Final Flashcards
what is coronary heart disease
occurs when coronary blood circulation fails to adequately supply the heart with blood
primarily caused by athlerosclerosis
risk of developing CHD is directly proportional to the levels of choleserol in the blood
CHD causes 1/3 of deaths in Canada
where is cholesterol synthesized
the liver
structure of lipoproteins
outer hydrophilic shell made of phospholipids
core is made of lipophilic cholesterol and TGs
have apolipoproteins embedded in the phospholipid shell
used to transport cholesterol and TGs in the blood
apolipiproteins
allow recognition of lipoproteins by cells
activate enzymes that metabolize lipoproteins
increase structural stability of lipoproteins
apolipoprotein A-I
non-hepatic tissue back to the liver
HDL
apolipoprotein B-100
liver to non-hepatic tissues
VLDL
LDL
is protein or lipid more dense
protein
VLDL
TGs from liver to adipose and muscle
TG-rich core and account for almost all TGs in the blood
some studies suggest that high VLDL contributes to athlerosclerosis
contain one apo B-100
LDL
cholesterol to non-hepatic tissue
cholesterol-rich core
one apo B-100
clear link between LDL cholesterol and development of athlerosclerosis, reducing LDL halts or even reverses it
“bad cholesterol”
HDL
cholesterol from non-hepatic tissue back to the liver
promote cholesterol removal from the blood
cholesterol is main core lipid
elevated HDL decreases the risk of CHD, protects against athlerosclerosis
A-I, A-II, A-IV
A-I mediates the beneficial effects
“good cholesterol”
athlerosclerosis
LDL initiates by moving into the sub-endothelial space of the arterial epithelium
LDL becomes oxidized
oxidation of LDL causes recruitment of monocytes, which are converted to macrophages
macrophages ingest oxidized LDL, become large and vacuolated, called foam cells
foam cells accumulate below the epithelium, a fatty streak appears
then platelets adhere, smooth muscle migrates and collagen synthesis occurs, forming a fibrous cap
end result is an athlerosclerotic lesion with lipid core and tough fibrous cap
cap can rupture and a thrombus can form and partially or completely block blood flow
what kind of process is athlerosclerosis
inflammatory
what does LDL do in atherosclerosis?
causes mild injury to the arterial endothelium
cholesterol screening
males over 40
females over 50 or post-menopausal
also diabetes heart disease or family history of it hypertension central obesity smoke or recently stopped inflammatory or renal disease
how is cardiovascular risk assessed?
Framingham Risk Score gender age total blood cholesterol smoking status HDL systolic blood pressure
gives 10 year risk
may underestimate youth, women and ppl with metabolic syndrome
metabolic syndrome
3 or more of: central obesity elevated TGs low HDL hyperglycemia hypertension
gives increased risk for CHD and type 2 DM
1 in 4 canadians
non-drug treatment for LDL
first line treatment is lifestyle
diet - less cholesterol and saturated fats, more fiber, plant sterols and stanols
weight control - weight loss lowers LDL and reduces risk of CHD
exercise - CV exercise decreases LDL, insulin resistance, blood pressure and increases HDL
smoking - smoking decreases HDL and increases LDL so should quit (especially important risk factor in ppl under 50)
when is drug treatment given for LDL
when targets arent reached through lifestyle intervention
what are the classes of drugs used to treat elevated blood lipids
statins bile acid sequestrants nicotinic acid cholesterol absorption inhibitors fibric acid derivatives (fibrates)
cholesterol synthesis
mevalonic acid pathway
acetyl-CoA (citric acid cycle) is converted to 3-OH-3-methylglutaryl CoA (HMG CoA)
HMG CoA is converted to mevalonic acid by HMG CoA reductase rate limiting step
eventually get cholesterol
synthesis is greatest during the night
how do statins work
they inhibit HMG CoA reductase, the rate limiting step of cholesterol synthesis
