Anti-Parkinson Drugs
The disease involves degeneration of dopaminergic neurons in the nigral-striatal pathway in the basal ganglia. The cause is usually unknown. Sometimes it is associated with hypoxia, toxic chemicals, or cerebral infections.

Strategy
1. Increase dopamine in basal ganglia.
2. Block muscarinic receptors in the basal ganglia, since cholinergic function opposes the action of dopamine in the basal ganglia.
3. Newer therapies, such as the use of β-adrenergic receptor blockers.

Drugs
a. L-dopa plus carbidopa (Sinemet).
b. Bromocriptine, pergolide, pramipexole, ropinirole.
c. Benztropine, trihexyphenidyl, biperiden, procyclidine.
d. Diphenhydramine.
e. Amantadine.
f. Tolcapone and entacapone.
g. Selegiline.

Mechanisms of action of three drugs affecting DOPA

1. L-dopa plus carbidopa:
L-dopa is able to penetrate the blood–brain barrier and is then converted into dopamine. Carbidopa inhibits dopa decarboxylase, which catalyzes the formation of dopamine.
Carbidopa does not penetrate the blood–brain barrier; it therefore prevents the conversion of L-dopa to dopamine outside the CNS but allows
the conversion of L-dopa to dopamine inside the CNS.

2. Bromocriptine, pergolide, pramipexole, and ropinirole are direct dopamine receptor agonists.
3. Benztropine, trihexyphenidyl, biperiden, and procyclidine are antimuscarinic drugs.
4. Diphenhydramine is an antihistamine that has antimuscarinic action.
5. Amantadine releases dopamine and inhibits neuronal uptake of dopamine.
6. Selegiline is an irreversible inhibitor of monoamine oxidase B (MAO-B), which metabolizes dopamine. Selegiline therefore increases the level of dopamine.
7. Tolcapone is an inhibitor of catechol-O-methyl transferase (COMT), another enzyme that metabolizes dopamine.
8. Entacapone is another COMT inhibitor.

Dopamine and acetylcholine.
 Loss of dopaminergic neurons in Parkinsonism leads to unopposed action by cholinergic neurons. Inhibiting muscarinic receptors can help alleviate symptoms of Parkinsonism

Adverse effects

1. L-dopa 
-  The therapeutic effects of the drug decrease with time.
- Oscillating levels of clinical efficacy of the drug (“on-off” effect).
- Mental changes—psychosis.
- Tachycardia and orthostatic hypotension.
- Nausea.
- Abnormal muscle movements (dyskinesias).

2. Tolcapone, entacapone (similar to L-dopa).

3. Direct dopamine receptor agonists (similar to L-dopa).

4. Antimuscarinic drugs
-  Typical antimuscarinic adverse effects such as dry mouth.

b. Sedation.

5. Diphenhydramine (see antimuscarinic drugs).

6. Amantadine
-  Nausea.
- Dizziness.
- Edema.
- Sweating.

7. Selegiline
- Nausea.
- Dry mouth.
- Dizziness.
- Insomnia.
- Although selegiline is selective for MAO-B, it still can cause excessive toxicity in the presence of tricyclic antidepressants, SSRIs, and meperidine.

Indications

Parkinson’s disease is the obvious major use of the above drugs. Parkinson-like symptoms can occur with many antipsychotic drugs. These symptoms are often treated with antimuscarinic drugs or diphenhydramine.

Dental implications of anti-Parkinson drugs
1. Dyskinesia caused by drugs can present a challenge for dental treatment.
2. Orthostatic hypotension poses a risk when changing from a reclining to a standing position.
3. The dentist should schedule appointments at a time of day at which the best control of the disease occurs.
4. Dry mouth occurs with several of the drugs.
 

Topical Anesthetics

Benzocaine

Benzocaine is a derivative of procaine, an ester type local anesthetic, and is poorly soluble in water and is

available only as a topical anesthetic.

-  Localized allergic reactions are sometimes encountered    

-  Overdosing is unlikely as benzocaine is poorly absorbed into the blood, which decreases the likelihood of systemic toxicity.

- The onset of surface anesthesia is rapid requiring less than one minute.

Tetracaine

- Tetracaine is an ester type local anesthetic

-  Topically applied tetracaine as opposed to benzocaine has a prolonged duration of action.

