drugs affecting the cns psychopharmacology by pharmacologist l mweetwa

L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY

Drugs Affecting the CNS

CNS Pharmacology

L.Mweetwa-Pharmacologist

University of Zambia Dept of Pharmacy

Faculty of Medicine


Credits and Thanks/Disclaimer!!!

First and Foremost May i say thank you to Many contributors on this subject here on slide share, whose part of work i have used.

Thank You All, Other slides available on request are:- Anti-infective Drugs Cardiovascular Drugs Autonomic Nervous System Drugs Antineoplastic Drugs etc


Physiology of synapse, neuromuscular junction and

neurotransmitters INTRODUCTION TO

PSYCHOPHARMACOLOGY

L.Mweetwa-PharmacologistUniversity of Zambia Dept of PharmacyFaculty of Medicine


What is a synapse?

A gap between two neurons

Mostly chemical

Rarely electricalMostly present in lower animals Gap junctions

Synapses could be Axo-dendriticAxo-somaticAxo-axonic


Many different types


Basic structure

Presynaptic membrane Contains neurotransmitter

vesicles

Synaptic cleft

Postsynaptic membrane Contains receptors for the

neurotransmitter


Synaptic transmission¨ Action potential passes from the

presynaptic neuron to the postsynaptic neuron

¨ Although an axon conducts both ways, conduction through synapse is one way

¨ A neuron receives more than 10000 synapses

¨ Postsynaptic activity is an integrated function


Neurotransmitters Chemicals that facilitate signal transmission across a

synapse

Neurotransmitters are released on the presynaptic side and bind to receptors on the postsynaptic side

Earliest neurotransmitter discovered was acetylcholine

There are different chemical types Amines

▪ Norepinephrine, Epinephrine, dopamine, serotonin (5HT), histamine Amino acids

▪ GABA, Glycine, Glutamate, Aspartate Peptides

▪ Beta endorphin, enkephalins, dynorphin Others

▪ Acetylcholine, nitric oxide


Neurotransmitter release

“At rest”, the synapse contains numerous synaptic vesicles filled with neurotransmitter

Intracellular calcium levels are very low

Arrival of an action potential causes opening of voltage-gated calcium channels

Calcium enters the synapse

Calcium triggers exocytosis and release of neurotransmitter

Vesicles are recycled by endocytosis


Ca2+ Ca2+


Neurotransmitter receptors

Once released, the neurotransmitter molecules diffuse across the synaptic cleft

When they “arrive” at the postsynaptic membrane, they bind to neurotransmitter receptors

Two main classes of receptors: Ligand-gated ion channels

transmitter molecules bind on the outside, cause the channel to open and become permeable to either sodium, potassium or chloride

G-protein-coupled receptors G-protein-coupled receptors have slower, longer-lasting and diverse postsynaptic

effects. They can have effects that change an entire cell’s metabolism or an enzyme that activates an internal metabolic change inside the cell activate cAMP activate cellular genes: forms more receptor proteins activate protein kinase: decrease the number of proteins


Excitation

Excitation 1. Na+ influx cause accumulation of

positive charges causing excitation

2. Decreased K+ efflux or Cl- influx

3. Various internal changes to excite cell, increase in excitatory receptors, decrease in inhibitory receptors.


Inhibition

Inhibition

1. Efflux of K+

2. Influx of Cl-

3. activation of receptor enzymes to inhibit metabolic functions or to increase inhibitory receptors or decrease excitatory receptors


EPSP/ IPSP

Excitatory effects of neurotransmitters EPSP: excitatory post synaptic potential

Inhibitory effects of neurotransmitters IPSP: inhibitory post synaptic potential


Postsynaptic activity

Synaptic integration On average, each neuron in the brain receives about

10,000 synaptic connections from other neurons

Many (but probably not all) of these connections may be active at any given time

Each neuron produces only one output

One single input is usually not sufficient to trigger this output

The neuron must integrate a large number of synaptic inputs and “decide” whether to produce an output or not


Neurotransmitters


Acetylcholine (Ach)

First neurotransmitter discovered in 1921 secreted by motor neurons, autonomic nerves, large

pyramidal cells of the motor cortex, basal ganglia (caudate & putamen), hippocampus.

It is generally excitatory receptors

▪ nicotinic (autonomic ganglia, NMJ) - Na influx▪ muscarinic (parasympathetc terminal)

sub types: M1(brain), M2, M3, M4, M5 second messenger cAMP

Common Ach blockers: plant poison (curare), botulinum toxin (food poison)

Loss of Ach neurons in Alzheimer’s patients


Norepinephrine

present in the autonomic nerves, brain stem, hypothalamus, locus ceruleus of the pons

Mostly it causes excitation but sometimes inhibition also happens

Increases BP and HRcontrol the overall activity of the brain and the mood

receptors 1, 2, 1, 2, 3

second messenger: cAMP


Dopamine present in the cerebral cortex, hypothalamus secreted by neurons in the basal ganglia Mainly inhibitory Involved in the reward mechanisms in the brain Drugs like cocaine, opium, heroin, and alcohol

increase the levels of dopamine receptors:

D1, D2, D3, D4, D5 second messenger: cAMP

Increased levels associates with schizophrenia, low levels are associated with Parkinsonism


GABA

Present in the basal ganglia Also present in the spinal cord,

cerebellum & many other areas of the Cortex

Major inhibitory neurotransmitter of the brain occurring in 30-40% of all synapses

receptors▪ GABAA increase Cl- influx

▪ GABAB act via G proteins, increase K+ influx

Low GABA levels are associated with anxiety and epilepsy


Glycine

Present in the synapses of the spinal cord, interneurons

also present in the retina Inhibitory (increase Cl influx) by its action on NMDA receptors it is

excitatory


Glutamate & Aspartate

Excitatory amino acids glutamate is present in presynaptic terminals in the sensory

pathways and other cortical areas Involved in the stretch reflex present in basal ganglia Main excitatory neurotransmitter in brain & spinal cord aspartate is present in cortical pyramidal cells & visual cortex receptors: metabotropic receptors, kainate, AMPA, NMDA NMDA receptors are present in hippocampus, involved in

memory & learning

Increased levels are associated with certain neurological diseases


Serotonin

secreted by the nuclei originating in the median raphe of the brain stem and terminate in dorsal horn of the spinal cord and hypothalamus

Inhibitory Control the mood of the person and

important in sleep also present in GIT, platelets & limbic

system receptors: 1A, 1B, 1D, 2A, 2C, 3, 4

Low levels are associated with depression and other psychiatric disorders. May be involved in migraine


Histamine

histamine: present in pathways from hypothalamus to

cortical areas & spinal cord receptors: H1, H2, H3 (all present in brain) functions related to arousal, sexual behaviour,

drinking, pain

Substance P found in primary nerve ending in the spinal

cord mediator of pain in the spinal cord


NEUROPEPTIDES

synthesized by ribosomes in the cell body

ER and Golgi apparatus enzymatically split the large molecule into smaller precursor or active molecules

Golgi apparatus makes vesicles

these vesicles are transported through the axoplasm slowly

remain in the terminal

release by a process similar to the other neurotransmitter


NEUROPEPTIDES

however vesicle is autolysed and not reused

quantity of neuropeptides released is smaller than that of other neurotransmitters

but the neuropeptides are thousand times more potent

they also cause much more prolonged action

generally only one type of small molecule neurotransmitter is released by a neuron

several neuropeptides could be released


NEUROPEPTIDES

Removal of neurotransmitter:by diffusion into the surrounding fluidsenzymatic destruction (Ach)active transport re-uptake into the presynaptic terminal

Actions prolonged closure of Ca pores prolonged changes in cell metabolism deactivation of specific genes prolonged changes in excitatory or inhibitory

receptors


OPIOID PEPTIDES

Endorphin present in pituitary, earliest discovered opioid peptide

enkephalins: met-enkephalin, leu-enkephalin present at substantia gelatinosa in the spinal cord & brain

stem reticular nuclei widely distributed

dynorphin recently discovered

opioid peptides are involved in the descending pain inhibitory pathway

receptors: , ,

Other peptides present in the CNS

Substance P ACTH Oxytocin Glucagon Somatostatin VIP Prolactin LH TRH Releasing hormones,

– GH– Gastrin– CCK– Neurotensin– Insulin– Angiotesin II– Bradykinin– Calcitonin gene

related peptide (CGRP)

– Neuropeptide YL Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY


Nitrous oxide (NO)

nitrous oxide (NO) present in brain probably involved in memory


Neuromodulators

Neurotransmitters transmit an impulse from one neuron to another

Neuromodulator modulate regions or circuits of the brain

They affect a group of neurons, causing a modulation of that group

Neuromodulators alter neuronal activity by amplifying or dampening synaptic activityeg. dopamine, serotonin, acetylcholine,

histamine, glutamate


Neuromuscular junction

This is a modified synapse

Consists of Presynaptic

membrane (nerve terminal)

Synaptic cleft Postsynaptic

membrane (motor end plate)


Presynaptic terminal (terminal knob, boutons, end-feet or synaptic knobs)

¨ Terminal has synaptic vesicles and mitochondria

¨ Mitochondria (ATP) are present inside the presynaptic terminal

Vesicles containing neurotransmitter (Ach)


Presynaptic terminal (terminal knob, boutons, end-feet or synaptic knobs)

¨ Presynaptic membrane contain voltage-gated Ca channels

¨ The quantity of neurotransmitter released is proportional to the number of Ca entering the terminal

¨ Ca ions binds to the protein molecules on the inner surface of the synaptic membrane called release sites

¨ Neurotransmitter binds to these sites and exocytosis occur


Ca2+ Ca2+


Postsynaptic membrane (motor end plate)

Postsynaptic membrane contain receptors for the neurotransmitter released

eg: Acetylcholine receptor

AchNa+

•This receptor is Ach-gated Na+ channel•When Ach binds to this, Na+ channel opens up•Na+ influx occurs


Na+ influx

Na+ influx causes depolarisation of the membrane End Plate Potential (EPP)

▪ This is a graded potential▪ Once this reaches the threshold level▪ AP is generated at the postsynaptic

membrane


Ach release

An average human end plate contains 15-40 million Ach receptors

Each nerve impulse release 60 Ach vesicles

Each vesicle contains about 10,000 molecules of Ach

Ach is released in quanta (small packets)


End plate potential

Even at rest small quanta are released

Which creates a minute depolarising spike called Miniature End Plate Potential (MEPP)

When an impulse arrives at the NMJ quanta released are increased in several times causing EPP


Acetylcholinerase (AchE)

After the Ach binding is over

Cholinesterase present in the synaptic cleft will hydrolyse Ach into choline and acetate

Choline is reuptaken to the presynaptic terminal

AchE is also found in RBC membranes


Axoplasmic transport

A cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, through the axoplasm

anterograde transport movement toward the synapse is called

retrograde transport Movement toward the cell body


Smooth muscles

NMJ not well developed

Smooth muscle does not depend on motor neurons to be stimulated

However, motor neurons (of the autonomic system) reach smooth muscle and can stimulate it — or relax it — depending on the neurotransmitter they release (e.g. noradrenaline or nitric oxide, NO))

Smooth muscle can also be made to contract by other substances released in the vicinity (paracrine stimulation)

Example: release of histamine causes contraction of the smooth muscle lining our air passages (triggering an attack of asthma)

by hormones circulating in the blood Example: oxytocin reaching the uterus stimulates it to contract to begin

childbirth.

The contraction of smooth muscle tends to be slower than that of striated muscle

It also is often sustained for long periods

L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY

FACULTY

1. Treatment of Parkinson Disease



CNS Pharmacology



Faculty of Medicine


Parkinson’s disease

Parkinsonism is a progressive degenerative, extrapyramidal disorder of muscle movement, due to dysfunction in basal ganglia, comprising four cardinal features:- Bradykinesia or hypokinesia. Muscle rigidity. Resting tremor. Impairment of postural balance leading to

disturbances of gait, and falling. The secondary manifestations are mask-like face, siallorrhoea, difficulty in speech, slowing of mental process and dementia.


Bradykinesia:

It is slowness in initiating and carrying out voluntary movements. It is called poverty and suppression of voluntary movements. It is caused partly by muscle rigidity and partly by inertia of the motor system, which means that motor activity is difficult to stop as well as to initiate. It is hard to start walking, and once in progress, the patient can not stop quickly.


Muscle rigidity:

Rigidity is due to increased muscle tone. The rigidity affects the opposing muscles equally, flexors and extensors. Rigidity is detectable as an increased resistance in passive limb movement.


Tremors:

Tremors are defined as rhythmic oscillatory movements caused by the opposing muscles around a joint. Tremors of Parkinsonism are slow. Hand tremors involve all the fingers and thumb (pill rolling tremor) which tend to diminish during voluntary activity. The “resting tremors” are present at rest and disappear (abate) during voluntary movements.


Dyskinesia: Abnormal involuntary movements

Chorea: It consists of irregular, unpredictable, involuntary muscle jerks that occur in different parts of the body and impaired voluntary activity.

Athetosis: Abnormal movements are slow and writhing in character

Dystonia: The abnormal movements are slow in character and are sustained so that they are regarded as abnormal postures

Tics: They are coordinated abnormal movements that tend to occur repetitively particularly about the face and head, especially in children


Etiology

The degeneration of neurons occurs in substantia nigra pars compacta and the nigrostriatal tract that are dopaminergic and inhibit the activity of striatal GABA ergic neurons. This results in deficiency of dopamine in striatum which controls muscle tone and coordinates movements. Nerve fibers from cerebral cortex and thalamus secrete acetylcholine in the neostriatum causing excitatory effects that initiate and regulate gross intentional movements of the body. In Parkinson’s disease, due to deficiency of dopamine in striatum, an imbalance between dopaminergic (inhibitory) and cholinergic (excitatory) system occurs, leading to excessive excitatory actions of cholinergic neurons on striatal GABA ergic neurons.


Etiology cont…d

Substantia Nigra: The substantia nigra pars compacta is the source

dopaminergic neurons that travel through nigrostriatal tract to terminate in the striatum. These dopaminergic neurons from the substantia nigra fire tonically, to produce a sustained influence on motor activity.

Striatum: The striatum is connected to the substantia nigra par

reticulata by neurons that secrete the inhibitory transmitter GABA at their endings in the substantia nigra. In turn, cells of the substantia nigra send neurons back to the striatum, secreting the inhibitory transmitter dopamine at their endings. Nerve fibers from the cerebral cortex and thalamus secrete Acetylcholine in the neostriatum causing excitatory effects.


Strategy of Treatment

In Parkinson’s disease dopaminergic inhibitory activity is reduced and cholinergic excitatory activity is increased. Therefore, therapy is aimed at restoring dopamine in the basal ganglia and antagonizing the excitatory effects of cholinergic neurons.


Drugs used for Parkinsonian Disease:

Drug therapy is aimed at restoring the balance between the dopaminergic and cholinergic components, which is achieved by: Increasing the central dopaminergic

activityOR

Decreasing the central cholinergic activity

OR BOTH.


Types of Parkison’s Diaease

Idiopathic Parkinson's disease Idiopathic Parkinson's disease - or Parkinson's - is

the most common type of parkinsonism. Unlike some other forms which have specific causes it is not known why idiopathic Parkinson's occurs.

The main symptoms of idiopatic Parkinson's are tremor, rigidity and slowness of movement.

Symptoms and the rate at which the condition progresses vary from person to person. This can make diagnosis difficult.