causes an upregulation of hepatic LDL receptors, so the liver removes more cholesterol from the blood
net effect is decrease in blood LDL levels, increase in HDL and decrease in TGs
are effective in both primary and secondary prevention
primary vs secondary prevention
primary = preventing development of disease
secondary = preventing recurrence
highest prescribed statins
atorvastatin (lipitor) is highest prescribed drug in Canada
rosuvastatin (crestor) is 4th highest in canada
atorvastatin
low oral bioavailability
large fraction of absorbed dose is extracted by the liver (site of action)
distributes primarily to liver, but also spleen, adrenal glands and skeletal muscle
metabolized by CYP3A4
predominantly eliminated in the feces, minimal renal excretion
rosuvastatin
low oral bioavailability
large fraction extracted by liver (site of action)
distributes mostly to liver, some to skeletal muscle
not extensively metabolized
eliminated mostly in feces, minimal renal
plasma concentrations are 2 times higher in asian patients compared to caucasians, so initial dose should be lower
adverse effects of statins
in general well tolerated
most common adverse effect is myopathy (muscle injury) - get muscle aches and weakness
rhabodomyolysis is rare but more serious - muscle lysis with severe pain, diagnosed by measuring blood levels of creatine kinase, also get hyperkalemia and may get acute kidney failure…treat with IV fluids to preserve kidney function
low incidence of hepatotoxicity - do liver function tests before and throughout
potentially teratogenic bc cholesterol is needed for cell membranes etc
nicotinic acid
niacin
LDL drug
inhibits hepatic secretion of VLDL and therefore decreases TGs in the blood
since LDL is a by-product of VLDL it also decreases LDL
increases HDL
side effects of niacin
intense facial flushing heptotoxicity hyperglycemia skin rash increase in uric acid levels
bile acids
negatively charged
produced in the liver from cholesterol
secreted into intestine for absorption of dietary fats and fat soluble vitamins
undergo entero-hepatic recycling (95% reabsorbed)
bile acid sequestrants
large and positively charged
attract and bind bile acids so they can’t be reabsorbed
causes an increased demand for bile acid synthesis which requires LDL
increase hepatic LDL receptors and increase uptake
get decreased plasma LDL
adverse effects of bile acid sequestrants
not absorbed so no systemic side effects
GI tract, ie constipation and bloating
bind negatively charged molecules so decrease the absorption of some drugs including thiazide diuretics, digoxin, warfarin, some antibiotics
NPC1L1
transporter that is responsible for intestinal uptake of the majority of dietary cholesterol
cholesterol absorption inhibitors
only one is ezetimibe (Zetia)
inhibits NPC1L1
decreases intestional cholesterol absorption and lowers LDL, however there can be a compensatory increase in hepatic cholesterol synthesis therefore often prescribed in combination with statin
vytorin
a new pill that contain simvastatin with ezetimibe
fibric acid derivatives
fibrates
most effective for lowering TGs
increase HDL, no effect on LDL though
bind to and activate PPARalpha (nuclear receptor)
1) increases synthesis of LPL to enhance clearance of TG-rich lipoproteins
2) decreases apolipoprotein C-III production, which allows for increases LPL activity
3) increases A-I and A-II levels (this is how it increases HDL)
adverse effects of fibrates
increased risk of gallstones
myopathy (need tone especially careful if using with statin, give low dose of statin and monitor)
hepatoxicity
hypertension definition
elevated systemic arterial blood pressure
blood pressure
the force against the walls of your arteries as blood is pumped through your body
measured with a sphygmomanometer
what should be done to accurately measure BP
sit for at least 5 min
no caffeine or nicotine within 30 in
feet touching the ground
arms elevated to heart level
two measurements in each arm 5 min apart
