Presented by Abdulaziz .M. Al-Saad Parkinson's disease CNS drugs act on brain and spinal cord in medical use (treatment of mental illness, suppression of seizures, relief of pain, and production of anesthesia) and nonmedical uses ( stimulants, depressants, euphoriants, and other mind altering uses. Presented by Abdulaziz .M. Al-Saad

Contents Definition & Pathophysiology . Static & Facts . Causes & Stages . Strategy of treatment . Drug therapy . Surgical approach . The future .

What is Parkinson's disease ? Parkinson’s disease is a disorder of the extrapyramidal system . Characterized by… It is progressive disease ?? Imbalance between the excitatory neurotransmitter Acetylcholine and inhibitory neurotransmitter Dopamine in the Basal Ganglia : DA ACh

Nonmotor symptoms Cognitive impairment, dementia** Psychiatric symptoms, particularly depression** Autonomic disturbances** Urinary urgency and frequency Constipation Hypotension with orthostasis Sweating disorders Sexual dysfunction Sleep disturbances**

Static and Facts Age at onset variable ( 50 – 80 years ) . Mean age 55 years Man and Woman are equally affected. Prevalence 100 case Per 100 000 Population . Incidence 20 case Per 100 000 People annually.

Static and Facts Progression highly variable. Within 10 – 20 years. Patient age at onset affect progression . ( high rate in older ) Mortality not caused by disease itself , but, due to complications related to immobility . Complication such as ( Aspiration Pneumonia , cardiovascular and cerebrovascular disease (

Causes : Drug induce PD : What is MPTP ? Idiopathic due to exposure to : Neurotoxins. Oxidative reactions. Genetic factors may be important. Others : Dopaminergic receptor antagonist ( Antipsychotic ) . Destruction of dopaminergic neurons ( MPTP ) . Drug induce PD : Reserpine ------------ depletion of dopamine storage. Halloperidole, phenothiazin , MPTP. What is MPTP ?

Stages of PD Stage 1 : Unilateral involvement Minimal or no functional impairment. Stage 2 : Bilateral involvement Without impairment of balance Stage 3 : Postural imbalance Some restriction of activity Mild – Moderate disability Stage 4 : Severely disable Cannot walk and stand Stage 5 : Restricted to the bed

Treatment of Parkinson’s Disease

Classification of Drug Therapy for Parkinson’s Disease Two major categories Dopaminergic agents : Promote activation of dopamine receptors Levodopa (Dopar) Anticholinergic agents : Prevent activation of cholinergic receptors Benztropine (Cogentin)

Blockade of muscarinic cholinergic receptors in the striatum Dopaminergic Agents Mechanism of Action Promotion of dopamine synthesis Prevention of dopamine degradation Promotion of dopamine release Direct activation of dopamine receptors Anticholinergic Agents Mechanism of action Blockade of muscarinic cholinergic receptors in the striatum

Levo- dopa Side Effects Immediate metabolic precursor of dopamine Dopamine not cross BBB. Levodopa cross BBB. After it cross BBB, decarboxylated to dopamine. Peripheral decarboxylation can be prevented by : Carbidopa This leads to decrease dose by 75 % Dose Sinemet ( 25 mg / 100 mg ) OR ( 25/ 250 ) OR Controlled release. Side Effects GIT . Cardiac abnormalities . CNS . Eye. Behavior changes. Fluctuations ------ Drug Holiday Wearing off ------- Treatment

Ergot Derivative Contraindications : Drug Interactions Psychotic Patients . Cardiac disease . Glaucoma . Peptic ulcer . Drug Interactions Pyridoxine ( Vit. B6 ) --------- Increase Periphral decarboxylations. MAOIs type A ----------------- Hypertensive crisis. Ergot Derivative 1- Bromocriptin : D2 agonist , widely used in PD. 2- Pergolide : - D1, D2 agonist , widely used in PD .