Vascular Parkinsonism:

Vascular parkinsonism is one of the atypical forms of parkinsonism.

The most likely causes of vascular parkinsonism are hypertension and diabetes. A stroke (cerebrovascular accident), cardiac disease or carotid artery pathology (another form of stroke) may also be involved.

Symptoms of vascular parkinsonism may include difficulty speaking, making facial expressions or swallowing.

Other signs can include problems with memory or confused thought, cognitive problems and incontinence.


Drug Induced Parkinsonism

A small number (around 7%) of people diagnosed with parkinsonism have developed their symptoms following treatment with particular medications.

Drugs - known as neuroleptic drugs - used to treat schizophrenia and other psychotic disorders block dopamine. These drugs are thought to be the biggest cause of drug-induced parkinsonism.

Dopamine is a chemical in the brain which allows messages to be sent to the parts of the brain that co-ordinate movement.

The symptoms of Parkinson's appear when the level of dopamine falls.

The symptoms of drug-induced parkinsonism tend to be static. Only in rare cases do they change in the manner that the symptoms of Parkinson's do.

Most people will recover within months, and often within hours or days, of stopping the drug that caused the dopamine block.


Dementia with Lewy bodies:

Dementia with Lewy bodies is similar, in some ways, to Parkinson's and Alzheimer's.

Symptoms differ slightly from Parkinson's and include problems with memory and concentration, attention, language and the ability to carry out simple actions.

People who have dementia with Lewy bodies commonly experience visual hallucinations and some Parkinson's-type symptoms, such as slowness of movement, stiffness and tremor.

Dementia with Lewy bodies is also a progressive condition, which means that the symptoms can become worse over time. Currently, there is no cure or treatment for the condition.


Inherited Parkinson's There is no conclusive evidence that Parkinson's

is a hereditary condition that can be passed on within families, apart from in exceptionally rare cases.

It is thought that although it is not directly inherited, some people may have genes that increase the possibility of developing Parkinson's.

People who have genes that are prone to Parkinson's may be more likely to develop the condition when combined with other factors, such as environmental toxins or viruses.

At present, it is estimated that up to 5% of people with Parkinson's may have a genetic cause.

The role genetics may play in the development of Parkinson's is currently the subject of much research.


Juvenile Parkinson's:

Juvenile Parkinson's is a term used when the condition affects people under the age of 20.


Causes of parkinsonism:

1) Idiopathic PD: - Due to loss of dopaminergic neurons of

the substantia nigra- Progressive loss of dopamine-containing neurons is a feature of normal aging; however, most people do not lose the 70% to 80% of dopaminergic neurons required to cause symptomatic PD- Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism

2) Secondary PD: e.g., following stroke, and intoxication with

dopamine-receptor antagonists as antipsychotics and antiemetics.


Treatment of parkinsonism

Aim of treatment is to enhance dopaminergic pathway or inhibit cholinergic pathway in the brain


ATI-PARKINSONIAN DRUGS

-Amantadine -Antimuscarinic agents e.g

benztropine,biperiden,trihexyphenidyl Bromocriptine Carbidopa Deprenyl (selegilline) Levodopa Pramipexole Ropinirole Tolcapone


Drugs used in the treatment of parkinsonism 1- Levodopa (1)

Levodopa is (the most effective drug used in the treatment of parkinsonism) Chemistry:• It is the metabolic precursor of dopamineMechanism of action:• In the brain, levodopa is converted to dopamine by decarboxylation

primarily within the presynaptic terminals of dopaminergic neurons in the stratium (by action of L-aromatic amino acid decarboxylase). The dopamine produced is responsible for the therapeutic effectiveness of the drug in PD; after release, it is either transported back into dopaminergic terminals by the presynaptic uptake mechanism or metabolized by the actions of MAO and catechol-O-methyltransferase (COMT) .



If levodopa is administered alone, the drug is largely decarboxylated by enzymes in the peripheral sites so that little unchanged drug reaches the cerebral circulation.

In addition, dopamine release into the circulation by peripheral conversion of levodopa produces undesirable effects,



• In practice, levodopa is administered in combination with a peripherally acting inhibitor of aromatic L-amino acid decarboxylase, such as carbidopa, that do not penetrate into the CNS.

• Inhibition of peripheral decarboxylase markedly increases the fraction of administered levodopa that crosses the blood-brain barrier and reduces the incidence of peripheral side effects.

• The most commonly prescribed form of carbidopa/levodopa is the 25/100 form, containing 25 mg carbidopa and 100 mg levodopa.



Adverse effects:A) Central:

1) long-term therapy leads to "wearing off" phenomenon: each dose of levodopa improves mobility for 1 to 2 hours, but rigidity and akinesia return at the end of the dosing interval. Increasing the dose and frequency of administration can improve this situation, but this often is limited by the development of dyskinesias (excessive and abnormal involuntary movements). Patients may fluctuate between being "off," having no beneficial effects from their medications, and being "on" but with dyskinesias, a situation called the on/off phenomenon.



2) Mental effects Depression, anxiety, agitation, insomnia, delusions, hallucinations, euphoria

3) Dyskinesias (excessive and abnormal involuntary movements) as chorea and tremor



B. Peripheral: Due to formation of dopamine peripherally1. The most common peripheral side effects are anorexia,

nausea, and vomiting (likely due to dopamine’s stimulation of the chemoreceptor trigger zone in the medulla oblongata).

2. Cardiovascular side effects in the form of orthostatic hypotension and cardiac arrhythmias

Abrupt withdrawal of levodopa may precipitate the neuroleptic malignant syndrome.



Drug Interactions:1. Pharmacologic doses of pyridoxine (vitamin B6)

enhance the extracerebral metabolism of levodopa and prevent its therapeutic effect unless a peripheral decarboxylase inhibitor is also taken.

2. Levodopa should not be given to patients taking monoamine oxidase A inhibitors or within 2 weeks of their discontinuance, because such a combination can lead to hypertensive crises.



Contraindications1. Psychotic patients2. Angle-closure glaucoma 3. Cardiac disease4. Peptic ulcer 5. Melanoma


Drugs used in the treatment of parkinsonism 2- Dopamine receptor agonists (1)

• Four orally administered dopamine-receptor agonists are available for treatment of PD:

1) Ergot derivatives: as bromocriptine or pergolide


Mechanism of action

Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D1 and D5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D2, D3 and D4 subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D2 and D3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D2-receptors. It also exhibits agonist activity (in order of decreasing binding affinity) on 5-hydroxytryptamine (5-HT)1D, dopamine D3, 5-HT1A, 5-HT2A, 5-HT1B, and 5-HT2Creceptors, antagonist activity on α2A-adrenergic, α2C, α2B, and dopamine D1 receptors, partial agonist activity at receptor 5-HT2B, and inactivates dopamine D4 and 5-HT7 receptors.


Mode of Action Summary

The dopamine D2 receptor is a 7-transmembrane G-protein coupled receptor associated with Gi proteins. In lactotrophs, stimulation of dopamine D2 receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca2+ from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D2receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders.


Non ergot derivatives

E.g ropinirole Mechanism of actionRopinirole binds the dopamine receptors D3 and D2.

Although the precise mechanism of action of ropinirole as a treatment for Parkinson's disease is unknown, it is believed to be related to its ability to stimulate these receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that ropinirole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum.



Adverse effects:I. Central:• Dyskinesias , mental Disturbances

II. Peripheral:A) Gastrointestinal Effects:• Anorexia and nausea and vomitingB) Cardiovascular effects:

1. postural hypotension2. cardiac arrhythmias 3. peripheral vasospasm (with ergot derivatives)



Contraindications1. Psychotic patients2. Angle-closure glaucoma 3. Cardiac disease4. Peptic ulcer 5. Peripheral vascular disease (ergot

derivatives).


Drugs used in the treatment of parkinsonism 3- Monoamine oxidase inhibitors (1)

Two types of monoamine oxidase (MAO) have been distinguished. Monoamine oxidase (A) metabolizes norepinephrine and serotonin; monoamine oxidase (B) metabolizes dopamine.

Selegiline:Mechanism of action:• It is therefore used as adjunctive therapy for patients with a declining response to levodopa. Although the mechanisms for selegiline's beneficial action in the treatment of

Parkinson's disease are not fully understood, the selective, irreversible inhibition of monoamine oxidase type B (MAO-B) is thought to be of primary importance. MAO-B is involved in the oxidative deamination of dopamine in the brain. Selegiline binds to MAO-B within the nigrostriatal pathways in the central nervous system, thus blocking microsomal metabolism of dopamine and enhancing the dopaminergic activity in the substantial nigra. Selegiline may also increase dopaminergic activity through mechanisms other than inhibition of MAO-B. At higher doses, selegiline can also inhibit monozmine oxidase type A (MAO-A), allowing it to be used for the treatment of depression.

Side effects:• May cause insomnia when taken later during the day. Drug interactions:• It should not be taken by patients receiving tricyclic antidepressants, or serotonin reuptake inhibitors

because of the risk of acute toxic interactions. • The adverse effects of levodopa may be increased by selegiline.


COMT inhibitors

Periphery CNS (striatum)

3-O-Methyldopa

L-DOPA

Dopamine

L-DOPA Dopamine

DOPAC

3-Methoxy tyramine

MAO-B

COMT

COMT

AAD

AAD

carbidopa x

tolcapone x

tolcapone x

selegiline x-


Drugs used in the treatment of parkinsonism 3- Catechol O methyl transferase inhibitors (1)

Tolcapone• Mechanism of action:

1. Inhibit catechol O methyl transferase (COMT) which is responsible for the conversion of dopa into methyl dopa. Elevated levels of methyldopa decreases the response to levodopa, because methyldopa competes with levodopa for an active carrier mechanism that governs its transport across the blood-brain barrier.

2. prolong the action of levodopa by diminishing its peripheral metabolism.

• These agents may be helpful in patients receiving levodopa to reduce dose and decrease fluctuations in response

• Side effects are similar to levodopa


Drugs used in the treatment of parkinsonism 4- Amantadine(1)

Amantadine, an antiviral agent. Its mode of action in parkinsonism is unclearClinical Use• Amantadine is less potent than levodopa and its effects disappear after only a few

weeks of treatment• Mechanism of Action The mechanism of its antiparkinsonic effect is not fully

understood, but it appears to be releasing dopamine from the nerve endings of the brain cells, together with stimulation of norepinephrine response. It also has NMDA receptor antagonistic effects. The antiviral mechanism seems to be unrelated

Adverse Effects1. Central nervous system effects 2. Peripheral edema3.Headache 4. Heart failure . 5.postural hypotension 6. urinary retention 7. gastrointestinal disturbances (eg, anorexia, nausea, constipation, and dry

mouth).

Contraindications• Amantadine should be used with caution in patients with a history of seizures or heart failure.


Drugs used in the treatment of parkinsonism 5.Antimuscarinic agents - Acetylcholine blocking

drugs(1)

Benztropine Mechanism of Action Benztropine is a selective M1 muscarinic acetylcholine

receptor antagonist. It is able to discriminate between the M1 (cortical or neuronal) and the peripheral muscarinic subtypes (cardiac and glandular). Benztropine partially blocks cholinergic activity in the CNS, which is responsible for the symptoms of Parkinson's disease. It is also thought to increase the availability of dopamine, a brain chemical that is critical in the initiation and smooth control of voluntary muscle movement.

Clinical Use Antimuscarinic drugs may improve the tremor and rigidity of

parkinsonism but have little effect on bradykinesia.


Adverse Effects 1) Central nervous system effects, including drowsiness,

restlessness, confusion, agitation, hallucinations, and mood changes. Dyskinesias occur in rare cases

2) Atropine – like actions: dryness of the mouth, blurring of vision, urinary retention, nausea and vomiting, constipation, tachycardia, palpitations, and cardiac arrhythmias.

withdrawal should be gradual in order to prevent acute exacerbation of parkinsonism.

Contraindications1. Prostatic hyperplasia, 2. Obstructive gastrointestinal disease (eg, paralytic ileus)3. Angle-closure glaucoma.


THANK You End



CNS Pharmacology2.Anxiolytic and Hypnotic Drugs



Faculty of Medicine


ANXIETY

Def: Anxiety is an unpleasant state of

tension, apprehension or uneasiness arising from unknown source. Anxiety is the most common mental disorder.


SEDATIVE-HYPNOTIC DRUGSSEDATIVE-HYPNOTIC DRUGS

SEDATION Reduction of anxiety Calming effectANXIOLYTIC Drug that reduces anxiety SedativeHYPNOSIS Induction of sleep


Manifestations of anxiety:

Verbal complaints. The patient says he/she is anxious, nervous, edgy.

Somatic and autonomic effects. The patient is restless and agitated, has tachycardia, increased sweating, weeping and often gastrointestinal disorders.

Social effects. Interference with normal productive activities.


Pathological Anxiety

Generalized anxiety disorder (GAD): People suffering from GAD have general symptoms of motor tension, autonomic hyperactivity, etc. for at least one month.

Phobic anxiety: Simple phobias. Agoraphobia, fear of animals, etc.Social phobias.

Panic disorders: Characterized by acute attacks of fear as compared to the chronic presentation of GAD.

Obsessive-compulsive behaviors: These patients show repetitive ideas (obsessions) and behaviors (compulsions).


Causes of Anxiety

1). Medical:

a) Respiratory

b) Endocrine

c) Cardiovascular

d) Metabolic

e) Neurologic.


Causes of Anxiety2). Drug-Induced:

Stimulants▪ Amphetamines, cocaine, TCAs, caffeine.

Sympathomimetics▪ Ephedrine, epinephrine, pseudoephedrine

phenylpropanolamine. Anticholinergics\Antihistaminergics

▪ Trihexyphenidyl, benztropine, meperidine diphenhydramine, oxybutinin.

Dopaminergics▪ Amantadine, bromocriptine, L-Dopa,

carbid/levodopa.


Causes of Anxiety

Miscellaneous:▪ Baclofen, cycloserine, hallucinogens,

indomethacin.

3). Drug Withdrawal:▪ BDZs, narcotics, BARBs, other

sedatives, alcohol.


Anxiolytics

Strategy for treatmentReduce anxiety without causing sedation.


Drug Classification


Sedative/Hypnotics

1) Benzodiazepines (BZDs):

Alprazolam, diazepam, oxacepam, triazolam

2) Barbiturates:

Pentobarbital, phenobarbital

3) Alcohols:

Ethanol, chloral hydrate, paraldehyde, trichloroethanol,

4) Imidazopyridine Derivatives:

Zolpidem

5) Pyrazolopyrimidine

Zaleplon


Sedative/Hypnotics6) Propanediol carbamates:

Meprobamate

7) PiperidinedionesGlutethimide

8) AzaspirodecanedioneBuspirone

9) -Blockers**Propranolol

10) 2-AR partial agonist**Clonidine


Sedative/Hypnotics

Others:11) Antyipsychotics **

Ziprasidone12) Antidepressants **

TCAs, SSRIs

13) Antihistaminic drugs **Dephenhydramine


Sedative/Hypnotics

The benzodiazepines are the most important sedative hypnotics.

Developed to avoid undesirable effects of barbiturates (abuse liability).


Mechanism of Action of Benzodiazepines

Benzodiazepines (BDZs) bind to the gamma sub-unit of the GABA-A receptor. Their binding causes an allosteric (structural) modification of the receptor that results in an increase in GABA A receptor activity. BDZs do not substitute for GABA, which bind at the alpha sub-unit, but increase the frequency of channel opening events which leads to an increase in chloride ion conductance and inhibition of the action potential


BDZ Mode of Action


BDZ Actions

BDZ have no antipsychotic activity nor any analgesic action and do not affect the autonomic nervous system.

