1. Which two main groups of drugs are important in the treatment of Parkinsonism?

Drugs that increase dopamine activity such as Levodopa, DA agonist (such as bromocriptine, pramipexole, ropinirole and rotigone) and MAO inhibitors (rasagiline and seligiline). And also, drugs that decrease cholinergic activty such as biperidine, orphenadrine, trihexyphenidyl and benztropine. 

2. In what way does amantadine act as a antiparkinsonism drug?

It is a mettaffinoid potentiator of dopamine, so basically what it does is increase dopamine activity by increasing dopamine release and synthesis, and inhibits DA reuptake. And its NDMA antagonist properties is effective  with the symptoms that appear in parkinsonism

3. Discuss the mechanisms of action of the antiparkinsonism drugs that indirectly increase dopamine concentration.

Levodopa - Is a DA precursor that is transported into the CNS via active transport and is converted to DA and also converts to DA in the peripheral system.

DA agonists

• Bromocriptine - an ergot derivative that is a partial D2 agonist, stimulates the dopamine receptor.
• Pramipexole - non-ergot derivative that is a D3 agonist
• Ropinirole - a D2 agonist that stimulates the dopamine receptor, increasing dopamine activity. 

4. Which of the dopamine agonists are ergot derivatives and which are not?

Bromocriptine is an ergot derivatives and Pramipexole, Ropinirole are non-ergot derivatives.

5. List the specific dopamine receptors that are stimulated by each agonist.

Bromocriptine - partial D2 agonist

Pramipexole - direct D3 agonist

Ropinirole - D2 agonist

6. Which of these drugs are classified as neuron protecting drugs?  What does this mean?

Pramipexole is a neuroprotective drug is a drug that protects the neuron against cell death by inhibiting the cascade effects that occur that may lead to cell degradation; with PD it may delay the progression of parkinsonism. And the MAO-B drugs are also neuroprotective.

7. What is the importance of monoamine oxidase B (MAO-B) selective drugs in the treatment of Parkinsonism?

It is used to decrease disease progression and is used in first line treatment of younger patients with moderate parkinsonism.

8. How do the COMT-inhibitors act in Parkinsonism?

COMT-inhibitors such as Entacapone metabolize levodopa to 3-O methyldopa (3OMD) and extends the duration of action of levodopa when it is used in combination therapy(entacapone-levodpa-carbidopa) and decrease the peripheral conversion of L-dopa to DA. 

9. How does istradephyline act?

Istradephyline is a adenosine a2 antagonist, it is used in combination therapy with levodopa and it reduces the levodopa doses and reduces the side effects that would normally be experienced with combination therapy of levodopa and carbidopa. And it is used in patients who experience on and off episodes with the combination therapy of levodopa-carbidopa.

10.  Discuss the MOA of safinamide

Safinamide increases DA activity and decreases glutamate activity. It increases DA activity by inhibition of MAO-B and also inhibits the reuptake of dopamine.

1. Classification of drugs used as antidepressants. 

• Tricyclic antidepressants(TADs)

There different kind of drugs listed under this group and differ with the type of amine they have in their structure. Amitriptyline(has a tertiary amine), Clomipramine(has a tertiary amine), Dosulepin(Dothiepin), Imipramine (a prototype and has a tertiary amine), Desimipramine (has a secondary amine), Trimipramine (Tertiary amine). These are called "tricyclic" because they all have a iminodibenzyl (tricyclic) core.

• Selective serotonin reuptake inhibitors (SSRIs)

The primary action of these antidepressant is the inhibition of the serotonin transporter(SERT). These include Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine and Sertraline. 

• Monoamine oxidase A inhibitor

These are antidepressants whose primary function is to inhibit the MAO A, and they are known as follows; Moclobemide and Selegiline. 

• MAO inhibitors(non selective)

These block either MAO A or B and is not selective. These are Phenelzine and Tranylcypromine.

• Unicyclic and tetracyclic antidepressants

These do not fit in the other groups and are named due to their chemical structure.  The unicyclic antidepressants include Bupropion and the tetracyclic antidepressants include Mianserin, Maprotiline, Mirtazepine. 

• 5-HT modulators 

These are also known as selective serotonin-norepinephrine reuptake inhibitors and include the following Nefazodone, Trazodone, Vortioxetine, Duloxetine, Venlafaxine and Reboxetine.

• The last antidepressant does not fall under any of these groups and it is Agomelatine, it also has different mechanism of action from the others.

2. What do the existing drugs all have in common regarding their mechanisms of action?

Most of them block NET and SERT, inhibit 5-HT2a receptors, block MAO-A and MAO-B and are antagonists on some 5-HT receptors respectively. 

3. How long does it take for the anti-depressive effects of these drugs to appear? What is the reason for this?

4. How do the TADs and the selective serotonin reuptake inhibitors (SSRI’s) differ in respect of:

a) efficacy

SSRIs are more effective for major depressive disorders and anxiety disorders and are the first line treatment drug while TADs are less effective, treat only major depression and are seen as second or third line treatment drugs especial in treatment resistant depression.

b) side effects

SSRIs have serotonergic effect such as nausea, diarrhea and other GIT symptoms, has sexual effects such as loss of libido, delayed orgasm and diminished arousal. It may also cause post birth complications such as pulmonary hypertension. 

TADs on the other hand are normally associated with anticholinergic effects such as dry mouth, confusion, urinary retention, constipation and blurred vision. May have orthostatic hypotension and weight gain and in some cases sedation.

c) safety?

SSRIs are deemed safe in overdose while TADs symptoms such as increase in blood pressure, anticholinergic effects such as altered mental state and seizures can be observed during an overdose or in the administration of the drug in high dose.

