonates
• Calcitonin (Salmon) – reduces bone resorption, but it is less than bisphosphonates
– intranasal administrn SE: rhinitis 3/18/2016 82ide • Is a rh. parathyroid hormone • Stimulates osteoblastic activity – Reserved for: • Patients unresponsive to other drugs ========================
End of endocrine pharmacology 3/18/2016 83الفصل السادس
Pharmacology II
– السنة الثالثة
------------------------------------------برنامج الطب
Drugs acting on the CNS
• Text book: • Lippincott’s illustrated reviews: Pharmacology (by: Richard D. Howland – Mary J. Mycek)- 7th edition
6/25/2023 84ychotic drugs – Anti-epileptics – Anesthetics – Opioid analgesics
6/25/2023 856/25/2023
86ors, muscular rigidity – Bradykinesia, postural, gait abnormalities – Most: over 65 yrs (1%)
6/25/2023 87• Etiology
– Unknown for most patients
– Is correlated with destruction of:
• dopaminergic neurons in the substantia nigra
• Substantia nigra:
• Figure 8.4
6/25/2023
8889• Neostriatum:
– Overactivity of acetylcholine:
• results in loss of the control of muscle
movements
• Secondary parkinsonism (pseudoparkinsonism):
– Phenothiazines and haloperidol
6/25/2023
9091DRUGS USED IN PARKINSON’S DISEASE
• Levodopa and carbidopa
– In early disease:
• 20% of DA neurones:
–is adequate for conversion of L-dopa to
dopamine
– L-dopa + carbidopa
• (Figure 8.5)
6/25/2023
926/25/2023
93idopa: • A DA decarboxylase inhibitor
6/25/2023 94• L-dopa Therapeutic uses:
– Parkinson’s disease:
• Patients typically experience a decline in
response:
–during the 3rd to 5th year of therapy
• Withdrawal from the drug must be gradual
6/25/2023
956/25/2023
96a Interactions: 6/25/2023 9798ne and rasagiline – At LD, MD: Selectively inhibits: • MAO-B not MAO-A
• (Figure 8.8). 6/25/2023 99100101– Entacapone and tolcapone:
• Selectively and reversibly inhibit COMT
– Both: reduce “off” phenomen
6/25/2023
102orexia
• Dyskinesias, hallucinations, and sleep disorders
– Hepatic necrosis: with tolcapone: • Largely replaced by Entacapone
6/25/2023 103r levodopa- fluctuations
6/25/2023 104• Side effects:
– (Figure 8.10).
6/25/2023
105106• Bromocriptine:
– Caution in MI or PVD
6/25/2023
107• Non-ergot drugs:
– Apomorphine, pramipexole, ropinirole, and
rotigotine:
• Pramipexole and ropinirole: oral
• Apomorphine: injectable
• Rotigotine:
–Transdermal
• Apomorphine:
– for acute “off” phenomenon
6/25/2023
1081096/25/2023
110• Amantadine
– Antiviral: for influenza
– Increases DA release
– Tolerance develops more readily
6/25/2023
111• Antimuscarinic agents
– Only adjuvant
– Benztropine, trihexyphenidyl
– Contraindicated in:
• glaucoma, prostatic hyperplasia, or pyloric
stenosis
===============================
6/25/2023
112xiolytic and Hypnotic drugs 6/25/2023 1136/25/2023
114• BENZODIAZEPINES
– Safer and more effective
• Mechanism of action:
– BNZs target:
• GABAA receptors
• BNZs increase:
– Frequency of Cl- channel openings
• (Figure 9.3)
6/25/2023
115116• Actions : BNZs
– Reduction of anxiety
– Sedative/hypnotic
– Anterograde amnesia
– Anticonvulsant
– Muscle relaxant
• Therapeutic uses :
• Anxiety disorders:
– e.g. panic disorder, GAD, social anxiety disorder,
posttraumatic stress disorder, obsessive–
compulsive disorder, anxiety (phobias: flying)
6/25/2023
117Useful in patients who experience frequent wakening
– Triazolam: • Short -acting • In treating individuals who have difficulty in going to sleep
6/25/2023 118• Seizures:
– Clonazepam: Adjunctive to antiepileptics
– Lorazepam and diazepam: status epilepticus
• Duration of action:
– Short -, intermediate-, and long-acting
• (Figure 9.4)
–
6/25/2023
1196/25/2023
120121ER ANXIOLYTIC AGENTS • Antidepressants: – First -line in addiction or dependence – Alone or combined with BNZ in first wks – Have become first-line treatment for GAD
6/25/2023 122w onset of action – Actions: • Mediated by: –5-HT1A receptors
• Adverse effects: is low: – Sedation and cognitive dysfunction: • are minimal
– Dependence is unlikely • Figure 9.7 6/25/2023 1231241256/25/2023
1261276/25/2023
128idem – Exhibits minimal rebound insomnia – Rapid onset: • Hypnotic effect: 5 hours
– A sublingual tablet: • For mid- night awakening ===============
6/25/2023 129بسم الله الرحمن الرحيم
Antidepressants
6/25/2023
130adness, hopelessness, inability to experience pleasure
– Changes in (sleep patterns and appetite) – Suicidal thoughts