Actions1. Reduction of anxiety: at low

dose they reduce anxiety by selectively inhibiting neuronal circuits in the limbic system of the brain


BDZ Actions

2. Sedative and Hypnotic action: All BDZ have sedative action and some produce hypnosis at higher doses.

3. Anticonvulsant action: Several BDZ have anticonvulsant action and used to treat epilepsy and seizure disorders.

4. Muscle relaxant: The benzodiazepines relax spasticity of skeletal muscle probably by increasing presynaptic inhibition in the spinal cord.


Therapeutic Uses

Pharmacokinetic variation and duration of action influence the choice of BDZ

1. Anxiety disorders associated with depression: longer acting drugs such diazepam are often preferred alprazolam is effective but may cause withdrawal reactions.

2. Muscular disorders: such as muscle strain, cerebral palsy diazepam is effective.


Therapeutic Uses

3. Seizures: Clonazepam is useful in chronic treatment of epilepsy, whereas diazepam is the drug of choice in terminating grand mal epileptic seizures and status epilepticus.

Chlordiazepoxide, Clorazepate, diazepam and oxazepam are useful in the acute treatment of alcohol withdrawal.


Therapeutic Uses

4. Sleep disorders: Not all BDZ have hypnotic action although all have sedative or calming action. Drugs of choice for sleep disorders include, long acting - flurazepam, intermediate acting – temazepam and short acting triazolam


Dependence

Psychological and Physical dependence BDZ can develop due to prolonged high dosage use over a prolonged period and abrupt discontinuation. Because of long half-lives of some BDZ, withdrawal symptoms may not occur until after a number of days.


SIDE EFFECTS

Drowsiness and Confusion Cognitive impairment Early morning insomnia Tolerance


Benzodiazepine Antagonist

Flumazenil Mechanism of actionFlumazenil, an imidazobenzodiazepine

derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man.


Pharmacokinetics of Benzodiazepines

· Although BDZs are highly protein bound (60-95%), few clinically significant interactions.*

· High lipid solubility high rate of entry into CNS rapid onset.

*The only exception is chloral hydrate



· Hepatic metabolism. Almost all BDZs undergo microsomal oxidation (N-dealkylation and aliphatic hydroxylation) and conjugation (to glucoronides).

· Rapid tissue redistribution long acting long half lives and elimination half lives (from 10 to > 100 hrs).

· All BDZs cross the placenta detectable in breast milk may exert depressant effects on the CNS of the lactating infant.



· Many have active metabolites with half-lives greater than the parent drug.

· Prototype drug is diazepam (Valium), which has active metabolites (desmethyl-diazepam and oxazepam) and is long acting (t½ = 20-80 hr).

· Differing times of onset and elimination half-lives (long half-life => daytime sedation).


Biotransformation of Benzodiazepines

From Katzung, 1998


Biotransformation of Benzodiazepines

Keep in mind that with formation of active metabolites, the kinetics of the parent drug may not reflect the time course of the pharmacological effect.

Estazolam, oxazepam, and lorazepam, which are directly metabolized to glucoronides have the least residual (drowsiness) effects.

All of these drugs and their metabolites are excreted in urine.


Properties of Benzodiazepines

BDZs have a wide margin of safety if used for short periods. Prolonged use may cause dependence.

BDZs have little effect on respiratory or cardiovascular function compared to BARBS and other sedative-hypnotics.

BDZs depress the turnover rates of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in various brain nuclei.


Toxicity/Overdose with Benzodiazepines

Drug overdose is treated with flumazenil (a BDZ receptor antagonist, short half-life), but respiratory function should be adequately supported and carefully monitored.

Seizures and cardiac arrhythmias may occur following flumazenil administration when BDZ are taken with TCAs.

Flumazenil is not effective against BARBs overdose.


Drug-Drug Interactions with BDZs BDZ's have additive effects with other CNS

depressants (narcotics), alcohol => have a greatly reduced margin of safety.

BDZs reduce the effect of antiepileptic drugs.

Combination of anxiolytic drugs should be avoided.

Concurrent use with antihistaminic and anticholinergic drugs as well as the consumption of alcohol should be avoided.

SSRI’s and oral contraceptives decrease metabolism of BDZs.


Barbiturates

Mechanism of action Barbiturates act on GABAA receptors,

increasing synaptic inhibition. This has the effect of elevating seizure threshold and reducing the spread of seizure activity from a seizure focus. Barbiturates may also inhibit calcium channels, resulting in a decrease in excitatory transmitter release. The sedative-hypnotic effects of Barbiturates are likely the result of polysynaptic midbrain reticular formation, which controls CNS arousal.


Actions

1. Depression of CNS: is dose dependant 2. Respiratory Depression: barbiturates

suppress the hypoxic and chemoreceptor response to CO2 and over dosage is followed by respiratory depression and death.

3. Enzyme induction: they induce Cyt-P450 microsomal enzymes in the liver and reduce the action of many drugs administered together with barbiturates.


Therapeutic Uses

1. Anaesthesia: e.g short acting drugs like thiopental.

2. Anticonvulsant : e.g Phenobarbital

3. Anxiety : used as a mild sedative to relieve anxiety nervous tension and insomnia.


Pharmacokinetics of Barbiturates

Rapid absorption following oral administration.

Rapid onset of central effects.Extensively metabolized in liver (except

phenobarbital), however, there are no active metabolites.

Phenobarbital is excreted unchanged. Its excretion can be increased by alkalinization of the urine.


Pharmacokinetics of Barbiturates

In the elderly and in those with limited hepatic function, dosages should be reduced.

Phenobarbital and meprobamate cause autometabolism by induction of liver enzymes.


Toxicity/Overdose

Strong physiological dependence may develop upon long-term use.

Depression of the medullary respiratory centers is the usual cause of death of sedative/hypnotic overdose. Also loss of brainstem vasomotor control and myocardial depression.


Toxicity/Overdose

Withdrawal is characterized by increase anxiety, insomnia, CNS excitability and convulsions.

Drugs with long-half lives have mildest withdrawal (.

Drugs with quick onset of action are most abused.

No medication against overdose with BARBs.

Contraindicated in patients with porphyria.


Miscellaneous Drugs

BuspironeChloral hydrateHydroxyzineMeprobamate (Similar to

BARBS)Zolpidem (BZ1 selective)Zaleplon (BZ1 selective)


BUSPIRONE

Most selective anxiolytic currently available. The anxiolytic effect of this drug takes

several weeks to develop => used for GAD. Buspirone does not have sedative effects

and does not potentiate CNS depressants. Has a relatively high margin of safety, few

side effects and does not appear to be associated with drug dependence.

No rebound anxiety or signs of withdrawal when discontinued.


BUSPIRONE

Side effects:• Tachycardia, palpitations,

nervousness, GI distress and paresthesias may occur.

• Causes a dose-dependent pupillary constriction.


BUSPIRONE

Mechanism of Action:• Buspirone binds to 5-HT type 1A serotonin

receptors on presynaptic neurons in the dorsal raphe and on postsynaptic neurons in the hippocampus, thus inhibiting the firing rate of 5-HT-containing neurons in the dorsal raphe. Buspirone also binds at dopamine type 2 (DA2) receptors, blocking presynaptic dopamine receptors. Buspirone increases firing in the locus ceruleus, an area of brain where norepinephrine cell bodies are found in high concentration. The net result of buspirone actions is that serotonergic activity is suppressed while noradrenergic and dopaminergic cell firing is enhanced.


Pharmacokinetics of BUSPIRONE

Not effective in panic disorders. Rapidly absorbed orally. Undergoes extensive hepatic metabolism

(hydroxylation and dealkylation) to form several active metabolites (e.g. 1-(2-pyrimidyl-piperazine, 1-PP)

Well tolerated by elderly, but may have slow clearance.

Analogs: Ipsapirone, gepirone, tandospirone.


Zolpidem

Structurally unrelated but as effective as BDZs.

Minimal muscle relaxing and anticonvulsant effect.

Rapidly metabolized by liver enzymes into inactive metabolites.

Dosage should be reduced in patients with hepatic dysfunction, the elderly and patients taking cimetidine.


Zolpidem

Mechanism of Action:• Zolpidem modulates the alpha-subunit,

known as the benzodiazepine receptor, within the GABAA receptor chloride channel macromolecular complex. Unlike the benzodiazepines,which non-selectively interact with all three alpha-receptor subtypes, Zolpidem preferentially binds to the alpha-1 receptor.

• Actions are antagonized by flumazenil


Hydroxyzine

Mechanism of action Hydroxyzine competes with histamine

for binding at H1-receptor sites on the effector cell surface, resulting in suppression of histaminic edema, flare, and pruritus. The sedative properties of hydroxyzine occur at the subcortical level of the CNS. Secondary to its central anticholinergic actions, hydroxyzine may be effective as an antiemetic.


Non Barbiturate Sedatives drugs.

Chloral hydrate Is used in institutionalized patients. It

displaces warfarin (anti-coagulant) from plasma proteins.

Extensive biotransformation.


Properties of Other Drugs

2-Adrenoreceptor Agonists (eg. Clonidine)

• Antihypertensive.• Has been used for the treatment of panic

attacks.• Has been useful in suppressing anxiety

during the management of withdrawal from nicotine and opioid analgesics.

• Withdrawal from clonidine, after protracted use, may lead to a life-threatening hypertensive crisis.


Properties of Other Drugs

-Adrenoreceptor Antagonists (eg. Propranolol)

• Use to treat some forms of anxiety, particularly when physical (autonomic) symptoms (sweating, tremor, tachycardia) are severe.

• Adverse effects of propranolol may include: lethargy, vivid dreams, hallucinations.


OTHER USES1. Generalized Anxiety Disorder

Diazepam, lorazepam, alprazolam, buspirone

2. Phobic Anxietya. Simple phobia. BDZsb. Social phobia. BDZs

3. Panic DisordersTCAs and MAOIs, alprazolam

4. Obsessive-Compulsive BehaviorClomipramine (TCA), SSRI’s

5. Posttraumatic Stress Disorder (?)Antidepressants, buspirone


End

THANK You End



CNS Pharmacology3. CNS Stimulants



Faculty of Medicine


Overview

We will look at two groups of drugs that act primarily to stimulate the central nervous system, i.e Psychomotor stimulants and Psychotomimetic drugs.


L MWEETWA-PharmacologistUNIVERSITY OF ZAMBIA

CNS STIMULANTS


Classification of CNS Stimulants


CNS stimulants

Few clinical uses, Important as drugs of abuse.Factors that limit the therapeutic usefulness

include:1. Dependence: Psychological and physiological.2. Tolerance to the euphoric and anorectic effects

are classified according to their action into:3. Psychomotor stimulants4. Hallucinogen (psychotomimetic or

psychedelics) drugs


CNS stimulants

1. Psychomotor stimulants cause: Excitement, Euphoria, Decrease feeling of fatigue & Increase motor activityEx., Methylxanthines (caffeine, theobromine, theophylline),

nicotine, cocaine, amphetamine, atomoxetine, modafinil, methylphenidate.

2. Hallucinogens (psychotomimetic):Affect thought, perception, and mood, therefore

produce profound changes in thought patterns & mood, little effect on the brain stem & spinal cord

Ex., Lysergic acid diethylamide (LSD), Phencyclidine (PCP), Tetrahydrocannabinol (THC), Rimonabant.


Psychomotor stimulantsQ. What are Stimulants?Answer. Chemical stracture are similar to

monoamine neurotransmitters. All are indirect-acting sympathomimetics:

1. Many CNS stimulants release catecholamines, Therefore, their effects are abolished by prior treatment with reserpine or guanethidine

Ex: amphetamine, dextroamphetamine, methamphetamine, methylphenidate (Ritalin), ephedrine, pseudoephedrine (a stereoisomer of ephedrine), tyramine.

2. Other CNS stimulants block the reuptake of catecholamines (NE and DA) and serotonin:

EX. Cocaine, sibutramine (reduct)®, modafinil


Psychomotor stimulants

3. Drugs with stimulant effects; however, they are marketed as antidepressants include:

Atomoxetine– a relatively selective NE reuptake inhibitor (ADHD),

Bupropion – blocks the reuptake of both NE and DA.4. The methylxanthines are adenosine receptor

antagonists. Drugs within this class are NOT generally considered “psychomotor” stimulants, but they have distinct stimulant effects caffeine, theophylline.

NB: MAO and COMT inhibitors (indirect-acting adrenergic agonists), but they are not traditionally considered to be stimulants.


Therapeutic Indications and Contraindications for CNS Stimulants

Obesity (anorectic agents). Attention Deficit Hyperactivity Disorder (ADHD); lack the ability to be involved in any one activity for longer than a few minutes. Narcolepsy: It is a relatively rare sleep disorder, that is characterized by uncontrollable bouts of sleepiness during the day. It is sometimes accompanied by catalepsy, a loss in muscle control, or even paralysis brought on by strong emotion, such as laughter.Contraindications: patients with anorexia, insomnia, asthenia, psychopathic personality, a history of homicidal or suicidal tendencies.


1. Psychomotor stimulants

A. methylxanthines1. Theophylline (found in tea) : long-acting,

prescribed for night-time asthma2. Theobromine: found in cocoa. 3. Caffeine: (short-acting) the most widely

consumed found in coffee (200 mg/cup), carbonated soft drinks (60 mg/can), cocoa and chocolate


Mechanism of action: includeseveral mechanism have been proposedMechanism of action of methylxanthine1-It inhibits phosphodiesterase enz. → ↑ cAMP

2- Adenosine (A1, A2 and A3) receptors antagonist almost equally, which explains many of its cardiac effects

A2 receptors antagonist responsible for CNS stimulation & smooth muscles relaxation

↓calcium inSmooth muscles

↑ calcium inCNS & heart


Actions

a. CNS: decrease in fatigue, increased alertness: 100-200 mg caffeine in 1 or 2

cups of coffees Anxiety & tremors- 1.5 g of caffeine: 12-15 cups of coffee Spinal cord stimulation: 2-5 g (very high dose)

Tolerance can rapidly developWithdrawal symptoms: feeling of fatigue & sedation.

b. CVS; at high dose of caffeine +ve inotropic and chronotropic effects on the heart, ↑COPc. Diuretic action: mild ↑ urinary output of Na+, Cl- and K+

d. Gastric mucosa: all methylxanthines stimulate secretion of HCl

e. Respiratory smooth muscle: bronchodilator, Rx asthma replaced by β-agonists, corticosteroids.


Pharmacokinetics

Pharmacokinetics The methylxanthines are well absorbed orally. Caffeine distributes throughout the body, including the

brain. The drugs cross the placenta to the fetus and is secreted into the mother's milk.

All are metabolized in the liver, generally by the CYP1A2 pathway, the metabolites are then excreted in the urine.

Adverse effects Moderate doses: insomnia, anxiety, agitation High doses: emesis, convulsion Lethal dose (10 gm of caffeine): cardiac arrhythmia Suddenly stop: lethargy, irritability, headache


B. Nicotine

Nicotine is the active ingredient in tobacco.

Used in smoking cessation therapy, Nicotine remains important, because:

it is 2nd only to caffeine as the most widely used CNS stimulant

and 2nd only to alcohol as the most abused drug.