before diagnosing hypertension repeat 3 time at least 2 weeks apart
systole
when the heart contracts
diastole
period of time when the heart fills after contracting
normal BP
sys <120 AND dia <80
prehypertension BP
sys 120-139
OR
dia 80-89
stage 1 hypertension BP
sys 140-159
OR
90-99
stage 2 hypertension BP
sys >160
OR
dia >100
primary hypertension
no known cause
most cases
secondary hypertension
identifiable cause
fewer cases
causes of secondary hypertension
kidney disease hyperthyroidism pregnancy erthropoetin pheochromocytoma (tumor on adrenal gland that release a lot of epinephrine) sleep apnea contraceptive use
factors that influence blood pressure
amount of water and salt in your body
condition of kidneys, nervous system and blood vessels
levels of certain hormones in the body
risk factors for hypertension
obesity stress smoking high salt diet diabetes African NSAIDs oral contraceptives pseudoephedrine
consequences of hypertension
myocardial infarction
kidney failure
stroke
renal damage
do you get symptoms as soon as you have hypertension
no is a “silent killer”
cardiac output
determined by heart rate, heart contractility, blood volume and venous return
increase in any = increase in blood pressure (bc CO increases)
peripheral resistance
determined by arteriolar constriction
constriction = rise in BP
what determines BP
cardiac output x peripheral resistance
what 3 body systems regulate BP?
sympathetic nervous system
renin-angiotensin-aldosterone system
renal regulation of BP
how does SNS regulate BP
through the baroreceptor reflex that keeps BP at a set level
baroreceptors in aortic arch and carotid sinus sense BP and send signal to brain
if too low brainstem sends impulses along SNS neurons to stimulate heart to increase cardiac output and to smooth muscle of arteries to constrict
if too high sympathetic activity is decreased = decreased CO and vasodilation
responds rapidly ie seconds or minutes
how does the activity of baroreceptors oppose drug therapy for BP
set point in patients with hypertension is high so tries to get back to that point
what does the RAAS system regulate and what organ does it target
BP, blood volume and electrolyte balance
targets kidney and vascular smooth muscle
timing of RAAS
hours or days
RAAS how it works
when there is decrease in blood volume, blood pressure or stimulate on beta 1 receptors of juxtaglomerular cells renin is released
renin is synthesized and released by juxtaglomerular cells of the kidney (into the blood)
it catalyzes the rate-limiting step, converts angiotensinogen to angiotensin I
angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II
angiotensin II is a potent vasoconstrictor by binding to AT1 receptors
angiotensin II stimulates aldosterone release from adrenal cortex which acts on kidneys to increase sodium retention and therefore water retention also
angiotensin II acts on the posterior pituitary to release ADH which also causes water retention in the kidneys
so overall get vasoconstriction = increased PR, salt and water retention = increased blood volume and CO
have increased BP
renal regulation of blood pressure
if BP is decreased for a long time the kidney retains water
get increased blood volume
causes increased CO and therefore BP
non-drug treatment for hypertension
if dia 90-95 or in combination with drug therapy
decreasing body weight restricting sodium intake exercise potassium supplementation DASH diet stopping smoking alcohol restriction
how does obesity cause hypertension
direct relationship between obesity and hypertension
obese have increased insulin which causes tubular reabsorption of Na and therefore water = higher blood volume
obese also have increase SNS activity
how does exercising help hypertension
regular exercise decreases extracellular fluid volume (i.e. blood volume) and circulating levels of catecholamines
potassium supplementation and hypertension
total body K levels are inversely correlated with BP
high K = lower BP
