Dopamine Pharmacology And Parkinson's Disease 8/15

Front 1

High doses of dopamine

Back 1

Vasoconstriction and increased cardiac inotropy and chronotropy

Front 2

Low doses of dopamine

Back 2

Vasodilatation (particularly in kidneys and mesentery) due to stimulation of specific dopamine receptors on vascular smooth muscle cells, used for treatment of some types of shock in emergency situations

Front 3

Midbrain dopamine neurons

Back 3

-Nigrostriatal neurons, primarily thought to mediate motor function and are preferentially lost in Parkinson's disease
-Mesocorticolimbic neurons, mediate cognitive functions, as well as emotional and reinforcement behaviors (drug addiction, and schizophrenia)

Front 4

Dopamine receptors (old knowledge)

Back 4

-D1 receptors, stimulatory and increase cAMP
-D2 receptors, inhibitory and decrease cAMP

Front 5

Dopamine receptors (modern thought)

Back 5

-D1 like receptors: stimulatory
---D1 R: striatum, neocortex
---D5 R: hippocampus, hypothalamus
-D2 like receptors: inhibitory
---D2 R: striatum, SNpc, pituitary
---D3 R: NAc, olfactory tubercle, hypothalamus
---D4 R: frontal cortex, medulla, midbrain

Front 6

D1 receptor family

Back 6

PKA dependent phosphorylation of the Ca channels leads to increased Ca currents, increased cAMP vis Gs

Front 7

D2 receptor family

Back 7

Inhibit adenylyl cyclase and Ca++ currents, as well as activate outward K+ currents, leading to hyperpolarization.

Front 8

Lewy bodies

Back 8

Proteinaceous inclusions in remaining dopamine neurons, also seen in other diseases.

Front 9

Hypotheses concerning causes of PD

Back 9

1. Oxidative stress and mitochondrial dysfunction
2. Environmental insults
3. Excitotoxicity
4. Deficiencies in protein degradation and autophagy pathways
5. Microgliosis

Front 10

Oxidative stress, ROS, and mitochondrial dysfunction

Back 10

Dopamine auto-oxidizes to produce toxic metabolites, as well as neuromelanin. Also MAO breaks down dopamine and results in ROS as minor by products. Evidence for this, however, is limited.

Front 11

MPTP and mitochondrial dysfunction

Back 11

MPTP neurotoxin, has been used to induce PD in lab rats and primates. Inhibits complex 1 in the mitochondria, cells cannot generate enough ATP.

Front 12

Environmental insults

Back 12

PD is prevalent in rural areas, due to exposure to heavy metals and pesticides, resulting in ROS.

Front 13

Excitotoxicity

Back 13

Overstimulation (like by glutamate) results in Ca accumulation in the neurons

Front 14

Deficiencies in protein degradation and or autophagy systems (particularly mitophagy)

Back 14

1. Accumulation of ubiquitanated proteins in Lewy bodies
2. Identification of genes associated with familial PD

Front 15

Pharmacology of PD

Back 15

Can only manage motor symptoms, either replacing DA or activating DA receptors

Front 16

L-DOPA therapy

Back 16

Most effective and widely used therapy, acts by replacing DA in striatal nerve terminals, short half life (but length of effect is longer), usually administered with an AADC (Carbidopa, Benserazide) to prevent peripheral degradation. During early stage, works very well.

Front 17

Problems with L-DOPA

Back 17

1.Side effects of motor dyskinesias, nausea, hallucinations and confusion, severe hypotension and cardiac arrhythmias.
2. Principle limitation is that L-DOPA therapeutic effects subside with long term usage

Front 18

Dopamine Receptor Agonists

Back 18

Not dependent on surviving DA nerve terminals, commonly D2 agonists are used Ropinirole, Pramipexole

Front 19

Selegiline and Rasagiline

Back 19

Irreversible MAO-B inhibtor

Front 20

COMT inhibtors

Back 20

Used in combo with L-DOPA, inhibits peripheral metabolism of L-DOPA, Toleapone, Entacapone

Front 21

Muscarinic ACh Receptor Antagonists

Back 21

An old tx for PD, only modestly effective, thought to reduce cholinergic effects and meet lower dopamine, bring back balance

Front 22

Drug induced PD

Back 22

Classic anti-psychotic drugs block dopamine (D2) receptors, produce PD like symptoms, called extrapyramidal side effects, which are reversible for the most part, newer gen antipsychotics have lower incidence of extrapyramidal side effects as they block D3 and D4 receptors, not D2. (Risperidone, clozapine)