Actions of Nicotine:Low dose: ganglionic depolarizationHigh dose: ganglionic blockade


Actions of Nicotine

I. CNS: 1. Low dose: euphoria, arousal, relaxation,

improves attention, learning, problem solving and reaction time.

2. High dose: CNS paralysis, severe hypotension (medullary paralysis)

II. Peripheral effects: Stimulation of sympathetic ganglia and adrenal

medulla→↑ BP and HR (harmful in HTN patients) Stimulation of parasympathetic ganglia→↑ motor

activity of the bowel At higher doses, BP falls & activating ceases in

both GIT and bladder


Pharmacokinetics: highly lipid soluble absorbed everywhere (oral

mucosa, lung, GIT, skin). Crosses the placental membrane, secreted with

milk. Most cigarettes contain 6-8 mg of nicotine, by

inhaling tobacco smoke, the average smoker takes in 1 to 2 mg of nicotine per cigarette.

the acute lethal dose is 60 mg, 90% of nicotine inhaled in smoke is absorbed. Tolerance to toxic effects of nicotine develops

rapidly.


Adverse effects CNS; irritability and tremors Intestinal cramps, diarrhea ↑HR & BP

Withdrawal syndrome: nicotine is addictive substance, physical dependence on

nicotine develops rapidly and can be severe.

Bupropion: can reduce the craving for cigarettes

Transdermal patch and chewing gum containing nicotine


C. Varenicline (Chantix in the USA and Champix in Canada):

partial agonist at Nn receptor in CNS.

It produces less euphoric effects than those produced by nicotine itself (nicotine is full agonist at these receptors).

Thus, it is useful as an adjunct in the management of smoking cessation in patients with nicotine withdrawal symptom.


D. Cocaine (highly addictive drug)

1. Mechanism of action: blockade of reuptake of the monoamines (NE, serotonin and dopamine)Thus, potentiates and prolongs the CNS and peripheral actions of these monoamines.


1. Mechanism of action

Initially produces the intense euphoria by prolongation of dopaminergic effects in the brain’s pleasure system (limbic system).

Chronic intake of cocaine depletes dopamine. This depletion triggers the vicious cycle of craving for cocaine that temporarily relieves severe depression.


2. Actions: a. CNS-behavioral effects result from powerful

stimulation of cortex and brain stem. Cocaine acutely increase mental awareness and

produces a feeling of wellbeing and euphoria similar to that produced by amphetamine.

Like amphetamine, cocaine can produce hallucinations and delusions of paranoia or grandiosity.

Cocaine increases motor activity, and at high doses, it causes tremors and convulsions, followed by respiratory and vasomotor depression.


2. Actions b. Sympathetic NS: peripherally potentiate the

action of NE→ fight or flightc. Hyperthermia: impair sweating & cutaneous vasodilation ↓Perception of thermal discomfort d. local anesthetic action: blockade of voltage-

activated Na+ channel. Cocaine is the only LA that causes

vasoconstriction, chronic inhalation of cocaine powder → necrosis and perforation of the nasal septum

Cocaine is often self-administered by chewing, intranasal snorting, smoking, or intravenous (IV) injection.


Adverse effects:

Anxiety reaction that includes: hypertension, tachycardia, sweating, and paranoia.

Because of the irritability, many users take cocaine with alcohol. A product of cocaine metabolites and ethanol is cocaethylene, which is also psychoactive and cause cardiotoxicity. Depression: Like all stimulant drugs, cocaine stimulation

of the CNS is followed by a period of mental depression. Addicts withdrawing from cocaine exhibit physical and

emotional depression as well as agitation. The latter symptom can be treated with benzodiazepines or phenothiazines.

Toxic effects: Seizures RX I.V diazepam fatal cardiac arrhythmias. propranolol

E. Amphetamine Is a non catecholamine, (shows neurologic and

clinical effects quite similar to those of cocaine), dextroamphetamine is the major member of this

class compounds. methamphetamine (speed) is a derivative of

amphetamine that can be smoked and it is preferred by many abusers.

Methylenedioxymethamphetamine (also known as MDMA, or Ecstasy) is a synthetic derivative of methamphetamine with both stimulant and hallucinogenic properties.



1. Mechanism of action:

Amphetamine, act by releasing intracellular

stores of catecholamines.

also inhibits MAO, high level CAOs are readily released into synaptic spaces.


2. Actions:a. CNS: the major behavioral effects of

amphetamine result from a combination of its dopamine and NE release enhancing properties.

Amphetamine stimulates the entire cerebrospinal axis, brainstem, and medulla.

This lead to increase alertness, decrease fatigue, depressed appetite, and insomnia.

b. Sympathetic Nervous System: indirectly stimulating the receptors through NE release.


Narcolepsy

Amphetamine, methylphenidate. Recently, a new drug, modafinil and its R-

enantiomer derivative, armodafinil, have become available to treat narcolepsy.

Modafinil produces fewer psychoactive and euphoric effects as well as, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants.


4. Adverse effects:

The amphetamines may cause addiction, dependence, tolerance, and drug seeking behavior.a. CNS: insomnia, irritability, weakness, dizziness, tremor, hyperactive reflex, confusion, delirium, panic states, and suicidal tendencies, especially in mentally ill patients. -Chronic amphetamine use produce a state of “amphetamine psychosis” that resembles the psychotic episodes associated with schizophrenia.-Whereas long-term amphetamine is associated with psychic and physical dependence, tolerance to its effects may occur within a few weeks.


4. Adverse effects:

Overdoses are treated with chlorpromazine or haloperidol, which relieve the CNS symptoms as well as the HTN because of their α–blocking effects. The anorectic effect of amphetamine is due to its action in the lateral hypothalamic feeding center.b. CVS: palpitations, cardiac arrhythmia, HTN, anginal

pain, and circulatory collapse. Headache, chills, and excess sweating may also occur.

c. GIT: anorexia, nausea, vomiting, abdominal cramps, and diarrhea.

Contraindications: HTN, CV diseases, Hyperthyroidism, Glaucoma, Patients with a history of drug abuse


Atomoxetine

approved for ADHD in children and adults. It is a NE reuptake inhibitor (should not be taken

by individual on MAOI). It is not habit forming and is not a controlled

substance.


Methylphenidate (Ritalin)® It has CNS stimulant properties similar to those of

amphetamine and may also lead to abuse, although its addictive potential is controversial.

It is taken daily by 4-6 million children in the USA. The pharmacologically active isomer, Dexmethylphenidate, has been approved in the USA for the Rx of ADHD.

Methylphenidate is a more potent dopamine transport inhibitor than cocaine, thus making more dopamine available.

It has less potential for abuse than cocaine, because it enters the brain much more slowly than cocaine and, does not increase dopamine levels as rapidly.


2. Therapeutic uses:

Methylphenidate has been used for several decades in the treatment of ADHD in children aged 6 to 16.

It is also effective in the treatment of narcolepsy.

Unlike methylphenidate, dexmethylphenidate is not indicated in the treatment of narcolepsy.


3. Adverse reactions:

GIT effects are the most common; abdominal pain and nausea.

Other reactions include anorexia, insomnia, nervousness, and fever.

In seizure patients, methylphenidate seems to increase the seizure frequency, especially if the patient is taking antidepressants.

Methylphenidate is contraindicated in patients with glaucoma.


II. Hallucinogens (psychotomimetic)

A few drugs have the ability to induce altered perceptual states reminiscent of dreams, are accompanied by bright, colourful changes in the environment and by a plasticity of constantly changing shapes and colour.

The individual under the influence of these drugs is incapable of normal decision making, because the drug interferes with rational thought.


A. Lysergic acid diethylamide Multiple sites in the CNS are affected by lysergic

acid diethylamide (LSD). The drug shows serotonin (5-HT) agonist activity

at presynaptic 5-HT1 receptors in the midbrain, and also stimulates 5-HT2 receptors.

Activation of the sympathetic nervous system occurs, which causes pupillary dilation, increased BP, piloerection, and increased body temperature.


A. Lysergic acid diethylamide Adverse effects:

include hyperreflexia, nausea, and muscular weakness.

High doses may produce long-lasting psychotic changes in susceptible individuals.

Haloperidol and other neuroleptics can block the hallucinatory action of LSD and quickly abort the syndrome.


B. Tetrahydrocannabinol (THC)

The main psychoactive alkaloid contained in marijuana is tetrahydrocannabinol (THC), which is available as dronabinol.

THC can produce euphoria, followed by drowsiness and relaxation.

affect short-term memory and mental activity, decreases muscle strength and impairs highly skilled motor activity, such as

that required to drive a car. Its wide range of effects includes:

appetite stimulation, xerostomia, visual hallucinations, delusions, and enhancement of sensory activity


Mechanism of action:

THC receptors, designated CB1 receptors, have been found on inhibitory presynaptic nerve terminals. CB1 is coupled to a G protein.

Interestingly, endocannabinoids have been identified in the CNS.

These compounds, which bind to the CB1 receptors, are membrane-derived and are synthesized on demand, and they may act as local neuromodulators.

The action of THC is believed to be mediated through the CB1 receptors but is still under investigation.


Mechanism of action:


Pharmacokinetics:

The effects of THC appear immediately after the drug is smoked, but maximum effects take about 20 minutes. By 3 hours, the effects largely disappear.

Dronabinol is administered orally and has a peak effect in 2 to 4 hours. Its psychoactive effects can last up to 6 hours, but its appetite-stimulant effects may persist for 24 hours.

It is highly lipid soluble and has a large volume of distribution.

THC itself is extensively metabolized by the mixed-function oxidases.

Elimination: is largely through the biliary route.


Therapeutic uses of Dronabinol

1. as an appetite stimulant for patients with acquired immunodeficiency syndrome who are losing weight.

2. It is also sometimes given for the severe emesis caused by some cancer chemotherapeutic agents.

Adverse effects: include increased heart rate, decreased blood pressure, and reddening of the conjunctiva. At high doses, a toxic psychosis develops.

Tolerance and mild physical dependence occur with continued, frequent use of the drug.


Rimonabant:

Rimonabant: The CB1-receptor antagonist, 1. Obesity (decrease appetite and body weight in

humans). 2. induce psychiatric disturbances, such as anxiety

and depression, during clinical trials.


Phencyclidine:

Phencyclidine (also known as PCP, or “angel dust”)

inhibits the reuptake of dopamine, 5-HT, and norepinephrine.

The major action of phencyclidine is to block the ion channel regulated by the NMDA subtype of glutamate receptor. This action prevents the passage of critical ions (particularly Ca2+) through the channel.

Phencyclidine also has anticholinergic activity but, surprisingly, produces hypersalivation.


Phencyclidine:

Phencyclidine, an analog of ketamine, causes dissociative anesthesia (insensitivity to pain, without loss of consciousness) and analgesia.

At increased dosages, anesthesia, stupor, or coma result, but strangely, the eyes may remain open. Increased sensitivity to external stimuli exists, and the CNS actions may persist for a week.


CNS STIMULANTS



CNS Pharmacology4. Anesthetics



Faculty of Medicine


Overview

General anesthesia (GA) is the state produced when a patient receives medications for amnesia, analgesia, muscle paralysis, and sedation. An anesthetized patient can be thought of as being in a controlled, reversible state of unconsciousness. Anesthesia enables a patient to tolerate surgical procedures that would otherwise inflict unbearable pain, potentiate extreme physiologic exacerbations, and result in unpleasant memories.


Overview

The combination of anesthetic agents used for general anesthesia often leaves a patient with the following clinical constellation:

1. Unarousable even secondary to painful stimuli 2. Unable to remember what happened

(amnesia) 3. Unable to maintain adequate airway

protection and/or spontaneous ventilation as a result of muscle paralysis

4. Cardiovascular changes secondary to stimulant/depressant effects of anesthetic agents


General anesthesia

General anesthesia uses intravenous and inhaled agents to allow adequate surgical access to the operative site. A point worth noting is that general anesthesia may not always be the best choice; depending on a patient’s clinical presentation, local or regional anesthesia may be more appropriate.

Anesthesia providers are responsible for assessing all factors that influence a patient's medical condition and selecting the optimal anesthetic technique accordingly. Attributes of general anesthesia include the following:

Advantages Reduces intraoperative patient awareness and recall Allows proper muscle relaxation for prolonged periods of time Facilitates complete control of the airway, breathing, and circulation Can be used in cases of sensitivity to local anesthetic agent Can be administered without moving the patient from the supine

position Can be adapted easily to procedures of unpredictable duration or

extent Can be administered rapidly and is reversible

http://emedicine.medscape.com/article/149178-overview

http://emedicine.medscape.com/article/1831870-overview


General anesthesia

Disadvantages Requires increased complexity of care and associated costs

Requires some degree of preoperative patient preparation

Can induce physiologic fluctuations that require active intervention

Associated with less serious complications such as nausea or vomiting, sore throat, headache, shivering, and delayed return to normal mental functioning

Associated with malignant hyperthermia, a rare, inherited muscular condition in which exposure to some (but not all) general anesthetic agents results in acute and potentially lethal temperature rise, hypercarbia, metabolic acidosis, and hyperkalemia


Drug Classification


Some Functions of adjuncts to anesthesia

1. Relieve anxiety- Benzodiazepines

2. Relax Muscles- Muscle relaxants 3. Prevention of fluids into the

respiratory tract- Anticholinergics 4. Rapid Induction of anesthesia-

Short acting Barbiturates 5. Prevention of Post Surgical

vomiting- antiemetic drugs


Ether Operation 1846


Introduction

General anesthesia includes: Analgesia Amnesia Loss of consciousness Inhibition of sensory and autonomic

reflexes Skeletal muscle relaxation. For the purpose of this lecture, only

commonly used anesthetic drugs will be discussed in details.


Mechanism of Action

Anesthetics depress activity of neurons in many regions of the brain.

A primary target of many anesthetics is the GABAA receptor channel

Anesthetics directly activate GABAA receptors, but can also facilitate the action of GABA.


Mechanism of Action Cont’d

Ketamine does not affect GABAA it antagonizes glutamic acid on NMDA receptor.

Inhaled anesthetics also cause membrane hyperpolarization via activation of potassium channels.


Stages of Anesthesia

1. Analgesia: first analgesia, later analgesia and amnesia.

2. Excitement: delirium, excitement, irregular respiration, vomiting & incontinency.


Stages of Anesthesia Cont’d

3. Surgical Anesthesia: the recurrence of regular respiration. The most reliable indication is loss of the eyelash reflex and regular respiratory pattern.

4. Medullary Depression: severe depression of the vasomotor and respiratory center.


MAC

MAC stands for: Minimum Alveolar Anesthetic Concentration

In steady state, the partial pressure of an inhaled anesthetic in the brain equals that in the lung

MAC is the concentration that results in immobility in 50% of patients when exposed to a noxious stimulus (eg, surgical incision).


MAC Cont’d

MAC values decrease in elderly patients and with hypothermia, but are not affected by sex, height, and weight.

Presence of adjuvant drugs can reduce MAC dramatically.

Nitrous oxide can be used as a "carrier" gas at 40% of its MAC, decreasing the anesthetic requirement of other inhaled anesthetics to 70% of their MAC


Equilibrium Dynamics

The rate at which a given concentration of anesthetic in the brain is reached depends on: Solubility properties

Concentration in the inspired air

Pulmonary ventilation

Pulmonary blood flow

Arteriovenous concentration gradient


Solubility Properties

Blood:gas partition coefficient defines the relative affinity of an anesthetic for the blood compared to air.