high K diets decrease BP by increasing sodium excretion, decreasing renin release and causing vasodilation
found in fresh fruits and vegetables
no high K diet for ppl on ACEIs
DASH diet
dietary approaches to stop hypertension
best results seen in ppl with prehypertension
eat lots of fruits, veggies, low fat dairy, lean meat. whole grains, nuts and legumes
cut out saturated fats, fats overall and cholesterol
smoking and hypertension
smoking acutely elevates BP but has not been causally linked to hypertension
stop though bc both smoking and hypertension are risk factors for CVD
alcohol and hypertension
excessive alcohol consumption elevates BP
it can also decrease the response to some antihypertensive meds
3 types of diuretics and where they work
diuretics block Na and Cl ion reabsorption in the nephron of the kidney and therefore prevent reabsorption of water = decreased CO and decreased BP
loop diuretics - thick ascending limb of loop of Henle (most effective)
thiazide diuretics - distal tubule (medium effective)
K sparing/aldosterone antagonists - collecting duct (least effective)
loop diuretics
most effective
thick ascending limb of loop of henle
reserved for situations that need rapid fluid loss
edema
severe hypertension that doesn’t respond to the diuretics
sever renal failure
adverse effects of loop diuretics
hypokalemia (can cause fatal dysrhythmias)
hyponatremia
dehydration
hypotension
thiazide diuretics
most commonly used for hypertension
block Na and Cl reabsorption in the distal tubule and decrease vascular resistance
max amount of diuresis is much less than loop diuretics
often alone thiazide diuretics can control hypertension
K sparing diuretics/aldosterone antagonists
minimal lowering of BP
inhibit aldosterone receptors in the collecting duct, causing increased sodium excretion and potassium retention
usually in combination with loop or thiazide
don’t use with ACEIs
thiazide diuretic adverse effects
hypokalemia
hyponatremia
dehydration
K sparing adverse effects
hyperkalemia
how do beta blockers work
block cardiac beta 1 receptors
-> binding of catecholamines to cardiac beta receptors causes increased CO (so blocking decreases)
block juxtaglomerular beta 1 receptors
-> binding releases renin which activates RAAS causing vasoconstriction (blocking decreases PR)
are antagonists
olol suffix
beta blockers
ie propanolol
classes of beta blockers
1st generation
non-selective, block beta 1 in heart and juxtaglomerular and beta 2 in the lung
2nd generation
only block beta 1
beta blocker adverse effects
2nd gen: bradycardia (slow HR) decreased CO heart failure rebound hypertension if stopped quickly (taper over 10-14 days)
1st gen:
same as 2nd plus
bronchoconstriction (bad for ppl with asthma or pulmonary diseases)
inhibition of hepatic and muscle glycogenolysis (bad in diabetics if accidentally take too much insulin)
how do ACEIs work
decrease production of angiotensin II
-> decreasing it causes vasodilation (bc its a vasoconstrictor)
-> decreasing it also decreases total blood volume
ie decrease CO and PR
also inhibit the breakdown of bradykinin
-> elevated bradykinin causes vasodilation
so get decreased angiotensin II and increased bradykinin
pril suffix
ACEIs
ie captopril
adverse effects of ACEIs
generally well-tolerated
effects due to decrease angiotensin II
- 1st dose hypotension (first few should be low)
- hyperkalemia (bc of decreased aldosterone release)
- *don’t give K supplements or K sparing diuretics**
effects due to increased bradykinin
- persistent cough
- angioedema
Note: use with certain NSAIDs will decrease the effectiveness of ACEIs
how do angiotensin receptor blockers (ARBs) work
block binding of angiotensin II to AT1 receptors (vascular smooth muscle)
therefore cause vasodilation
also cause decreased aldosterone release from the adrenal cortex = increased sodium and water retention
sartan suffix
ARBs
ie losartan
adverse effects of ARBs
don’t give cough like ACEIs bc they don’t affect bradykinin
do not cause hyperkalemia