5. What is the action of mirtazapine?

It is tetracyclic antidepressant and a noradrenergic and a specific 5-HTerfic agent (NaSSA).  It blocks a2 receptors, 5-HT2a receptors, 5-HT3 receptors and H1 and a2 receptors. And it indirectly stimulates 5-HT1a receptors.

6. What is the action of venlafaxine?

It is a 5-HT and noradrenergic reuptake inhibitor(SNRIs), moderately selectively blocks NET and SERT and is more potent for 5-HT than for NA.

7. What is the action of agomelatine?

It is a melatonin 1 and melatonin 2 receptor agonist and also a 5-HTC antagonist with antidepressant properties. 

1. NAME AN EXAMPLE OF EACH OF THE THREE PHENOTHIAZINE SUB-FAMILIES AND STATE HOW THEY DIFFER FROM ONE ANOTHER IN TERMS OF POTENCY AND SIDE EFFECTS

Aliphatic derivatives (chlorpromazine), Piperdine derivatives (thioridazine) and Piperazine derivatives (perphenazine).  Aliphatic and Piperdine derivatives are the least potent and have side effects such as sedation and weight gain while Piperazine derivatives are the more potent drugs and have side effects such as blurring of vision, clumsiness and skin rash or itchiness. 

2. WHICH RECEPTORS IN PARTICULAR ARE BLOCKED BY THE TYPICAL ANTIPSYCHOTICS DRUGS?

There is a blockade of D2 receptors and blockade of 5HT2a receptors.

3. HOW DOES THE MECHANISM OF ACTION OF THE ATYPICAL DRUGS DIFFER FROM THAT OF THE TYPICAL DRUGS?

Atypical drugs have a higher affinity to block 5-Ht2a receptors than D2 receptors while typical antipsychotics have a higher affinity to block D receptors than 5HT2a receptors.

4. WHICH OF THE RECEPTORS BLOCKED BY THE OLDER DRUGS REDUCE THE RISK OF EXTRAPYRAMIDIAL SIDE EFFECTS?

The blockade of serotonin (5HT2a) receptors and the fact that the drugs are low potent so they have a weaker bond to the dopamine receptors so this reduces the risk of EPS.

5. WHICH OF THE DRUGS HAS A HIGH INCIDENCE OF EXTRAPYRAMIDIAL SIDE EFFECTS? WHATS THE REASON FOR THIS?

Haloperidol, it has a high affinity for D2 receptors and has a high potency so that means it has a stronger bond to the dopamine receptors and thus has a high incidence of EPS than most of the other typical antipsychotics.

6. BECAUSE OF WHICH RECEPTOR BLOCKADE DO THE ALIPHATIC GROUP OF DRUGS HAVE A HIGH INCIDENCE OF AUTONOMIC SIDE EFFECTS?

 A blockade of alpha 1 receptors may lead to autonomic side effects such as urinary problems(retention), hypertension and orthostatic hypotension. 

1. WHICH TYPES OF ION CHANNELS ARE FOUND ON THE NERVE CELL MEMBRANES?

There are three types of ion channels that are found on the nerve cell membranes; namely the voltage-gated channel, the intracellular ligand-gated channel and the extracellular ligand-gated channel.

2. NAME THREE DIFFERENCES BETWEEN VOLTAGE-GATED AND LIGAND-GATED ION CHANNELS

Voltage-gated ion channels respond to changes in the membrane potential of cell while ligand-gated ions channels on the other hand open and close due to the attachment of ions on the cell membranes or the binding of a neurotransmitter controls the gating of the channels.

3. COMPARE IONOTROPIC AND METABOTROPIC RECEPTORS 

Neurotransmitters exert their effects on neurons by binding to two distinct classes of receptors mainly ionotropic and metabotropic receptors. Ionotropic receptors, the first class of receptors, consist of multiple sub units and binding of the neurotransmitter ligand directly opens the channel, which is an integral part of the receptor complex. While metabotropic receptors are seven transmembrane G protein-coupled receptors, where the binding of a neurotransmitter doesn't result in the direct gating of the channel but the production of second messengers that mediate intracellular signaling cascades.

4.  CLASSIFY THE CNS RECEPTORS INTO IONOTROPIC OR METABOTROPIC AND KNOW THE TRANSUCTION MECHANISM OF EACH RECEPTOR

The ionotropic receptors include the GABA receptors, nicotinic, excitatory amino acid and 5-HT3 receptors. For example, when a GABA binds the GABA receptor they change shape slightly to allow ions to pass through their central channel. This channel mainly allows negatively charged chloride ions to enter the neuron, thus reducing its excitability.

The metabotropic receptors include glutamate receptors, muscarinic acetylcholine receptors, GABA_B receptors, most serotonin receptors, and receptors for norepinephrine, epinephrine, histamine, dopamine, neuropeptides, and endocannabinoids. For example, glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation. 

5. DIFFERENCE BETWEEN IPSP AND EPSP AND EXAMPLES OF EACH 

IPSP also known as the inhibitory postsynaptic potential is when the inhibitory pathway is stimulated, the postsynaptic membrane is hyperpolarized owing to the selective opening of chloride channels and produces a potential. Example is when the Gamma-butyric acid binds to the GABA receptors and opens the chloride channels, this results in hyperpolarization.

EPSP also known as excitatory postsynaptic potential is when the excitatory pathway is stimulated then a small depolarization is recorded. Example is when the acetylcholine bind to the nicotinic receptors and opens the sodium channels and this results in depolarization.

6. THE ROLE OF CALCIUM IN THE DEVELOPMENT OF A SYNAPTIC POTENTIAL

It is released from a neurotransmitter at the synaptic cleft and bind to the neuron and an effect is elicited.