The partition coefficients for poorly soluble gases are < 0.5 and for very soluble gases can be more than 10


Solubility Properties Cont’d

If blood solubility is low, few molecules raise the arterial tension quickly and vice versa

Compounds that are not very soluble in blood, rapidly equilibrate with the brain and have fast onset of action.


Concentration in Air

It is directly proportionate to the rate of induction of anesthesia by increasing the rate of transfer into the blood.


Pulmonary Ventilation

The rise of gas tension in arterial blood is directly dependent on both the rate and depth of ventilation.

Increase in ventilation has a slight effect for gases with low blood solubility but significantly increases tension of agents with moderate or high blood solubility.


Pulmonary Blood Flow

Increase in pulmonary blood flow (increased cardiac output) slows the rate of rise in arterial tension.


Arteriovenous Concentration Gradient

Pulmonary veins contain less anesthetic than arteries. The greater this difference, the more has been taken up by the body and achievement of equilibrium with the brain is more delayed.


Elimination

One of the most important factors governing rate of recovery is the blood:gas partition coefficient

Elimination by hyperventilation is limited since the concentration in the lungs cannot be reduced below zero.


Elimination Cont’d

Gases that are relatively insoluble in blood and brain are eliminated faster.

The duration of exposure to the anesthetic have a marked effect on the time of recovery, especially for more soluble gases.



Despite their solubilities, the elimination of halothane is more rapid than enflurane because 40% of halothane versus 10% of enflurane is metabolized.

Sevoflurane is degraded by contact with the carbon dioxide absorbent in anesthesia machines, yielding "compound A" that causes renal damage if high concentrations are absorbed.



In terms of the extent of metabolism of inhaled anesthetics, the rank order is:

Methoxyflurane > Halothane > Enflurane > Sevoflurane > Isoflurane > Desflurane > Nitrous Oxide


Cardiovascular System

All gases decrease arterial pressure in direct proportion to their alveolar concentration.

Halothane and enflurane reduce cardiac output

Isoflurane, desflurane, and sevoflurane decrease systemic vascular resistance

Bradycardia is often seen with halothane (vagal stimulation).


Cardiovascular System Cont’d

Nitrous oxide in combination with potent gases produces sympathetic stimulation that minimizes cardiac depressant effects.

Halothane & isoflurane sensitize the myocardium to catecholamines. Arrhythmias may occur in patients with cardiac disease who are given sympathomimetics or are anxious.


Respiratory System

All gases are respiratory depressants but it is lessened by surgical stimulation.

Isoflurane and enflurane are the most depressant.

Inhaled anesthetics decrease the ventilatory response to hypoxia.

Concentrations that still exist during recovery depress the increase in ventilation during hypoxia.


Respiratory System Cont’d

Inhaled anesthetics are bronchodilators.

Halothane and sevoflurane the anesthetics of choice in patients with airway problems.

The pungency of enflurane may elicit breath holding, which can decrease the speed of induction.


Nervous System

Most volatile agents decrease cerebral vascular resistance, increase cerebral blood flow and ICP.

It is prudent not to use enflurane in patients with a history of seizure.

Nitrous oxide has analgesic and amnesic actions which in combination with other agents is useful in general and dental anesthesia.


Other Systems

Kidney All gases decrease GFR and renal plasma flow

in spite of well-maintained or even increased perfusion pressures

Liver All gases decrease hepatic blood flow from 15%

to 45%.

Uterine smooth muscle The halogenated gases are potent uterine

muscle relaxants. (Useful for intrauterine fetal manipulation or manual extraction of a retained placenta).


Toxicity

Hepatotoxicity Hepatotoxicity due to halothane is one in

20,000–35,000. Obese patients having several exposures to halothane are more susceptible.

Nephrotoxicity Metabolism of methoxyflurane releases

nephrotoxic inorganic fluoride so it is obsolete for most purposes.


Toxicity Cont’d

Malignant hyperthermia It is an autosomal dominant genetic

disorder of skeletal muscle occurs by inhaled agents and muscle relaxants (eg,succinylcholine).

Consists of: the rapid onset of tachycardia, hypertension, severe muscle rigidity, hyperthermia, hyperkalemia and acidosis

Treatment consists of correction of metabolic disturbances and administration of dantrolene.


Toxicity Cont’d

Reproduction Female operating room personnel have a

higher than expected incidence of miscarriages but the evidence is not strong.

Hematotoxicity Prolonged exposure to nitrous oxide

causes megaloblastic anemia especially in poorly ventilated dental operating suites.


Intravenous Anesthetics

Intravenous anesthetics have an onset of action faster than the fastest of the gaseous agents so they are used for induction of anesthesia.

Consist of: Barbiturates (thiopental, methohexital)

Propofol

Etomidate

Ketamine


Thiopental

Thiopental can produce loss of consciousness (hypnosis) in one circulation time.

Because of its rapid removal from brain tissue a single dose of thiopental is so short-acting.

Large doses of thiopental decreases blood pressure and cardiac output and depresses respiration

Cerebral blood flow is decreased. (A desirable drug for patients with head trauma or brain tumors)


Propofol

Its onset of action is similar to thiopental but recovery is more rapid (similar to the shortest-acting inhaled anesthetics).

Postoperative nausea and vomiting is less common because propofol has antiemetic actions.

Because of strong negative inotropic effects, propofol causes a marked decrease in blood pressure and is a respiratory depressant.


Etomidate

Etomidate causes minimal cardiovascular and respiratory depression.

Etomidate produces a rapid loss of consciousness and rapid recovery (< 5 minutes).

Etomidate causes a high incidence of pain on injection, myoclonus, and postoperative nausea and vomiting.

Etomidate may cause adrenocortical suppression and decrease in hydrocortisone after a single dose.


Ketamine

Ketamine produces dissociative anesthesia, characterized by: catatonia, amnesia, and analgesia, with or without loss of consciousness.

Ketamine is the only intravenous anesthetic that possesses analgesic properties and produces cardiovascular stimulation.

Ketamine markedly increases cerebral blood flow and intracranial pressure.


Ketamine Cont’d

Ketamine may produce postoperative sensory and perceptual illusions, disorientation and vivid dreams (emergence phenomena).

It is considered useful for poor-risk geriatric patients and in cardiogenic or septic shock.

It is also used in children undergoing painful procedures (eg, dressing changes for burns).


Adjuvant Drugs

Remifentanil (opioid) has an extremely short duration of action

Fentanyl and droperidol together produce analgesia and amnesia and are used with nitrous oxide to provide neuroleptanesthesia.

Midazolam is frequently given intravenously before induction of general anesthesia because it causes amnesia (> 50%)


Thank youTwalumba!



CNS Pharmacology5. Antidepressant Drugs



Faculty of Medicine


Psychopharmacology

L MWEETWA-Pharmacologist


Antidepressants

Introduction If you fail an important examination, lose a loved

one or a job, or get dumped in a relationship, it is normal to feel depressed. But if you remain depressed for more than two weeks, long after the event has passed, then you may have a common clinical disorder calleddepression. Clinical depression, also called major depressive disorder, is characterized by a sad or blue mood that affects nearly every aspect of your life every day – your family and social relationships, your work or school performance, even your desire to do simple things such as exercise or go out with friends.

http://psychcentral.com/blog/archives/2009/07/09/6-steps-for-beating-depression/

http://psychcentral.com/disorders/depression/


Depression Overview

What causes depression? Like most mental disorders, the

causes of depression are largely unknown. Researchers and clinicians theorize that depression is the result of three related factors – biological, psychological and social


Symptoms of Depression

loss of interest or pleasure in daily activities consistently for at least a 2 week period.

Depressed mood most of the day, as indicated by either the person’s own feeling (e.g., feeling sad or empty) or as observed by others (e.g., appears tearful). (In children and adolescents, this may be characterized as an irritable mood.)

Significant weight loss when not dieting or weight

Can’t sleep (insomnia) or sleeping too much (hypersomnia) psychomotor agitation, Psychomotor retardation Fatigue or loss of energy Feelings of worthlessness or excessive or inappropriate guilt

Diminished ability to think or concentrate, or indecisiveness Recurrent thoughts of death (not just fear of dying), recurrent suicidal

ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide


Antidepressant Drug Classification


AD Classification

1) Tricyclics and Tetracyclics (TCA)Imipramine Doxepin Desipramine Amoxepine TrimipramineMaprotiline Clomipramine Amitriptyline Nortriptyline Protriptyline

2) Monoamine Oxidase Inhibitors (MAOIs)

Tranylcypramine Phenelzine Moclobemide

3) Serotonin Selective Reuptake Inhibitors (SSRIs) Fluoxetine Fluvoxamine

Sertraline Paroxetine Citalopram

4) Dual Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)

Venlafaxine Duloxetine

5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs)

Nefazodone Trazodone 6) Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)

Bupropion 7) Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs)

Mirtazapine 8) Noradrenalin Specific Reuptake Inhibitor (NRI)

Reboxetine 9) Serotonin Reuptake Enhancer

Tianeptine


Mechanism of Action TCA

They inhibit the reuptake of norepinephrine and serotonin almost equally and also inhibit the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Pharmacologically this action may potentiate or prolong neuronal activity since reuptake of these biogenic amines is important physiologically in terminating transmitting activity. This interference with the reuptake of norepinephrine and/or serotonin is believed by some to underlie the antidepressant activity.


SIDE EFFECTS OF TCA

TCA are effective in treating severe major depression but have the following side effects:-

1. Antimuscarinic effects e.g dry mouth,urinary retention due to blockade of Ach receptors.

2. CV e.g slowing of atrioventricular conduction 3. Othorstatic hypotension and reflex

tachycardia 4. Prominent sedation in early weeks 5. Use with caution in manic Patients as it can

unmask disease


Mechanism of Action of SSRI

Blocks the reuptake of serotonin selectively at the serotonin reuptake pump of the neuronal membrane, enhancing the actions of serotonin on 5HT1A autoreceptors. SSRIs bind with significantly less affinity to histamine, acetylcholine, and norepinephrine receptors than tricyclic antidepressant drugs.


Side effects of SSRI

1. Nausea 2. Insomnia 3. Anorexia 4. Sexual Dysfunction, loss of libido,

delayed ejaculation and anorgasmia. 5.Weight loss 6. Tremors


Mechanism of Action of MAO Irreversibly block the action of monoamine oxidase

(MAO) in the nervous system. MAO subtypes A and B are involved in the metabolism of serotonin and catecholamine neurotransmitters such as epinephrine, norepinephrine, and dopamine. MAO are nonselective inhibitors, they bind irreversibly to monoamine oxidase–A (MAO-A) and monoamine oxidase–B (MAO-B). The reduced MAO activity results in an increased concentration of these neurotransmitters in storage sites throughout the central nervous system (CNS) and sympathetic nervous system. This increased availability of one or more monoamines is the basis for the antidepressant activity of MAO inhibitors.


Side effects of MAO

Used in patients who are unresponsive to/ or allergic to TCA

Side effects are severe and unpredictable:- 1. Tyramine induced side effects, foods such as

aged cheeses, chicken liver,beer and red wine is normally inactivated by MAO in the gut. Individuals receiving MAO inhibitors are unable to degrade tyramine obtained from the diet. Tyramine causes the release of large amounts of stored catecholamine from nerve terminals resulting in headache,tachycardia, Hypertension,cardiac arrhythmias and stroke.


Side effects of MAO

2. Blurred Vision 3. Dryness of mouth Constipation


Mechanism of Action of Lithium

The precise mechanism of action of Li+ as a mood-stabilizing agent is currently unknown. It is possible that Li+ produces its effects by interacting with the transport of monovalent or divalent cations in neurons. An increasing number of scientists have come to the conclusion that the excitatory neurotransmitter glutamate is the key factor in understanding how lithium works. Lithium has been shown to change the inward and outward currents of glutamate receptors (especially GluR3), without a shift in reversal potential. Lithium has been found to exert a dual effect on glutamate receptors, acting to keep the amount of glutamate active between cells at a stable, healthy level, neither too much nor too little. It is postulated that too much glutamate in the space between neurons causes mania, and too little, depression. Another mechanism by which.


Mechanism of Action of Lithium lithium might help to regulate mood include the non-

competitive inhibition of an enzyme called inositol monophosphatase. Alternately lithium's action may be enhanced through the deactivation of the GSK-3B enzyme. The regulation of GSK-3B by lithium may affect the circadian clock. GSK-3 is known for phosphorylating and thus inactivating glycogen synthase. GSK-3B has also been implicated in the control of cellular response to damaged DNA. GSK-3 normally phosphorylates beta catenin, which leads to beta catenin degratation. When GSK-3 is inhibited, beta catenin increases and transgenic mice with overexpression of beta catenin express similar behaviour to mice treated with lithium. These results suggest that increase of beta catenin may be a possible pathway for the therapeutic action of lithium


Side effects of lithium

1. Ataxia 2.Tremors 3. Confusion All the stated side effects are less

common.



CNS Pharmacology6. Neuroleptics/AntipsychoticsL.Mweetwa-Pharmacologist


Faculty of Medicine


Schizophrenia

Schizophrenia is a mental disorder characterized by a breakdown of thought processes and by impairedemotional responses.Common symptoms include delusions, such as paranoid beliefs; hallucinations; disorganized thinking; and negative symptoms, such as lack of emotion and lack of motivation. Schizophrenia causes significant social and work problems. Diagnosis is based on observed behaviour and the person's reported experiences

http://en.wikipedia.org/wiki/Mental_disorder

http://en.wikipedia.org/wiki/Cognitive_psychology

http://en.wikipedia.org/wiki/Emotion

http://en.wikipedia.org/wiki/Symptom

http://en.wikipedia.org/wiki/Delusion

http://en.wikipedia.org/wiki/Paranoia

http://en.wikipedia.org/wiki/Hallucination

http://en.wikipedia.org/wiki/Thought_disorder

http://en.wikipedia.org/wiki/Negative_symptoms

http://en.wikipedia.org/wiki/Blunted_affect

http://en.wikipedia.org/wiki/Avolition


Schizophrenia


Causes of Schizophrenia

1. A combination of genetic and environmental factors play a role in the development of schizophrenia ]People with a family history of schizophrenia who have a transient psychosis have a 20–40% chance of being diagnosed one year later.

http://en.wikipedia.org/wiki/Environmental_factor



Schizophrenia is not characterized by any reproducible neurochemical abnormality. However, structural and functional abnormalities have been observed in the brains of schizophrenic patients:

1) Enlarge cerebral ventricles.2) Atrophy of cortical layers.3) Reduced volume of the basal ganglia

IdiopathicBiological Correlates4) Genetic Factors5) Neurodevelopmental abnormalities.6) Environmental stressors.