also have lower incidence of angioedema than ACEIs
how do direct renin inhibitors (DRIs) work
bind renin and block the conversion of angiotensinogen to angiotensin I rate-limiting step
decrease plasma renin a lot, but the BP lowering effects are about the same as ARBs and ACEIs
adverse effects of DRIs
hyperkalemia
don’t use with ACEIs, K sparing diuretics etc
very low incidence of persistent cough and angioedema
diarrhea
how do claim channel blockers (CCBs) work
block the entry of Ca into heart cells and smooth muscle cells, which decreases contraction
types of CCBs
dihydropyridine CCBs
non-dihydropyridine CCBs
dihydropyridine CCBs
significantly reduce Ca influx into smooth muscle of arteries
causes vasodilation
at therapeutic doses DO NOT act on the heart
dipine suffix
dihydropyridine CCBs
non-dihydropyridine CCBs
block Ca influx in both the heart and arterial smooth muscle
vasodilation and decreased CO
adverse effects of dihydropyridine CCBs
flushing dizziness headache peripheral edema reflex tachycardia rash
adverse effects of non-dihydopyridine CCBs
constipation dizziness flushing headache edema may compromise cardiac function **be careful if using in patients with heart failure**
centrally-acting alpha 2 agonists
bind to and activate alpha 2 receptors in the brainstem
decreases SNS output to heart and blood vessels
get decreased CO and PR (SNS normally causes increased CO and vasoconstriction)
adverse effects of centrally-acting alpha 2 agonists
drowsiness
dry mouth
rebound hypertension if withdrawn abruptly
treatment for prehypertension only
lifestyle
if not then thiazide diuretic
treatment for stage 1 hypertension only
lifestyle
then thiazide diuretic
if not then thiazide diuretic + ACEI, ARB, BB or CCB
treatment for stage 2 hypertension only
lifestyle + thiazide + ACEI, ARB, BB or CCB
treatment for hypertension with moderate renal disease or diabetes
lifestyle + thiazide + ACEI or ARB
treatment for hypertension with severe renal disease
lifestyle + loop + ACEI or ARB
neuropharmacology
study of how drugs affect the CNS
treat the symptoms not the cause rn
resting cell membrane potential
-70 mV
signal transmission at synapse
action potential reaches pre-synaptic nerve terminal, causes influx of Ca
Ca influx causes vesicles containing neurotransmitters to fuse and release contents
neurotransmitters bind to receptors on post-synaptic nerve terminal
monoamines
norepinephrine - depression and anxiety
epinephrine - anxiety
dopamine - parkinson’s and schizophrenia
serotonin - depression and anxiety
amino acids
excitatory - glutamate and aspartate (Alzheimer’s)
inhibitory - GABA and glycine (anxiety)
other neurotransmitter
acetylcholine - Alzeheimer’s and Parkinson’s
basic mechanisms for CNS drug therapy
replacement - NTs that are low
agonist/antagonist - bind to receptors on post-synaptic membrane
inhibiting breakdown - more NT
blocking reuptake - more NT in synapse
nerve stimulation - directly stimulate nerve to release more NT
what happens to the brain in parkinson’s
progressive loss of dopaminergic neurons in the substantia nigra (more than with normal aging)
symptoms of parkinson’s
tremor (especially extremities i.e. hands, arms, legs, jaw)
rigidity (join stiffness and increased muscle tone)
bradykinesia (especially slow to initiate movements)
masklike face (can’t show facial expression, difficulty blinking, swallowing)
postural instability (difficulty balancing while walking)
dementia (later in disease)
pathophysiology of parkinson’s
imbalance between acetylcholine and dopamine in the brain, causes increased BAGA release
decreased dopamine = not enough dopamine to inhibit GABA release
excess acetylcholine = increased GABA release
excess GABA (inhibitory NT) causes the movement disorders seen in PD
aetiology of PD
largely idiopathic
drugs - MPTP causes irreversible death of dopaminergic neurons (byproduct of illicit street drug synthesis)
genetics - mutations in alpha synuclein, parkin, UCHL1 and DJ-1 predispose