Cocaine

- Cocaine is a ester type anesthetic that is used exclusively as a topical agent.

- Cocaine is unique among topical and injectable anesthetics in that it has vasoconstrictive as well as anesthetic properties. It is used sparingly because of its abuse potential but is still used when hemostasis of mucous membranes is essential.

- Cocaine is generally available in concentrations of 2-10 % solution.

Lidocaine

- Lidocaine is an amide local anesthetic that is available in injectable and topical formulations.

- It is available in gel, viscous solution, ointment and aerosol preparations in concentrations ranging from 2-10 %.

- The onset of anesthesia is slower relative to benzocaine but, the duration is about the same.

- Absorption into the bloodstream is greater than benzocaine providing a greater risk of systemic toxicity.

Serotonin-norepinephrine reuptake inhibitors(SNRIs)

e.g. venlafaxine and duloxetine
- Inhibit the reuptake of both 5-HT and norepinephrine 
- Has a more favourable adverse effect profile than TCAs

Norepinephrine reuptake inhibitor

e.g. bupropion, reboxetine

Monoamine receptor antagonists

e.g. mirtazapine, trazodone, mianserin

Specific Agents

Hydralazine [orally effective]

MOA: Not completely understood. Seems to be partially dependent on the release of EDRF and perhaps partially due to K+-channel activation
- in clinical doses action is manifest primarily on vascular smooth muscle (non-vascular muscle is not much affected).
- Re: Metabolism & Excretion. In cases of renal failure the plasma half life may be substantially increased (4-5 fold). One mode of metabolism is
via N-Acetylation (problem of slow acetylators)

Side Effects

- those typical of vasodilation = headache, nasal congestion, tachycardia etc.
- chronic treatment with high doses > 200 mg/day may induce a rheumatoid-like state which may resemble lupus erythematosus.

Minoxidil (Loniten) [orally effective]

MOA: K+-channel agonist

-    very effective antihypertensive. Used primarily to treat life-threatening hypertension or hypertension resistant to other agents.

Side effects - growth of hair

Diazoxide (Hyperstat) [used only IV]

MOA: K+-channel agonist

- Administered by rapid IV injection; action appearing after 3-5 min; action may last from 4 to 12 hours.

Nitroprusside (Nipride) [used only IV]

MOA: increase in cGMP

- unlike the other vasodilators, venous tone is substantially reduced by nitroprusside.
- rapid onset of action (.30 sec); administered as an IV-infusion.
- particularly useful for hypertension associated with left ventricular failure.
 

FUNDAMENTALS OF INJECTION TECHNIQUE

There are 6 basic techniques for achieving local anesthesia of the structures of the oral cavity:

 1. Nerve block

 2. Field block

 3. Infiltration/Supraperiosteal

 4. Topical

 5. Periodontal ligament (PDL)

 6. Intraosseous

 Nerve block- Nerve block anesthesia requires local anesthetic to be deposited in close proximity to a nerve trunk. This results in the blockade of nerve impulses distal to this point. It is also important to note that arteries and veins accompany these nerves and can be damaged. To be effective, the local anesthetic needs to pass only through the nerve membrane to block nerve conduction Field block/Infiltration/Supraperiosteal - Field block, infiltration and supraperiosteal injection techniques, rely on the ability of local anesthetics to diffuse through numerous structures to reach the nerve or nerves to be anesthetized:

  - Periosteum

 - Cortical bone

 - Cancellous bone

 - Nerve membrane

Topical - Topical anesthetic to be effective requires diffusion through mucous membranes and nerve membrane of the nerve endings near the tissue surface

PDL/Intraosseous - The PDL and intraosseous injection techniques require diffusion of local anesthetic solution through the cancellous bone (spongy) to reach the dental plexus of nerves innervating the tooth or teeth in the immediate area of the injection. The local anesthetic then diffuses through the nerve membrane

Classification

1. Natural Alkaloids of Opium

Phenanthrenes -> morphine, codeine, thebaine

Benzylisoquinolines -> papaverine, noscapine

2. Semi-synthetic Derivatives

diacetylmorphine (heroin) hydromorphone, oxymorphone hydrocodone, oxycodone

3. Synthetic Derivatives

phenylpiperidines pethidine, fentanyl, alfentanyl, sufentnyl

benzmorphans pentazocine, phenazocine, cyclazocine

propionanilides methadone

morphinans levorphanol