4. Substance use About half of those with schizophrenia use drugs

or alcohol excessively, Amphetamine, cocaine 5. Developmental factors Factors such as hypoxia and infection, or stress

and malnutrition in the mother during fetal development, may result in a slight increase in the risk of schizophrenia later in life. People diagnosed with schizophrenia are more likely to have been born in winter or spring (at least in the northern hemisphere), which may be a result of increased rates of viral exposures in utero.

http://en.wikipedia.org/wiki/Fetal_development

http://en.wikipedia.org/wiki/Fetal_development

http://en.wikipedia.org/wiki/Northern_hemisphere

http://en.wikipedia.org/wiki/In_utero

http://en.wikipedia.org/wiki/In_utero


Definition

Neurosis Abnormal behavior characterized by increased

anxiety, tension and emotionalism

Psychosis Severe psychiatric illness with distortion of

thought and behaviors, capacity to recognized reality and of perception Depression

Depressant

Mental state characterized by depressed mood with feelings of frustration and hopelessness


Psychotic disorders

1.) Psychoses (a) Schizophenia (split mind)

splitting of perception and interpretation from reality

inability of thinking coherently

(b) Mania Elation, hyperactivity,

uncontrollable thought and speech

maybe associated with violet behaviour

(c) Depression Sadness, guilt, physical and

mental slowing self-destructive ideation

2.) Neuroses (less seriousness)

(a) AnxietyAn unpleasant emotional state associated with uneasiness and concern for the future

(b) Obsessive / Compulsivelimited abnormality of talk or behaviour


Schizophrenia

One of the psychotic disorders Major disturbances in:

Thought Emotion Behavior

Disordered thinking Faulty perception and attention Inappropriate or flat emotions Bizarre motor activity Disrupted interpersonal relationships


Schizophrenia

Disorder impacts families & friends Difficult to live with someone who experiences delusions,

hallucinations, and paranoia. Social skills deficits common

▪ Isolation, few social contacts Symptoms impact employability

Often lead to unemployment & homelessness Substance abuse & suicide rates high


Positive Symptoms: Behavioral excesses

Delusions Firmly held beliefs Contrary to reality Resistant to

disconfirming evidence Persecutory delusions

common▪ “The CIA has planted a

listening device in my head”

Hallucinations Sensory experiences in the

absence of sensory stimulation Types of hallucinations

Audible thoughts Voices commenting Voices arguing

Increased levels of activity in Broca’s area during hallucinations


Symptoms: Behavioral excesses

Positive Symptoms. Hallucinations, delusions, paranoia, ideas of

reference.

Negative Symptoms. Apathy, social withdrawal, anhedonia, emotional

blunting, cognitive deficits, extreme inattentiveness or lack of motivation to interact with the environment.

These symptoms are progressive and non-responsive to

medication.


Negative Symptoms: Behavioral deficits

Avolition Lack of interest and drive

Alogia Poverty of speech Poverty of content

Anhendonia Inability to experience pleasure

Flat affect Exhibits little or no affect in face or voice

Asociality Inability to form close personal relationships


Other Symptoms

Catatonia Motor abnormalities Repetitive, complex gestures

▪ Usually of the fingers or hands Excitable, wild flailing of limbs

Catatonic immobility Maintain unusual posture for long periods of time

▪ e.g., stand on one leg Waxy flexibility

Limbs can be manipulated and posed by another person

Inappropriate affect Emotional responses inconsistent with situation

▪ e.g., laugh uncontrollably at a funeral


Neuroleptic Drug Classification


CLASSIFICATION

A. Typical Antipsychotics: (traditional/older)

1.Phenothiazines:

a. Aliphatic side chain: Chlorpromazine,

Triflupromazine

b. Piperidine side chain: Thioridazine

c. Piperazine side chain: Trifluoperazine,

perphenazine Fluphenazine

2.Butyrophenones: Haloperidol, Trifluperidol, Penfluridol,

droperidol, domperidone


CLASSIFICATION

3.Thioxanthenes: Flupenthixol 4. Other heterocyclics: Pimozide, Loxapine,

molindone, sulpiride, amisulpiride, penfluridol, Remoxipride, metoclopramide

B. Atypical/newer antipsychotics:: Clozapine,

Risperidone, Olanzapine, Quetiapine, Aripiprazole, Ziprasidone,

paloparidone


Traditional Vs. Atypical

Mainly DA Mainly D2 Treat mostly

POSITIVE symptoms

More adverse effects

Less useful in refractory disease

DA and 5HT D2+D4+5HT Treat POSITIVE and

NEGATIVE symptoms

Lesser adverse effects

Useful in refractory disease


Mechanism of Action:

-Antipsychotic blocks D₂receptors in the brain'sDopaminergic pathway.

-Some also block or partially

block serotonin receptors(particularly 5HT2A, C and5HT1A receptors) -But antipsychotic drugs

can alsoblock wide range of

receptortargets.


In the Mesolimbic- Mesocortical and Nigrostriatal pathway Antipsychotic blocks:


In the Tuberoinfundibular pathway Antipsychotics block:

Dopamine released at this site regulates the secretion of prolactinfrom anterior the pituitary gland.Antipsychotics blocks D₂ receptor at this site.


Antipsychotic blocks D₂ receptors

Some also block or partially block serotonin receptors


Pharmacology of Antipsychotics:Typical Antipsychotics

Phenothiazine Absorption Concentration Metabolism Vd Dose

Chlorpromazine (CPZ)

More consistent effect in IV and IM administration

Highly bound to plasma and tissue protein

Metabolized in liver by CYP2D6 enzyme

Large 20 L/kg

Acute single dose lasts 6-8 hours t⅟₂ is 18-30 hrs

Triflupromazine More potent than CPZ

-- -- --

Thioridazine Low potency with anticholinergic action

-- -- --

Trifluoperazine, Fluphenazine

High potency with Autonomic action

-- -- -- Depot IM inj every 2-4 weeks (25mg/ml )


Butyrophenones Potency t⅟₂ Dose

Haloperidol Potent antipsychotic Produces few autonomic effects

24 hours. --

Trifluperidol Similar toHaloperidol but slightly more potent

-- --

Penfluridol Exceptional long acting neuroleptic, used for chronic Schizophrenia, affective withdrawl and social mal-adjustment

-- 20-60 mg , once weekly


Thioxanthenes

Flupenthixol Less sedative than CPZ, indicated for Schizophrenia and other Psychoses.

Other heterocyclics t⅟₂

Pimozide Specific DA antagonist with little adrenergic or cholinergic blocking activity. Used in Gilles de la Tourett’s syndrome and ticks. Long Duration of action.

48-60 hrs. (after single dose)


Atypical Antisychotic drugs

These are newer 2nd

Generation antipsychotics

that have weak D₂ receptor

blocking but potent 5-HT₂

antagonistic activity. They

May improve the impaired

Cognitive function inpsychotics.


Atypical Blocking activity Metabolism(Enzyme)

t⅟₂ and Dose

Clozapine A very potent antipsychotic

D₂, D₄, 5HT₂, α receptors

By CYP3A4 t⅟₂ - 12 hours

Risperidone

-- Combination of D₂+5HT₂ , High affinity for α₁, α₂ and H₁ receptors

-- Dose - Low dose <6 mg/day

Olanzapine Potent antipsychotic Broader spectrum of efficacy

Monoaminergic (D₂, 5HT₂, α₁, α₂) as well as muscarinic and H₁ receptors

By CYP1A2 and Glucuronyl transferase

t⅟₂ - 24-30 hours

Quetiapine New short- acting antipsychotic

5HT₁А, 5HT₂, D₂, α₁, α₂ and H₁ receptor

By CYP3A4 --

Aripiprazole

Unique antipsychotic which is partial agonist at D₂ and 5HT₁А

5HT₂ By CYP2D6 and CYP3A4

t⅟₂ - 3days

Ziprasidone Latest antipsychotic , moderately potent inhibitor.

Combination D₂+5HT₂A/₂C +H₁ + α₁,Na reuptake

-- t⅟₂ - 8 hours


Adverse effects:

On CNS: - Drowsiness - lethargy - mental confusion - seizure. CVS: - Postural hypotension - palpitation - arrythmia in elderly Anticholinergic: - Dry mouth - blurring of vision - constipation - urinary

inconsistency


Endocrine: - Hyperprolactinemia - amenorrhoea - infertility - gelactorrhoea and gynaecomastia. Extrapyramidal disorders: - Parkinsonism - Acute muscular

dystonias - Akathisia - Malignant Neuroleptic

Syndrome - Tardive dyskinesia Miscellaneous: - Weight gain - Blood sugar – lipid rise - worsening of diabetes.

Adverse effects:


DRUG TREATMENT OF PSYCHOSIS

To understand the management of schizophrenia its important to understand the etiology of the disease.


Psychosis Producing Drugs

Drugs inducing psychosis1) Levodopa2) CNS stimulants

a) Cocaine b) Amphetaminesc) Khat, cathinone, methcathinone

3) Apomorphine 4) Phencyclidine


Etiology of Schizophrenia

Idiopathic

Biological Correlates1) Genetic Factors2) Neurodevelopmental

abnormalities.3) Environmental stressors.


Etiology of Schizophrenia

Schizophrenia is not characterized by any reproducible neurochemical abnormality. However, structural and functional abnormalities have been observed in the brains of schizophrenic patients:

1) Enlarge cerebral ventricles.2) Atrophy of cortical layers.3) Reduced volume of the basal ganglia.


Dopamine Theory of Schizophrenia

Many lines of evidence point to the aberrant increased activity of the dopaminergic system as being critical in the symptomatology of schizophrenia.



Dopamine Correlates:• Antipsychotics reduce dopamine synaptic activity.• These drugs produce Parkinson-like symptoms.• Drugs that increase DA in the limbic system cause

psychosis.• Drugs that reduce DA in the limbic system

(postsynaptic D2 antagonists) reduce psychosis.• Increased DA receptor density (Post-mortem, PET).• Changes in amount of homovanillic acid (HVA), a DA

metabolite, in plasma, urine, and CSF.



Evidence against the hypothesis Antipsychotics are only partially effective in

most (70%) and ineffective for some patients.

Phencyclidine, an NMDA receptor antagonist, produces more schizophrenia-like symptoms in non-schizophrenic subjects than DA agonists.

Atypical antipsychotics have low affinity for D2 receptors.

Focus is broader now and research is geared to produce drugs with less extrapyramidal effects.


Dopamine System

There are four major pathways for the dopaminergic system in the brain:

I. The Nigro-Stiatal Pathway.II. The Mesolimbic Pathway.III. The Mesocortical Pathway.IV. The Tuberoinfundibular Pathway.


THE DOPAMINERGIC SYSTEM


Catecholamines

Tyrosine Tyrosine hydroxylase

L-Dopa Dopa decarboxylase

Dopamine (DA) Dopamine hydroxylase

Norepinephrine (NE)(Noradrenaline)

Phenylethanolamine-

-N-methyltransferase

Epinephrine (EPI)(Adrenaline)


Dopamine Synapse

DA

L-DOPA

Tyrosine

Tyrosine


Dopamine System

DOPAMINE RECEPTORS

There are at least five subtypes of receptors:ReceptorD1D2D3D4D5


Dopamine Reuptake System


Antipsychotic treatments

Schizophrenia has been around perhaps, since the beginning of humankind, however, it was not until the last century that it was established as a separate entity amongst other mental disorders.

Many treatments have been devise:

Hydrotherapy: “The pouring of cold water in a stream, from a height of at least four feet onto the forehead, is one of the most certain means of subsiding violent, maniacal excitement that we have ever seen tried”... wrote an anonymous physician in the early 1800’s.


Antipsychotic treatments

Lobotomies (Egaz Moniz received the Nobel Prize).

In 1940’s Phenothiazenes were isolated and were used as pre-anesthetic medication, but quickly were adopted by psychiatrists to calm down their mental patients.

In 1955, chlorpromazine was developed as an antihistaminic agent by Rhône-Pauline Laboratories in France. In-patients at Mental Hospitals dropped by 1/3.


Antipsychotics treatment

Antipsychotics/Neuroleptics Antipsychotics are the drugs currently

used in the prevention of psychosis. They have also been termed neuroleptics,

because they suppress motor activity and emotionality.

** These drugs are not a cure ** Schizophrenics must be treated with

medications indefinitely, in as much as the disease in lifelong and it is preferable to prevent the psychotic episodes than to treat them.


Antipsychotics/Neuroleptics

Although the antipsychotic/neuroleptics are drugs used mainly in the treatment of schizophrenia, they are also used in the treatment of other psychoses associated with depression and manic-depressive illness, and psychosis associated with Alzheimer’s disease. These conditions are life-long and disabling.


Antipsychotic/Neuroleptics

Three major groups :1) Phenothiazines2) Thioxanthines

3) Butyrophenones

OLDER DRUGS


Dopamine Synapse

DA

L-DOPA

Tyrosine

Tyrosine

Old antiphsychotics /neuroleptics are D2 dopamine receptor antagonists. Although they are also effective antagonists at ACh, 5-HT, NE receptors.


dopaminereceptorantagonist

D2



It appears that the specific interaction of antipsychotic drugs with D2 receptors is important to their therapeutic action.

The affinities of most older “classical” agents for the D2 receptors correlate with their clinical potencies as antipsychotics.



Both D1 and D2 receptors are found in high concentrations in the striatum and the nucleus accumbens.

Clozapine has a higher affinity for the D4 receptors than for D2.

Recently it has been found that most antipsychotic drugs may also bind D3 receptors (therefore, they are non-selective).



Antipsychotics produce catalepsy (reduce motor activity).

BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.

Antipsychotics reverse hyperkinetic behaviors (increased locomotion and stereotyped behavior).

BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.

Antipsychotics prevent the dopamine inhibition of prolactin release from pituitary.

BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.

hyperprolactinemia


PharmacokineticsAbsorption and

Distribution Most antipsychotics are readily but incompletely absorbed.

Significant first-pass metabolism. Bioavailability is 25-65%. Most are highly lipid soluble. Most are highly protein bound (92-

98%). High volumes of distribution (>7 L/Kg). Slow elimination.**Duration of action longer than expected,

metabolites are present and relapse occurs, weeks after discontinuation of drug.**


Pharmacokinetics

Metabolism

Most antipsychotics are almost completely metabolized.

Most have active metabolites, although not important in therapeutic effect, with one exception. The metabolite of thioridazine, mesoridazine, is more potent than the parent compound and accounts for most of the therapeutic effect.


Pharmacokinetics

Excretion

Antipsychotics are almost completely metabolized and thus, very little is eliminated unchanged.

Elimination half-lives are 10-24 hrs.



1) Phenothiazines

Chlorpromazine Thioridazine FluphenazineTrifluopromazine Piperacetazine Perfenazine

Mesoridazine AcetophenazineCarphenazineProchlorperazineTrifluoperazine

Aliphatic Piperidine Piperazine*

* Most likely to cause extrapyramidal effects.



[Drug dose]

Eff

ect

Piperazine

Aliphatic

Piperidine



2) ThioxanthinesThiothixeneChlorprothixene

Closely related to phenothiazines



3) ButyrophenonesHaloperidolDroperidol



[Drug dose]

Eff

ect

Phenothiazine d.

Thioxanthene d.

Butyrophenone d.



Newer drugs have higher affinities for D1, 5-HT or -AR receptors.

NE, GABA, Glycine and Glutamate have also been implicated in schizophrenia.



The acute effects of antipsychotics do not explain why their therapeutic effects are not evident until 4-8 weeks of treatment.

Blockade of D2 receptors

Short term/Compensatory effects:Ý Firing rate and activity of nigrostriatal

and mesolimbic DA neurons.Ý DA synthesis, DA metabolism, DA release



Presynaptic EffectsBlockade of D2 receptors

Compensatory Effects

Ý Firing rate and activity of nigrostriatal and mesolimbic DA neurons.

Ý DA synthesis, DA metabolism, DA release.

Postsynaptic EffectsDepolarization Blockade

Inactivation of nigrostriatal and mesolimbic DA neurons.