environmental toxins - some pesticides
brain trauma - increased risk
oxidative stress - ROS are known to cause degeneration of dopaminergic neurones **link between diabetes induced oxidative damage and PD
2 strategies for treating PD
increasing dopamine
decreasing acetylcholine
5 agents for increasing dopamine in PD
dopamine replacement dopamine agonist dopamine releaser catecholamine-o-methyltransferase inhibitor monoamine oxidase-B inhibitor
how does L-DOPA work
dopamine replacement
most effective drug for PD
however, beneficial effects decrease over time as disease progresses
crosses the BBB by active transport is a prodrug that is converted to dopamine in dopaminergic nerve terminals by decarboxylases in he brain vitamin B6 (pyridoxine) speeds up this reaction
why L-DOPA instead of dopamine
dopamine won’t cross BBB
dopamine has a very short half life in blood
L-DOPA adverse effects
nausea and vomiting - due to dopamine-mediated activation of the chemoreceptor trigger zone in the medulla
dyskinesias (abnormal involuntary movements)
cardiac dysrhythmias - conversion of L-DOPA to dopamine in the periphery can activate cardiac 1 beta receptors
orthostatic hypotension (when you stand up)
psychosis (hallucinatoins, vivid dreams/nightmares, paranoid thoughts)
L-DOPA peripheral metabolism and how we combat this
very little L-DOPA reaches the brain
the rest is metabolized in peripheral tissue, mostly the intestine
for this reason L-DOPA is usually given with carbidopa, a decarboxylase inhibitor
this allows a lot more to reach the brain, so you can lower the dose which will decrease the incidence of cardiac dysrhythmias and nausea and vomiting
2 types of loss of effect of L-DOPA
wearing off - gradual
on-off - abrupt
wearing off of L-DOPA
gradual
normally at the end of the dosing interval, indicates that drug levels may be low
minimized by:
- shortening dosing interval
- giving a drug that inhibits L-DOPA metabolism (i.e. a COMT inhibitor)
- add a dopamine agonist to therapy
on-off on L-DOPA
abrupt
can occur even when drug levels are high
minimized by:
- dividing medication into more doses per day
- using a controlled release formulation
- moving protein-containing meals to the evening
how do dopamine agonists work for PD
directly activate dopamine receptors on the post-synaptic cell membrane
not as effective as L-DOPA
first line treatment for PD patients with milder symptoms
dopamine agonist adverse effects
hallucinations
daytime drowsiness
orthostatic hypertension
how do dopamine releasers work for PD
stimulate release of dopamine from dopaminergic neurons AND block dopamine repute into pre-synaptic nerve terminals
AND block NMDA receptors
response is rapid, 2-3 days
not as effective as L-DOPA, given in combination with it or alone for milder symptoms
blockade of NMDA receptors is thought to decrease dyskinesia side effect of L-DOPA
dopamine releaser side effects
dizziness nausea vomiting lethargy anticholinergic side effects (i.e. dry mouth, hallucinations, sedation)
how do catecholamine-o-methyltrasferase inhibitors (COMTs) work for PD
COMT adds methyl groups to both dopamine and L-DOPA to inactivate them
inhibit COMT = greater fraction of L-DOPA that is available to be converted to dopamine
only moderately effective for PD, often given in combination with L-DOPA
adverse effects of COMTs
similar to L-DOPA
nausea
orthostatic hypotension
vivid dreams and hallucinations
how do monoamine oxidase- B (MAO-B) inhibitors works for PD
MAO-B metabolizes dopamine and L-DOPA by oxidizing them, inactivates them
is in both the brain and periphery
inhibit oxidation, more L-DOPA can be converted to dopamine in the brain
inhibition of dopamine metabolism allows more dopamine to remain in nerve terminals and be released
only moderately effective, usually given with L-DOPA
at therapeutic doses does not inhibit MAO-A in the liver, so won’t cause hypertensive crisis with tyramine
what does excessive acetylcholine do in PD?