SE: ( fatiguge , insomnia , dyskinisia , confusion ) Non-Ergot Derivative Advantage : 1- Newer Agents 2- Effective against PD. 3- Approved by FDA. 4- Lower SE Than old group. 1- Ramipexole : D3 receptor Effective as monotherapy in mild cases Adjunctive + LD --------- decrease dose and fluctuation with LD. 2- Roprinil : D2 receptor SE: ( fatiguge , insomnia , dyskinisia , confusion )

Mechanism of action ( Selegiline) : Selective inhibitor of Monoamine Oxidase type B . ( what do you think about non-selective ? ) . Too much- anxiety, panic anorexia, excitability, insomnia Too Little- Depression, ADD/ADHD 2. Too much- Psychoses, Tourettes/Tics, chorea Too little- Parkinson’s ADD/ADHD, depression 3. Too much-delirium, confusion, psychoses Too little-Alzheimers 4. Too much- Sleep, Hallucinations,Decreased appetite, anxiety Too little- Depression, OCD, pain sensitivity 5. Too much- CNS depression, Resp. depression, Sedation Too little- Seizures, Movement disorders Too much- Seizures, neuronal degeneration Too little-schizophrenia, depression, cognitive impairment MAO B L -dopa Dopamine Reuptake COMT

Advantages of Selegiline : Enhance and prolongs the anti-parkinsonism effect of Levo – dopa . Reduce the dose of Levo – dopa . Dose : ( 5 mg at break fast ) ( 5 mg at lunch ) SE : increase insomnia with LD. Not used with TCAs. L - dopa The blood brain barrier- impedes entry of drugs into the brain, limited to lipid soluble agents or drugs by specific transport systems in an intact barrier, this is positive (protection from toxic substances), and negative (obstacle to therapeutics) not fully developed at birth. 70 % 29 % GIT 1 – 3 % Prephral tissues Brain

Effect of adding selegiline to levodopa in early, mild Parkinson’s disease 4 Evidence is insufficient to show that combined treatment increases mortality . Proportions of deaths and overall mortality in 11 clinical studies of treatment of Parkinson’s disease with selegiline : Study Selegiline No selegiline Olanow et al 1998 14/297 17/292 Caraceni et al 1997 25/155 25/156 Di Rocco et al 1996 30/109 40/67 Rinne et al1-151 3/30 10/30 Parkinson’s Study Group 1998 70/399 67/401 Birkmayer et al 1985 118/564 114/377 Ben-Shlomo et al 1998 103/271 73/249 Total 363/1825 (19.9%) 346/1572 (22%)

Catichol-O-Methyltransferase Inhibitor ( COMT ) 1- Tolcapone & entacapone Prolong duration of action of LD. SE : Similar to LD . 2- Amantadine Antiviral agents. Potentiate action of DA by increase synthesis ,release and decrease reuptake. Therapeutic effect short – lived. SE : Restlessnes, agitation, depression , irritability ( CNS se ) Is a degenerative disorder of the CNS caused by death of neurons that produce the brain neurotransmitter dopamine. It is the most common degenerative disease of the nerves. sym

Experimental approach to treat PD Acetyl choline- blocking agents : Antimuscarinc Agents: Bnzotropine , biperiden, orphenadrin. Effective against PD . SE : Drowsiness, hallucination , restlessness, depression Other : dry mouth , Mydriasis, urinary retention . Experimental approach to treat PD Vitamin E: Free radical scavenger. Neurotropfic factor e.g. Glial –derived neurotropfic factor Explanation of symptoms- A disruption of neurotransmission within the striatum (proper function requires balance between dopamine and acetylcholine.

Surgical Procedure : Used in poorly responsive PD patients to pharmacotherapy .. High Frequency Deep Brain Stimulation ( Thalamic Stimulation ). Transplantation of Dopaminergic tissue

Conclusion Patients with Parkinson's disease have a constellation of clinical symptoms that evolve over the course of the condition. Patient management involves the accurate clinical diagnosis of the disease, multidisciplinary management of clinical problems and the use of a number of therapeutic options. Until disease-modifying drugs become available, we must focus on reducing the burden of Parkinson's disease by treating the symptoms and helping our patients cope with their disability by improving their quality of life.

The end Treatment strategy- Restore balance between DA and ACH by activating DA receptors or blocking ACH receptors.

Pain Management in Patients with CA CNS Pharmacology

Pain Management Pain Unpleasant sensory and emotional experience associated with tissue damage Patient’s pain description is the cornerstone of pain assessment

Types of Pain Nociceptive pain Results from injury to tissues Called somatic or visceral pain Neuropathic pain Results from injury to peripheral nerves Responds poorly to opiods

Clinical Approach to Pain Management A- Ask and assess B- Believe C- Choose D- Deliver E- Empower and enable

Pain Assessment Assessment parameters of pain Onset and temporal patterns Location Quality Intensity Modulating Factors Previous treatment Impact

WHO Analgesic Ladder Step 1- Mild to moderate pain Nonopiod analgesic Step 2- More severe pain Add opioid analgesic Step 3- Severe pain Substitute opioid-morphine