PHARMACODYNAMICS:
METABOTROPIC RECEPTOR-COUPLING MECHANISMS:
| Gs |
Stimulates adenylate cyclase (cAMP) |
|
| Gi |
Inhibits adenylate cyclase |
alpha2-Receptors have Gi ------>
inhibit post-synaptic adrenergic neurons |
| Gq |
Stimulates Phospholipase-C (IP3/DAG) |
alpha1-Receptors have Gq ------> Ca+2
in smooth muscle |
| Go |
Inhibits Ca+2 channels |
|
| Gi |
Opens K+ channels |
|
- cAMP PATHWAY (beta-Adrenergic)
- HORMONE RECEPTORS: beta-Adrenergic, GH, most
hypothalamic and pituitary hormones.
- Signal Transduction Pathway:
- Adenylyl Cyclase ------> cAMP ------> PKA
------> phosphorylate target protein.
- Phosphodiesterase then
cleaves cAMP ------> 3',5'-AMP
- The GTP on the G-Protein spontaneously
cleaves back to GDP, to inactive the G-Protein.
- Xanthines: Caffeine inhibits
phosphodiesterase ------> cAMP.
- Desensitization:
- beta-Arrestin Kinase (betaARK)
is activated by tonically high cAMP levels. cAMP phosphorylates
betaARK to activate it.
- betaARK phosphorylates the regulatory
domain of the target receptors ------> prevent cAMP activation.
- PHOSPHO-INOSITOL PATHWAY (alpha-Adrenergic)
- HORMONE-RECEPTORS: alpha-Adrenergic
- Signal Transduction Pathway:
- Phospholipase-A2 cuts apart PIP2
------> IP3 + DAG
- IP3 goes to Rough-ER where it
opens calcium channels ------> Ca+2
- DAG phosphorylates PKC, a
calmodulin-kinase, which then phosphorylates the target protein,
whenever Ca+2 (from IP3) is available.
- Ca+2 is then sequestered back
into the Rough-ER by active transport.
- STEROID RECEPTORS:
- HORMONES: Cortisol, sex steroids, Thyroid
Hormone, Aldosterone
- Signal Transduction:
- Heat-shock proteins
normally bind to the nuclear receptor to hold it inactive.
- The hormone (Cortisol, Sex Steroids,
Tyrosine) bind to the nuclear receptor, releasing the heat shock
protein.
- The hormone-receptor complex then binds to
DNA to effect transcription.
- Cortisol stimulates Lipocortin
------> inhibit Phospholipase-A2 ------> inhibit synthesis of
prostaglandins ------> anti-inflammatory properties.
- TYROSINE-KINASE RECEPTORS
- Hormones: Insulin, IGF, EGF
- Pathway: auto-phosphorylation of tyrosine
------> phosphorylate target protein.
- NITRIC OXIDE:
- NO-Synthases:
- Constitutive NO-Synthase:
Present in most cells, and is responsible for ACh-activated smooth
muscle relaxation.
- Inducible NO-Synthase:
Induced by cytokines to cause acute vasodilation.
- NO Functions:
- Forms free radical intermediates in PMN's
and macrophages.
IONOTROPIC RECEPTOR-COUPLING MECHANISMS:
- GABA RECEPTOR:
- RECEPTOR MECHANISM: In the CNS, it is a Cl-
channel. GABA binds ------> Cl- comes into neuron ------>
hyperpolarization ------> Inhibitory effects in CNS.
- Barbiturates (Phenobarbitol):
It binds at an allosteric site to increase the effectiveness of GABA. It
is GABAergic, but it is not a GABA agonist, because it does not
bind to the same site as GABA.
- Benzodiazepines (Diazepam, Valium):
It binds at a separate site than the barbiturates, but it is
still GABAergic and binds at an allosteric site.
- Picrotoxin: GABA Antagonist,
it antagonizes GABA, causing excitability in the CNS. Thus it is a
convulsive agent.
- NMDA RECEPTOR: N-Methyl-D-Aspartate
- MECH: It binds excitatory neurotransmitters,
glutamate and aspartate. It lets in Ca+2 (primarily) and also
Na+.
- Alzheimer's Disease: The NMDA
receptor may play a role in the pathogenesis of Alzheimer's Disease.
- Leaky NMDA Channels ------> Na+
comes in the neuron ------> water follows Na+ ------>
reversible cell damage to neurons (hydropic swelling).
- Leaky NMDA Channels ------> Ca+2
builds up in neuron ------> irreversible, oxidative damage (free
radicals) to neuron ------> permanent damage and cell death.
- MK-801 is an NMDA
Receptor Blocker that has been tried as experimental treatment
for Alzheimer's. But it doesn't work because it has a stimulatory effect
on the hippocampus, causing hallucinations, similar to taking
phencyclidine (PCP).
- ACETYLCHOLINE NICOTINIC RECEPTOR:
- MECH: It is a Na+ channel. When 2
ACh's bind, Na+ comes in, depolarizing the membrane.
- Desensitization: If you let
ACh hang around long enough (such in the presence of cholinesterase
inhibitors), then some of the ACh-receptors will convert to a
high-affinity state, and the ACh will stay locked onto the
receptors.
- RESULT: Fewer receptors are available
------> ACh's effect is therefore antagonized ------>
depolarization blockade.
- This explains the way in which
cholinesterase inhibitors cause paralysis.
- Succinylcholine binds to the
ACh with a higher affinity than ACh.
- Early on, you will see fasciculations, as
it has its stimulatory effect on ACh.
- After that you see paralysis.
Succinylcholine becomes an ACh antagonist, as all the receptors
convert to the high-affinity state, and the molecule locks on.
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