Flashcards in The Adrenergic System III Deck (37):
How do we measure blood pressure?
By the use of a sphygmomanometer (blood pressure cuff)
It gives two numbers: the systolic pressure (maximum pressure in the arteries after the ventricles contract) and the diastolic pressure (minimum pressure between ventricular contractions)
BP is reported as systolic/diastolic (e.g., 120/80)
What is high blood pressure? What is important?
The definitions of high blood pressure will vary greatly and which parameters are most important will also change
Blood pressure must be more stringently controlled in diabetics than non-diabetics
As you get older than 65, systolic pressure will rise
Shorter people will tend to have lower blood pressure than taller people
What is considered normal blood pressure?
What is considered high blood pressure?
Systolic: over 139-159
Diastolic: over 89-99
What is considered high blood pressure for diabetics?
Systolic: over 140
Diastolic: over 80
What is a hypertensive crisis?
Medical emergency. Patient requires IMMEDIATE emergency medical treatment
Systolic: over 180
Diastolic: over 110
Does a single high blood pressure reading mean the patient is hypertensive?
No. Other factors need to be considered (what time of day, did the person eat recently, etc.). Other readings need to be taken
What are adrenergic receptors and responses important for controlling blood pressure?
In the kidneys, beta1 stimulation releases renin
In the arterioles (peripheral vascular skeletal muscle), alpha 1 stimulation causes vasoconstriction and beta2 stimulation causes vasodilation
In the heart, beta1 stimulation increase heart rate and contractile force
Mathematically, what is blood pressure?
BP = CO * SVR (aka TPR)
BP = HR * SV * SVR
What can blood pressure result from?
Increased cardiac output via heart rate or stroke volume
Increased total peripheral resistance (probably more important)
How do NA and A affect blood pressure?
They activate alpha1 receptors, so they increase TPR
They activate beta1 receptors, so they increase CO
Adrenaline activates beta1, so it increases TPR
The net effect is a small increase in blood pressure, but it depends on the amounts
Given the physiologic definition of blood pressure, there are two main ways to controlling blood pressure. What are they?
Decrease TPR via vasodilation
Decrease CO via decreasing HR and/or decreasing SV or contractile force
How do we cause vasodilation?
Block alpha1 receptors to prevent NA and A induced vasoconstriction
Block AT1 receptor with AT1 receptor antagonist
Production of NO, hydrochlorothiazide, hydrazine
Calcium channel blockers (nifedipine, felodipine, amlodipine only)
How do we decrease SV or contractile force?
Block beta1 receptors to prevent NA and A induced increase in HR and contractile force
Calcium channel blockers (verapamil and diltiazem only)(
What are alpha-receptor antagonists used for?
There are many uses including controlling high blood pressure, as well as treating benign prostatic hyperplasia (BPH; aka benign prostatic hypertrophy)
What is a major problem with alpha-receptor antagonists? Why is this?
A major problem with alpha-receptor antagonists is (mush like antimuscarinics) many drugs that are otherwise targeted to other receptor groups have some alpha-rectpeor antagonist activity
The main reason for this is the flexible and "generic" SAR for alpha-receptor antagonists which means that many drugs have unintended alpha-receptor antagonist activity (cause of many side effects)
What are the minimum requirements to ensure alpha adrenergic antagonist activity (see diagram)?
1. N must be charged for affinity and is often a tertiary amine. But sometimes R1 may be H (secondary amine)
2. R1 and R2 must be CH3 or larger than t-butyl
3. (C)n may be 1 to 3 heavy atoms (normally carbon)
4. X may not be present but if it is, it is usually capable of forming H bonds
5. There may be two rings attached to X but only one is needed and one or both are aromatic
6. The aromatic ring substitution(s) R3 may not be present, however if it/they are having para and meta substituents will favour binding to alpha1 receptors over alpha2 receptors
What are the uses of alpha adrenergic antagonists?
Hypertension (major use)
Benign prostatic hyperplasia (BPH; major use)
Raynaud's disease (congenital peripheral vasoconstriction)
What are the two types of alpha adrenergic antagonists?
Non-selective (not used much anymore; Phenoxybenzamine, which is irreversible, phentolamine, which is reversible)
Selective (most important are alpha1 quinazolines, such as parson, terazosin, doxazosin; tamsulosin for BHP)
Describe the mechanism of phenoxybenzamine
Ionized form of the drug is stable
At physiological pH, it becomes unionized and is unstable
It has the basic SAR need to bind to the alpha1 and alpha2 receptors
Once bound to the alpha receptor, the drug can dissociate as a reversible competitive antagonist
It can react with a nucleophile (Nu) in the receptor (typically a Cys or Ser residue)
When covalently bound to the receptor it is now an irreversible non-competitive inhibitor
What is phenoxybenzamine?