• MECHANISM OF ANTIDEPRESSANT DRUGS • Most: – Potentiate: • NE and/or 5-HT in the brain • Biogenic amine hypothesis of depression
• (Figure 10.1) 6/25/2023 131132• SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIs):
– Have greater selectivity (10Xs) for the serotonin
transporter;
• as compared to the NE transporter
– Little blocking at:
• Muscarinic, α-adrenergic, and H1 receptors
– Safe in overdose
– Largely replaced TCAs and MAOIs
– Include fluoxetine, citalopram, escitalopram,
fluvoxamine, paroxetine, and sertraline
• (Figure 10.2)
6/25/2023
133134– Actions
• Antidepressants:
–at least 2 weeks
–Max benefit: 12 weeks or more
–80% respond to one drug
• Therapeutic uses
– Depression
– Obsessive –compulsive disorder
– Anxiety disorders
• (Figure 10.3)
6/25/2023
1356/25/2023
136137gure 10.5) 6/25/2023 138139140141• Nefazodone and trazodone
– Weak inhibitors of serotonin reuptake
– Both agents are sedating (H1 block)
– Trazodone is commonly used off-label for the
management of insomnia
• TRICYCLIC ANTIDEPRESSANTS
– Block NE and 5-HT reuptake
– Tertiary amines:
• Imipramine, amitriptyline
– Secondary amines:
• Desipramine and nortriptyline
6/25/2023
142echanism of action – Inhibition of neurotransmitter reuptake – Maprotiline and desipramine are: • relatively selective inhibitors of NE reuptake
– Block α-, M, H1 receptors – Onset: 2 weeks or longer
• Therapeutic uses – Moderate to severe depression – Bed -wetting in children older than 6 years: – For Migraine headache and treat chronic pain syndromes (for example, neuropathic pain)
6/25/2023 1436/25/2023
144– Life -threatening arrhythmias in overdose – Block α-receptors – H1 block
• Narrow TI: – 5 – 6 Xs dose of imipramine can be lethal
• Drug interactions with the TCAs: – Figure 10.8.
6/25/2023 14523 146the gut and liver
• Include: – Phenelzine, tranylcypromine,
• Use of MAOIs is limited due to the complicated dietary restrictions
• Mechanism of action: (Figure 10.9) 6/25/2023
1476/25/2023
148– High incidence of drug–drug and drug–food interactions
• Therapeutic uses – Last - line agents in many treatment settings – For unresponive or allergic to TCAs and SSRIs
• Adverse effects – Tyramine: aged cheeses and meats
6/25/2023 149– Hypertensive crisis:
• Occipital headache, stiff neck, tachycardia,
nausea, hypertension, cardiac arrhythmias,
seizures, and, possibly, stroke
– SE of MAOIs :
• Drowsiness, orthostatic hypotension, blurred
vision, dry mouth, and constipation
======================
6/25/2023
150Antipsychotic Drugs 6/25/2023 151Schizophrenia
25.6.2023
1526/25/2023
153SCHIZOPHRENIA – About 1% of the population – Has a strong genetic component – Mesolimbic or mesocortical DA dysfunction
• ANTIPSYCHOTIC DRUGS – First - and second-generation – First –generation antipsychotics: • Chlorpromazine, haloperidol: –D2 receptor antagonist – EPS
• (Figure 11.2). 6/25/2023
1556/25/2023
156Figure 13.3 Relative
affinity of
clozapine,
chlorpromazine,
and haloperidol at
D1- and D2-
dopaminergic
receptors.
25.6.2023
157• Second-generation antipsychotic drugs
– Atypical antipsychotics
– Most of second: inhibition of 5-HT
– Lower incidence of EPS
– E.g. Risperidone
– Many of 1st gen:
• block M, NA, and H1 recepors
• (Figure 11.4).
–
6/25/2023
1586/25/2023
159• All antipsychotics – reduce “positive” symptoms: • hallucinations and delusions:
• Many SGA: – Ameliorate the negative symptoms: • blunted affect, apathy (careless) • impaired attention, cognitive impairment
6/25/2023 160• Neuroleptic is an antipsychotic drug that
causes (Extrapyramidal symptoms: EPS) in
human and catalepsy in rodents
25.6.2023
162• Extrapyramidal effects: EPS
– Blockade of DA receptors in the nigrostriatal
pathway
– Dystonias - Tardive dyskinesia
• For EPS : Use benztropine
• Therapeutic uses
– Treatment of schizophrenia
– First -generation:
• positive symptoms
– Atypical antipsychotics: 5-HT2A :
• negative symptoms
6/25/2023
163– Prevention of nausea and vomiting:
• Most commonly, prochlorperazine
– Quetiapine: for bipolar and refractory depression
• Long -acting injectable (LAI) formulations:
– Up to 2 to 4 weeks: for non-adherent pts:
6/25/2023
1646/25/2023
165• Maintenance treatment: – Two or more psychotic episodes: • Maintenance therapy for at least 5 years
– Rate of relapse may be lower with SGAs ==============================
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