Receptor Supersensitivity



PimozideMolindoneLoxapineClozapine

OlanzapineQetiapine

RisperidoneSertindole

ZiprasidoneOlindone

Newer Drugs



Clinical Ex. Py.Drug Potency toxicity Sedation

Hypote.Chlorpromaz. Low Medium MediumHighHaloperidol High Very High Very High LowThiothixene High Medium Medium MediumClozapine Medium Very low Low MediumZiprasidone Medium Very Low Low Very lowRisperidone High Low Low LowOlanzapine High Very Low Medium Very lowSertindole High Very Low Very low Very Low



Chlorpromazine: 1 = 5-HT2 = D2 > D1 > M > 2

Haloperidol: D2 > D1 = D4 > 1 > 5-HT2

>H1>M = 2

Clozapine: D4 = 1 > 5-HT2 = M > D2 = D1

= 2 ; H1

Quetiapine: 5-HT2 = D2 = 1 = 2 ; H1

Risperidone: 5-HT2 >> 1 > H1 > D2 > 2 >> D1

Sertindole: 5-HT2 > D2 = 1



Clinical Problems with antipsychotic drugs

include:

1) Failure to control negative effect2) Significant toxicity

a) Parkinson-like symptomsb) Tardive Dyskinesia (10-30%)c) Autonomic effectsd) Endocrine effectse) Cardiac effects

3) Poor Concentration



Some antipsychotics have effects at muscarinic acetylcholine receptors:

▪ dry mouth▪ blurred vision▪ urinary retention▪ constipation

ClozapineChlorpromazine

Thioridazine



Some antipsychotics have effects at -aadrenergic receptors:

• orthostatic hypotension

ChlorpromazineThioridazine

Some antipsychotics have effects at H1-histaminergic receptors:

• sedation

RisperidoneHaloperidol



Blockade of D2 receptors in lactotrophs in breast increase prolactin concentration and may produce breast engorgement and galactorrhea.



Neuroleptic Malignant Syndrome

Is a rare but serious side effect of neuroleptic (antipsychotic) therapy that can be lethal. It can arise at any time in the course of treatment and shows no predilection for age, duration of treatment, antipsychotic medication, or dose.



Neuroleptic Malignant Syndrome Occurs in pts. hypersensitive to the Ex.Py. effects

of antipsychotics. Due to excessively rapid blockade of postsynaptic

dopamine receptors. The syndrome begins with marked muscle rigidity. If sweating is impaired, a fever may ensue. The

stress leukocytosis and high fever associated with this syndrome may be mistaken for an infection.

Autonomic instability with altered blood pressure and heart rate is another midbrain manifestation.

Creatine kinase isozymes are usually elevated, reflecting muscle damage.



Neuroleptic Malignant Syndrome

Treatment Vigorous treatment with antiparkinsonian

drugs is recommended as soon as possible.

Muscle relaxants such as diazepam, dantrolene or bromocriptine may be helpful.



Drug Interactions Additive effects with sedatives. Additive effects with anticholinergics. Additive effects with

antihistaminergics. Additive effects with -AR blocking

drugs. Additive effects with drugs with

quinidine-like action (thioridazine).


THANK YOU



CNS Pharmacology7. Antiepileptic Drugs



Faculty of Medicine


ANTISEIZURE DRUGS

Antiepileptic drugs


Epilepsy

Chronic disorder characterized by recurrent seizures

Seizures is a sudden, excessive, abnormal discharge of cerebral neurons

Causes of seizures Heredity – major contributing factor may occur due to infection, neoplasm or head

injury Environmental causes-alteration in blood gases,

pH, electrolytes, or glucose availability


Seizure classified into two broad groups

Partial: simple or complex

Generalized: absence, tonic, clonic, tonic-clonic, myoclonic, febrile


PARTIAL SEIZURES

Simple partial seizures (without loss of consciousness) confined to a single locus in brain abnormal activity in one limb or muscles With autonomic symptoms (nausea, blood

pressure changes,...)

Complex partial seizures (with loss of consciousness) Simple partial followed by a loss of

consciousness Impaired consciousness from the onset Exhibits complex sensory hallucination Motor dysfunction may involve chewing

movements, diarrhea or urination


Generalized seizures

Electrical discharge spread to both hemisphere

May be convulsive (shaken repeatedly) or non convulsive

Immediate loss of consciousness occurs Types

generalized tonic-clonic (grand mal) seizures

absence (petit mal) seizurestonic seizuresatonic seizuresclonic and myoclonic seizuresfebrile seizures


Seizures

Partial Seizures localized onset of attack ascertained, either by clinical observation or by EEG – attack begins in a specific locus in brain

Simple Partial seizures – least complicated, characterized by minimal spread of abnormal discharge, normal consciousness and awareness are preserved – pt may have a sudden onset of clonic jerking of an extremity lasting 60-90 secs; residual weakness lasts for 15-30 mins after attack.

Pt completely aware of attack, can describe it in detailEEG may show an abnormal discharge highly localized to the involved portion of brain


Seizures

Complex Partial seizures – localized onset, discharge becomes more widespread (usually bilateral) and almost always involves limbic systemmost (not all) CPS arise from one of the temporal lobes, possibly because of the susceptibility of this area to insults such as hypoxia or infection

Clinically, pt may have a brief warning followed by an alteration of consciousness during which some pts may stare and others may stagger or even fallMore, however, demonstrate fragments of integrated motor behavior called automatisms for which pt has no memoryafter 30-120 secs, pt makes a gradual recovery to normal consciousness but may feel tired or ill for several hours after attack


Generalized Seizures Tonic-clonic seizures

characterized by tonic phase continuous rigidity of all

extremities

clonic phase massive jerking of body ( rapid contraction and relaxation)

Tongue or cheek bitten, urinary incontinence common

Seizure followed by period of confusion and exhaustion due to depletion of energy


Absence seizure (petit mal)

Typical absence seizures consists of staring for a few seconds (altered consciousness) then returning to full function, as if nothing occurred

Brief duration (< 10 secs) ass with mild clonic jerking of eyelids,

patient stares & exhibit rapid eye blinking

begin in childhood or adolescence and may occur up to hundreds of times a day

The patient has no recollection of the event.


Myoclonic seizures

Myoclonic jerking – seen in generalized tonic-clonic seizures, partial seizure, absence seizures, and infantile spasms

Short episode of muscle contractions

Occurs due to permanent nurologic damage due to hypoxia, uremia, encephalitis or drug poisoning


Atonic seizures

sudden loss of postural tone, if standing pt falls suddenly and may be injured, if seated, may suddenly drop forward


Infantile spasms

characterized clinically by brief recurrent myoclonic jerks of body with sudden flexion or extension of the body and limbs

90% of affected pts have their 1st attack before age of 1 yr

Most pts mentally retarded cause infection, kernicterus and

hypoglycemia


Febrile fits

Frequently occurs in young children (6 months- 6 yrs) during high grade fever

Characterized by tonic clonic convulsions of short duration (1 to 5 min), eye rolling & unresponsiveness

Benign, do not cause death, nurologic damage, injury, or learning disorder

Status epilepticus Continuous, rapid, recurrent seizures


Antiepileptic drugs

Primary drugs Phenytoin Carbamazepine Clonazepam (BZ) Clorazepate (BZ) Diazepam (BZ) Ethosuximide Lorazepam (BZ) Phenobarbital Primidone Valproic acid

Adjunct drugs Fel bamate Gaba pentin Lamo trigine Leve tira cetam Tiaga bine Topira mate Zoni samide Viga batrin


Pathophysiology of Seizures

Increased CNS excitability

Membrane depolarization Increased excitatory input Decreased inhibitory (GABA) input


Strategies in Treatment

Stabilize membrane by blockade of voltage gated channels (Na & Ca) prevent depolarization by action on ion channels

Increase GABAergic transmission

Decrease Excitatory glutamate transmission


Classification of Anticonvulsants

Action on Ion Channels

Enhance GABATransmission

Inhibit glutamateTransmission

Na+: Phenytoin, Carbamazepine, LamotrigineTopiramateValproic acidCa++: EthosuximideValproic acid

Benzodiazepines BarbituratesValproic acid GabapentinVigabatrinTopiramateFelbamate

FelbamateTopiramate


Phenytoin

Diphenylhydantoin – oldest antiseizure drug

Mechanism of action. Blocks voltage gated Na+ channels in

inactive state, slows recovery blocks repetitive firing of action potentials,

promotes stabilization of membrane, reduce propagation of abnormal impulse in brain

At higher dose blocks Ca 2+ conductance Interfere with release of neurotransmitters

norepinephrine, acetylcholine Produces drowsiness and lethargy


Phenytoin /Clinical use

Highly effective in Partial seizures (simple and complex) Tonic-clonic seizures Status epilepticus Arrhythmia

Not effective in absence seizures


Phenytoin /Adverse effects

Depression of CNS Sedation, Nystagmus, diplopia and ataxia, confusion & hallucination

Reversible Gingival hyperplasia and hirsutism

GIT nausea & vomitingLong term use Coarsening of facial features occurs in

children Mild peripheral neuropathy deep

tendon reflexes in lower extremities Osteomalacia due to abnormalities of

vitamin D metabolism


Phenytoin /Adverse effects

Megaloblastic anemia due to folate deficiency

Inhibition of antidiuretic hormone secretion

Hyperglycemia and glycosuria insulin secretion

Teratogenic effects fetal hydantoin syndrome includes cleft lip, cleft palate, congenital heart disease, growth retardation and mental deficiency


Phenytoin/ Drug Interactions

Phenytoin metabolism decrease by Cimetidine, isoniazid, Chloramphenicol, dicumarol, sulfonamide

Phenytoin metabolism increase by Carbamazepine


Carbamazepine

M.O.A By blocks sodium channels reduce the

propagation of abnormal impulses inhibits high-frequency repetitive firing in

neurons decrease synaptic transmission, inhibits

uptake and release of NE from brain postsynaptic action of GABA

potentiated


Carbamazepine /Clinical use

Drug of choice in all partial seizures Highly effective in tonic–clonic

seizures Trigeminal neuralgia Use in Manic depressive patient to

decrease the symptoms


Carbamazepine Adverse effects

Respiratory depression Drowsiness, vertigo, diplopia, blurred

vision, ataxia & coma Irritating to stomach n & v may occurs Serious liver toxicity hyponatremia and water intoxication Idiosyncratic blood dyscrasias,including

fatal cases of aplastic anemia and agranulocytosis

Is an enzyme inducer


Drugs inhibiting metabolism of Carbamazepine

Cimetidine Diltiazem Erythromycin Isoniazid Propoxyphene


Phenobarbital

clinically useful as antiseizure drugs phenobarbital, mephobarbital, metharbital,

Mechanism of Action Elevate seizure threshold Limits the spread of seizure discharge in

brain Binds to a regulatory site on GABA

receptor, prolonging the openings of Cl- channels

Blocks excitatory responses induced by glutamate


Phenobarbital/ clinical uses

Doc in children with febrile fits Effective in simple partial seizuresRecurrent tonic clonic seizuresRelieve anxiety insomnia


Phenobarbital adverse effects

Sedation Ataxia Nystagmus Vertigo N &v Morbilliform rash (measles like) Agitation & confusion Rebound seizures can occur on

discontinuation of drug


Primidone

2-deoxyphenobarbital Metabolized to Phenobarbital and

phenyl-ethyl-malonamide All 3 are active anticonvulsants M.O.A. – similar to Phenobarbital Effective against partial and tonic

clonic seizures


Valproic acid

Drug of choice for myoclonic seizures Effective in tonic clonic & absence

seizures Block sodium channels & enhance

GABAergic transmission Adverse effects N, V, ataxia,

sedation, tremors, rash & alopecia


Ethosuximide

Inhibit T-type calcium channels in brain reduce propagation of abnormal electrical activity

First choice in absence seizures


Benzodiazepines

Benzodiazepines are safest antiepileptic drugs

Clonazepam use for chronic treatment of absence & myoclonic seizures

Chlorazepate effective in partial seizures Diazepam & lorazepam drug of choice

in acute treatment of status epilepticus (interrupt repeated seizures)

A/E sedation, drowsiness, fatigue, ataxia, respiratory and cardiac depression


Adjunct antiepileptic drugs

Newer agents Use as add on therapy in refractory

epilepsies Also effective as monotherapy


Lamotrigine

M.O.A. –blocks sodium channels, voltage activated calcium channels & decreased synaptic release of glutamate

Add on therapy, monotherapy for partial seizures, absence and myoclonic seizures in children

Dizziness, headache, diplopia, nausea, somnolence, and skin rash – potentially life-threatening dermatitis develops in 1-2% of pediatric pts


Felbamate

Broad spectrum Use only in refractory cases (may

cause aplastic anemia & hepatic failure)

block sodium channels & inhibits glycin & glutamate transmission

Effective in partial seizures


Gabapentin

Amino acid, analog of GABA, effective against partial seizures

M.O.A. – in spite of its close structural relationship to GABA, it appears not to act on GABA receptors, interfere with voltage gated calcium channels

Used in Partial and G tonic clonic seizures, diabetic neuropathic pain, postherpetic neuroralgia in adults


To-pira-mate

Effective in refectory partial and secondary generalized seizures

M.O.A. Blocks voltage dependent sodium

channels Potentiate inhibitory effect of GABA,

acting at a site different from BNZs or barbs


Ti-aga-bine

M.O.A. – inhibitor of GABA uptake Prolongs inhibitory action of synaptically

released GABA Indicated for adjunctive treatment of

partial seizures


Zonisamide

Primary site of action is on sodium channel

Also act on voltage dependent calcium channels

Effective against partial and G tonic clonic seizures, also against infantile spasms and certain myoclonias

S/E – drowsiness, cognitive impairment, serious skin rashes


Levetiracetam

M.O.A. – unknown Effective for the treatment of

refectory partial seizures S/E – somnolence, asthenia,

dizziness


Acetazolamide

Inhibits carbonic anhydrase Mild acidosis in brain – mech by

which drug exerts its antiseizure activity

Used for all types of seizures Use severely limited by rapid

development of tolerance usually within weeks



CNS Pharmacology7. Opioid Analgesics and

Antiepileptic DrugsL.Mweetwa-Pharmacologist


Faculty of Medicine


Opioid Analgesics


INTRODUCTION

Analgesics are medications used to relieve pain without reducing the consciousness of the patient.

They work by reducing the amount of pain felt and this is generally achieved by interfering with the way the pain message is transmitted by the nerves. Analgesics will not treat the cause of the pain but they will provide temporary relief from pain symptoms.


Types of Opioid Analgesics

• OPIOID

ANALGESICS

• NON - OPIOID

ANALAGESCIS

• ADJUVANT

ANALGESICS


OPIOID ANALGESICS

The opioid analgesics which are prescription only medicines that are very potent, being chemically related to morphine.

Opioid analgesics are prescribed for moderate to severe pain, particularly of visceral origin, and are used in step two and step three of the analgesic ladder.


Dependence and tolerance are well known features with regular use although this should not inhibit prescribing in palliative care.

Some chronic non-malignant conditions benefit from analgesic control with opioids, but patients should be reviewed regularly.


OPIUM, the greek name for poppy juice. Is obtained from the juice of the papaver somniferum.