An irreversible antagonist
The effects last for days because the receptors are irreversibility alkylated resulting in long term antagonist activity (new receptors must be made to restore receptors to normal activity)
What are the uses of phenoxybenzamine?
Used the treat pheochromocytoma (adrenal gland tumour producing increased NA and A)
For non selective receptor antagonists, patient may get reflex tachycardia due to decreased blood pressure
May also decrease the effectiveness of the baroreceptor reflex because of inhibition of alpha1 receptors in vasculature
Also has antimuscarinic activity and increases release of histamine
Describe phentolamine SAR
It has no alpha-agonist activity (like xylometazoline and clonidine)
Receptor affinity is enhanced by additional aromatic ring substitution to N
It is not selective for alpha1 or alpha2 receptors
It has antimuscarinic activity ad causes the release of histamine
It is used to treat cocaine and amphetamine induced hypertensive crisis
Describe quinazolines SAR
N in the X position in this case
The meta and para substituents on the aromatic ring increase affinity for alpha1 receptors vs alpha2
R is typically a heterocyclic ring
Guanidine-like group is important for increasing affinity for alpha receptors (unlike alpha receptor agonists, this does not increase affinity for alpha2 receptors)
What are the uses of quinazolines?
They decrease BP without increasing HR or CO (no or very little reflex tachycardia)
They do not bind to muscarinic or histamine receptors do not increase release of histamine
They are very selective for alpha1 receptors and they do not block alpha2 receptors
They are used to treat hypertension
They are used to treat BPH (especially terazosin and doxazosin)
Brand name: Minipress
Highly metabolized by the liver. Very high first pass metabolism results in low bioavailability. Planarity of molecule results in increase in metabolism
Brand name: Hytrin
Less potent than parson but same maximal efficacy
More soluble in water than parson with higher bioavailability and longer half life
Induces apoptosis of prostate smooth muscle cells, not dependent on alpha1 blockade. More useful than prazosin for BPH
Brand name: Cardura
Like terazosin, induces apoptosis of prostate smooth muscle cells, not dependant on alpha1 blockade. More useful than prazosin for BPH
What is the dosing for quinazolines?
For all quinazolines, starting dose is 1 mg HS to reduce the incidence of postural hypotension (aka orthostatic hypotension). Dose it titrated to BP
Describe the metabolism of quinazolines
Phase I O- or N-dealkylation by CYP450 enzymes results in an active metabolite
Phase II reactions cause conjugation and/or elimination
What are the side effects of quinazolines?
Orthostatic hypotension (because of the decrease in effectiveness of baroreceptor reflex
Syncope (passing out or fainting can happen because of orthostatic hypotension; starting at a low dose of 1 mg and increase slow)
What is orthostatic hypotension
A significant drop in BP that occurs when changing from a sitting or lying position to a standing position
Also called postural hypotension
Patients taking quinazolines are most at risk a few hours to days after initiating dose, changing a dose or adding another antihypertensive drug. But it can be a long term problem
What is tamsulosin?
Brand name: Flomax
Alpha1 receptor antagonist with some selectivity for alpha1A (and alpha1D) subtypes compared to alpha1B (10-40 times more potent at alpha1A than alpha1B)
This selectivity favours blockade of alpha1A receptors in the prostate
Tamsulosin is used in the treatment of BPH
It has little or no effect on blood pressure
How are alpha1 antagonists used to treat BPH?
Alpha1-antagonist efficacy in BPH results from relaxation of smooth muscle via alpha1 receptor antagonism in the bladder and prostate
Because of the distribution of alpha1 receptors in the bladder prostate alpha1-antaonists reduce bladder obstruction possibly by affecting the tone in the sphincters without affecting muscular contractility of the bladder
What are some unintended alpha-antagonists?
Chlorpromazine neuroleptic (antipsychotic)
Haloperidol neuroleptic (antipsychotic)
Many of these compounds also fit the SAR for muscarinic antagonists
What are general alpha-adrenergic antagonist side effects?
Orthostatic hypotension and syncope
Nasal congestion (dilation of the blood vessels in nasal mucosa)
Headache (vasodilation of the meninges, causing vascular headache)
Reflex tachycardia (especially with non-selective alpha blockers)
None of these side effects are likely to be causes by tamsulosin at normal doses