causes diaphoresis (excess sweating), salivation and urinary incontinence
how do anticholinergic drugs work for PD
are antagonists, block the binding of acetylcholine to its receptor
may increase the effectiveness of L-DOPA
decrease the incidence of diaphoresis, salivation and incontinence
usually only for younger patients
adverse effects of anticholinergic drugs
dry mouth blurry vision urinary retention constipation tachycardia
elderly patients may experience sever CNS side effects i.e. hallucinations, confusion and delirium, so usually only give to younger patients
is Alzheimer’s more common in men or women
women
symptoms of Alzheimer’s
memory loss
problems with language, judgement, behaviour and intelligence
early symptoms - confusion, memory loss and difficulty with conducting routine tasks
later on problems with eating, bathing, speaking, controlling bladder and bowel function
pathophysiology of Alzheimer’s
degeneration of cholinergic neurons in the hippocampus early in disease
degeneration of neurons in the cerebral cortex later
linked to decreased cholinergic nerve function (have very little function)
have enlarged ventricles and a decreased brain size
how to diagnose Alzheimer’s
cannot do until after death and sample brain
hallmarks are neurofibrillary tangles and neuritic plaques
neurofibrillary tangles
form inside neurons when MT arrangement is disrupted
cause is abnormal production of tau, a protein that is responsible for forming cross bridges between MTs to keep their structure
neuritic plaques
outside of neurons
made mainly of beta amyloid
beta amyloid has been shown to kill hippocampal cells and causes Alzheimer’s like symptoms when injected into monkeys
aetiology of Alzheimer’s
mostly unknown
some cases are genetic i.e. DNA mutations
people with 2 copies of ApoE4 are at increased risk - ApE4 promotes formation of neuritic plaques by binding to beta amyloid
also increased incidence in people with mutations in the amyloid precursor gene
head injury is also a risk factor
is drug treatment of Alzheimer’s effective?
no shows only minimal improvement in the symptoms
classes of drugs for treatment of Alzheimer’s
cholinesterase inhibitors
NMDA receptor antagonists
cholinesterase inhibitors of Alzheimer’s
inhibit acetylcholinesterase from metabolizing acetylcholine
more acetylcholine stays in the synaptic cleft
can only enhance cholinergic neurotransmission in the remaining healthy neurons
minimal benefit on some measures of memory
only effective in a small proportion of patients
adverse effects of cholinesterase inhibitors
nausea and vomiting
diarrhea
insommnia
NMDA receptor antagonists for Alzheimer’s
NMDA is a Ca channel that is normally blocked by magnesium, when glutamate binds, Mg dissociates and Ca can enter the post-synaptic neutron
normal Ca influx is needed for learning and memory
in Alzheimer’s there is excess glutamate release so the NMDA receptor remains open and excess Ca enters the cell
- > this is detrimental to learning and memory
- > causes degradation of neurons
so antagonists block the calcium influx so that the increased glutamate ant cause prolonged Ca influx
adverse effects of NMDA receptor antagonists
well tolerated
no significant adverse effects in clinical trials (i.e. none were more than placebo)
schizophrenia
makes it hard to tell the difference between real and unreal experiences, to think logically, to have normal emotional responses and to behave normally in social situations
do not have multiple personalities
are not usually violent
common mental disease, usually begins in adolescence or early adulthood
positive symptoms of schizophrenia
exaggerate or distort normal neurological function
delusions hallucinations agitation paranoia combativeness disorganized speech disorganized thinking
negative symptoms of schizophrenia
loss of normal neurological function
social withdrawal poverty of speech poor self care poor insight poor judgement emotional withdrawal blunted affect lack of motivation
etiology of schizophrenia
largely unknown
risk factors:
- family history, more likely if both parents have it
- drug abuse (crystal meth/methamphetamine, phencyclidine/PCP/angel dust, lysergic acid diethylamide/LSD) are all known to cause it
- low birth weight
- low IQ
basal ganglia in schizophrenia
involved in movement and emotions
in schizophrenia abnormal activity is thought to play a role in paranoia and hallucinations