ACTIONS OF OPIOID ANALGESICS

Opioid analgesics interacts with four major receptors in the CNS

Mu receptorsKappa receptorsSigma receptors and Delta receptors


RECEPTORS EFFECTS

MU Analgesia, Respiratory depression and euphoria

KAPPA Respiratory depression, sedation

SEGMA Hallucination, Dysphoria, Seizures

DELTA Analgesia


CLASSIFICATION OF OPIOID ANALGESICS

Natural Alkaloids Morphine CodeineSemi Synthetic Compounds Pethidine Methadone TramadolMixed Agonist-Antagonists

PentazocineBuprenorphine


MORPHINE

Morphine is the most important alkaloid of of opium.

Morphine produces analgesia through actions in the brain and spinal cord.

Morphine is readily absorbed from the GI tract and subcutaneous and muscle tissue.

Morphine is administered intravenously, epidurally, and intrathecally.


PHARMACOTHERAPEUTICS

Morphine sulfate is primarily used to relieve moderate to severe pain.

It is used pre operatively, its effect is on reducing patients anxiety and in assisting in induction of anesthesia.

It is the drug of choice for clients with pain from MI, Pulmonary edema and dyspnea from acute left ventricular failure.


PHARMACOKINETICS

Absorption• It depends on the route of

administration,• Morphine ingested orally is

generally absorbed in one and half to two hours.

• It reaches liver for metabolism before reaching systemic circulation.

• Absorption after IM or SC injection occurs in 30 to 60 minutes.


PHARMACOKINETICS

Distribution• It occurs quickly.,• After administration morphine

leaves the blood and directly enters the kidney, lungs, liver and spleen.

• Its action on skeletal muscle is limited, since the drug is not very lipid soluble, it does not cross the BBB easily

• .


DURATION OF ACTION

METHOD OF ADMINISTRATION ONSET OF ACTION

Oral 4 to 12 hours

IM or SC 10 to 30 minutes

IV 15 to 30 minutes


PHARMACOKINETICS

BIOTRANSFORMATION• It occurs in the liver.• Excretion occurs in the kidney.

• Only traces of morphine is founded in body after 48 hours..


PHARMACODYNAMICS

Morphine produces analgesia by binding preferentially to the mu and delta receptors.

Morphine targets the areas involved with regulation of pain perception, respiration and affective behaviors.


THERAPEUTIC USES

AnalgesiaSuppression of cough and

dyspnea.Sedation In the treatment of diarrheaAs preanesthetic medication In the treatment of the left

ventricular failure.


CONTRAINDICATIONS

Head Injury, because morphine can cause increased intracranial tension, which can leads to marked respirator depression.

Myxedema Bronchial asthma – Morphine releases

histamine which can trigger bronchoconstriction.

Elderly patients In hypotensive states.


ADVERSE REACTIONS

CNS Side effectsConfusion, anxiety, lethargy, nausea

and vomiting.GIT Side effectsConstipationOther Side effectsUrinary retention, dry mouth,

dysphoria, hypotension, skin rash, itching and urticaria.


MORPHINE POISONING

Acute poisoning with morphine and other opioids occurs with overdoses.

Signs and SymptomsComa, Pinpoint pupils, and respiratory depression which frequently called triad.

TREATMENTAdministration of antagonist

Naloxone,NaltrexoneSupport of Respiratory and Cardio

Vascular function.


END

Thank YOU


Dugs Affecting the CNS

CNS Pharmacology9. Alzheimer's Disease



Faculty of Medicine


What is Alzheimer’s?

Alzheimer's is the most common form of dementia. It is a neurodegenerative disease that occurs in the

brain. Alzheimer’s disease causes a deterioration in the brain

by destroying the nerve cells. Once the nerve cells begin to deteriorate it causes a reduction of responses to other nerve cells.

The condition spreads out causing chemical interruptions, the transmission of impulses is slow, and finally tissues in the brain begin to get worse.

In Alzheimer’s disease, nerve cells in the brain die gradually. This makes it increasingly difficult for your brain’s signals to be sent properly.

There are 7 stages of Alzheimer's


How you get the disease?

They still don’t know how the Alzheimer’s disease process begins, it seems likely that damage to the brain starts a decade or more before problems become evident.

People who have relatives with Alzheimer’s have a higher risk than the general population for developing the disease.

People who have a parent or sibling with Alzheimer's disease are 3.5 times as likely to develop it.

This strong tendency of Alzheimer's disease to run in families is due, in part, to mutations in certain genes.


Where does AD affect

Alzheimer’s affects the brain. Alzheimer's causes neurons to die which causes the

brain to shrink. This leads to a loss of functioning capabilities in almost all parts of brain, not just the ones that affect memory.

This leads to the formation of clumps and tangles within the brain and eventually leads to death.

When you have Alzheimer’s the cerebral cortex shrinks massively. The cerebral cortex is the outer surface of the brain and it is responsible for all intellectual functioning.

The spaces in the folds of the brain (the sulci) are grossly enlarged.

You cannot catch or spread Alzheimer’s


Normal Brain Alzheimer’s Brain


When do you get Alzheimer's?

Alzheimer’s disease can occur at any age, even as young as 40 years, but its occurrence is much more common as the years go by

Early Alzheimer's starts at 65 years of age or younger. Late Alzheimer's starts after age 65

One in ten people over 65 years of age suffer from the disease, and over half the people over 85 have Alzheimer’s disease.

At first the symptoms are difficult to recognise. In the first 2 stages of Alzheimer's you cannot

recognise that you have it. Often it is difficult to pinpoint when the Alzheimer’s

disease actually began in a person.


Symptoms of Alzheimer's

Short term memory loss – forgetting recent events, names and places

Difficulty performing familiar tasks Disorientation especially away from your normal

surroundings Increasing problems with planning and managing Trouble with language Rapid, unpredictable mood swings Lack of motivation Changes in sleep and confusion about the time of

day Reduced judgement e.g. being unaware of danger


7 stages of Alzheimer’s

Stage 1: Normal Stage 2: Normal aged

forgetfulness Stage 3: Mild cognitive impairment Stage 4: Mild Alzheimer’s Stage 5: Moderate Alzheimer’s

disease Stage 6: Moderately severe

Alzheimer's disease Stage 7: Severe Alzheimer's

disease


Cure and Treatment for Alzheimer’s

Currently there is no cure for Alzheimer’s. However there are several drugs that may be prescribed to help people with Alzheimer’s. They are not a cure, but can help with some of the symptoms of the disease.

Drugs such as donepezil (Aricept), rivastigmine (Exelon), and galantamine which is a competitive acetylcholinesterase inhibitor (Reminyl) are used to treat symptoms in Alzheimer's disease.

Antidepressants, anti-anxiety medications, and antipsychotics are used to treat the symptoms of depression, anxiety, agitation, and the hallucinations and delusions that may occur in Alzheimer's disease patients


Risk Factors for Alzheimer’s disease

Age Family history Lifestyle Physical exercise Mental exercise Diet Tobacco Head injury Hypertension Elevated serum cholesterol Elevated serum homocysteine


Pathophysiology

Beta amyloid plaques

Neurofibrillary tangles (NFT)

Amyloid formed from APP (amyloid precursor

protein) by secretase NFT - silver stained fibrils of

abnormally phosporylated Tau protein


Biochemical changes

Decrease in cortical level of Acetyl choline,choline acetyl transferances,nicotinic receptors

Degeneration of cholinergic neurons in nucleus basalis of Meynert.

Degenertion of loculus ceruleus & dorsal raphe

- noradrenergic & serotonergic depletion


Cascade of mechanism

Amyloid

inflammation abnormal tau phosphorylation

free radical toxicity

synaptic loss


Cascade of mechanism

cholinergic dysfunction

neuronal loss

norepinephrine dysfunction

serotonergic dysfunction


Current Treatment

Symptomatic - Cognitive

- Behavioral


Treatment of mild-moderate AD

Choline esterase inhibitors - Donepezil - Rivastigmine - Galantamine

Improves cognition & daily activities


Treatment of severe AD

NMDA antagonists - Memantine

Slows intracellular Ca accumulation and delay nerve damage

Used in combination with Donepazil


Dosage

Donepezil – 5mg/day x 4-6 wks,then 10mg/d to max.tolerated dose. min dose-5mg/d

Rivastigmine – 1.5mg bd,then step up monthly to 6mg bd(max). min.dose-6mg/

Galantamine- 8mg/d,monthly increase to 16mg/d 24 mg/d (max). min dose- 16mg/d Memantine – 5mg daily,in a week then 5mg Bd 15mg/d- (5 & 10), max dose-10mg

bd


Current available therapy

characteristic

DONEPAZIL RIVASTIGMINE

GALANTAMINE

MEMANTINE

Chemical class

piperidine carbamate phenanthrenealkaloid

Similar to amantadine

Primary mechanism

AchE inh AchE inh AchE inh NMDA antagonist

Other mechanism

None

None Nicotine modulator

HT3 receptor antagonist

Half life 70 h 90 min 7 h 70 h

Metabolism Hepatic Renal Hepatic Hepatic


Current status of AChE Inhibitors

Effective in 6 month & 12 month trials

Early initiation of therapy Delay institutionalization Decrease troublesome behaviours


Treatment of secondary symptoms

Behavioural intervention Neuroleptic agents - FDA in 2005 black box warning for atypical neuroleptics - 2008 ,

haloperidol,chlorpromazine, thioridazine included -CATIE-AD study showed cognitive decline with atypical neuroleptics -recommended in low doses in frail, elderly


Treatment

Antidepressants & mood stabilizers -citalopram ( Nyth et al study) - 20 mg /day in elderly ,max-40mg - sertaline & fluvoxetine – no benefits (Wintraub & Petrecca et al study) - mirtazipine has no benefial effect ( Banerjee et al) Anticonvulsants - gabapentin,valproate can be used


Experimental Therapy

Anti amyloid therapy - vaccination with amyloid species - monoclonal anti amyloid antibodies - IVIG containing amyloid binding

antiboies - selective amyloid lowering agents - chelators of amyloid polymerization - beta secretase inhibitors

Till date no phase 3 trials for anti amyloid therapy shown acceptable efficacy


Vaccination

Anti Abeta immunotherapy reduces amyloid deposition and improved spatial cognition in mice

Clinical trial in 298 patients with AD:18 developed inflammatory meningoencephalitis: study halted

Autopsy in one: “less amyloid than expected”

Orgogozo J-M et al Neurology 2003;61:46 Mathews P & Nixon R Neurology 2003;61:7


Vaccination

In subgroup of 30 patients, those who generated Abeta antibodies had reduced disease progression

Attempts being made to reformulate vaccine

Passive immunization considered


Antibiotics for AD

Higher than normal titres of Chlamydia in people with AD

Multicentre Canadian double blind placebo controlled RCT

101 patients with mild to moderate AD (MMSE 11-25)

Daily doxycycline 200mg plus rifampin 300mg or placebo for 3 months


Antibiotics for AD

Standardized ADAS Cog @ 6 months difference of 2.75/70 between treated and placebo group (significant @ 6 but not 12 months)

Standardized MMSE score 2.2/30 higher @12 (but not 3 or 6) months

Intriguing results! Larger study in planning stages


Secretase inhibitors

Inhibit production of Amyloid Tarenflurbil and Semagacestat. Two placebo controlled trials showed

no efficacy



Reversal of excess Tau phosphoryation Free radical scavengers - vitamin E – reduce oxidative stress - high dose Vit E (2000U/day) for 2 yr slowed progression of AD ( large double blind placebo trial ,Sano etal 1997) - Alzheimer Disease Cooperative Study ( 769

pts) showed no benefit vs placebo (Peterson etal

2005) - cause cardiovascular side effects - not recommended currently



Estrogen replacement therapy - postmenopausal woman - RCT with 351 pts for 2 weeks showed no beneficial effects

Cholesterol lowering agents -no beneficial effects - RCT,double blinded study with 748 pts for 6 months failed to prove efficacy


Lipid lowering and AD

Previous observations suggested lower risk of AD in those taking “statins”

Recently presented at 8th International Symposium on Advances in AD therapy

Atorvostatin treatment associated with less decline in memory, function, mood & behaviour in people with AD

Premature to decide until full details available in peer reviewed publication


Ongoing trials

Tramiprosate (Alzhemed) - homotaurine - binds to soluble & insoluble Abeta

and in reduction - protect against amyloid neurotoxicity - reduce tau abnormal phosphorylation

RCT, double blind,placebo conrolled trial (2009)



Cerebrolysin - peptidergic drug from purified pig brain - neurotrophic & neuroprotective

RCT,double blind, placebo controlled trial (2010)

Latreperidine(Dimebom) - anti histamine - inhibit burylcholine esterase, AchE, NMDA signalling pathway RCT, phase 3 trial ongoing ( jan 2011)


Clincal trials - completed

Selegelline RCT trial conducted in 2010 failed to give promising results Nimodipine - prevent Ca accumulation in neurons - cause vasodilation - RCT in March 2010 in 500 pts showed positive results - given 90mg/d & 180mg/d for 12,24,52

weeks - improves cognition & global impression



Metal protein attenuating compound(MPAC) (clinoquinol) - solubilize & clearance of Abeta - RCT,double blind study with 36 pts has no change in ADAS Cog @ 36

wks. Mertrifonate - irreversible AchE inhibitor - RCT, double blinded phase 3 study - 60-80mg/d for 26 weeks showed

improvement MMSE-1.86/30 & ADASCog- 3.24/70



Lecithin - major source of choline - RCT,double blind placebo

controlled study failed to show efficacy



Huperzine A from chinese club moss

Huperzia serrata reversible AchE inhibitor RCT, double blinded

Chinese study with 482 pts showed

improvement in MMSE-2.8/30 & ADASCog -

1.91/70 @ 6 wks



Transcutaneous electrical nerve stimulation

(TENS) - change neurotransmitters,help

in neuro regeneration - 3 RCT in Netherland & Japan - duration,waveform,current

amplitude, - data limilted ,shows little

improvement


Stem cell therapy

South Florida university with Cryo- cell International

Mouse model study in 2009 Several infusions of stem cells from

umblical cord Myeloid protein reduced by 62% Cerebral amyloid angiopathy by 82% Hope to begin human trials by 2014.



Neural growth factor (NGF) -Injecting into spinal cord - trials going to formulate oral

preperation - still on pipe line.


Dietary measures

No special diet for AD

Axona (caprylidine) improves cognition


Prevention of ad

Omega 3 fatty acids - French study(2005) showed

decrease in risk of AD in elderly > 60 yr - 2 RCT double blinded studies are

ongoing Mediterranean diet Light to moderate alcohol -Finnish study showed no

beneficial effects


Who are the AD Caregivers?

• Spouses – the largest group. Most are older with their own health problems.

• Daughters – the second largest group. Called the “sandwich generation,” many are married and raising children of their own. Children may need extra support if a parent’s attention is focused on caregiving.

• Grandchildren – may become major helpers.

• Daughters-in-law – the third largest group.

• Sons – often focus on the financial, legal, and business aspects of caregiving.

• Brothers and Sisters – many are older with their own health problems.

• Others-friends,relatives

Support for Caregivers

Slide 37


Technology and Caregiving

The NIA is studying how computers can provide information and support to family caregivers through:

These features have become very popular among users because they reach many people at once, are private and convenient, and are available around the clock.

• computer-based bulletin boards• chat rooms• Q & A modules• medical advice forums

Support for Caregivers


conclusion

Most common dementing disease worldwide

Pschyco-social,economic burden Current therapy is symptomatic and

limited New clinical trials & treatment

approaches on pipeline Social support for caregivers &

alzheimer support societies .


Thank You….

drugs affecting the cns psychopharmacology by pharmacologist l mweetwa

Health & Medicine